Prostate Cancer

Prostate cancer is the most common noncutaneous cancer in men in the United States. Although prostate cancer can be slow growing, thousands of men die of the disease each year. It is the second most common cause of cancer death in US males (see Epidemiology).

Marked variation in rates of prostate cancer among populations in different parts of the world suggests the involvement of genetic factors. Familial predisposition also occurs. Environmental factors, notably diet, are also important (see Etiology).

Currently, the majority of prostate cancers are identified in patients who are asymptomatic. Diagnosis in such cases is based on abnormalities in a screening prostate-specific antigen (PSA) level or findings on digital rectal examination (see Presentation and Workup).

Screening for prostate cancer is a controversial topic, in large part because of the conflicting findings from prospective, randomized studies (see Workup). Education about the risks and benefits is important to help men make informed decisions regarding screening and, in those diagnosed with prostate cancer, the various treatment options (see Treatment). (See the image below.)

If detected, prostate cancer is assigned a grade and stage followed by a risk group determination for consideration of therapy. Prostate cancer grading has traditionally been performed according to the Gleason Grading system. In this two-number system, the first number is assigned to the predominant focus of tumor and the second, to the second more predominant pattern (see the image below); each is graded on a scale of 1-5 and the sum of the two is the overall grade.[10] Generally, the cut-off for prostate cancer starts with Gleason grade 3+3. However, the International Society of Urological Pathology (ISUP) has modified the Gleason system to a grade group system such that grade group 1 now encompasses Gleason 3+3 disease (see the Table below) 

Prostate cancer. The standard approach for grading prostate cancer depends on a Gleason score, which is based on pathologic evaluation of a prostatectomy specimen and is commonly estimated from prostate biopsy tissue. Prostate cancer patterns are assigned a number from 1-5; the score is created by adding the most common pattern and the highest-grade patterns. Courtesy of Wikimedia Commons.

Table 1. Comparison of Gleason grade and modern Grade Groups. (Open Table in a new window)

See also the following Medscape articles:

• Precancerous Lesions of the Prostate
• Prostate Cancer Diagnosis and Staging
• Metastatic and Advanced Prostate Cancer
• Neoadjuvant Androgen Deprivation Therapy in Prostate Cancer
• Prostate Cancer and Nutrition

The prostate lies below the bladder and encompasses the prostatic urethra. It is surrounded by a capsule and is separated from the rectum by a layer of fascia termed the Denonvilliers aponeurosis. (See the image below.)

Prostate cancer. This diagram depicts the relevant anatomy of the male pelvis and genitourinary tract.

The inferior vesical artery, which is derived from the internal iliac artery, supplies blood to the base of the bladder and prostate. The capsular branches of the inferior vesical artery help to identify the pelvic plexus arising from the S2-4 and T10-12 nerve roots. The neurovascular bundle lies on either side of the prostate on the rectum. It is derived from the pelvic plexus and is important for erectile function. Venous drainage of the prostate occurs via the dorsal vein and Santorini's plexus, the latter of which might be responsible for hematogenous spread to the axial skeleton. 

Prostate cancer develops when the rates of cell division exceed those of cell death, leading to uncontrolled tumor growth. Following the initial transformation event, further mutations of a multitude of genes, including the genes for p53 and retinoblastoma, can lead to tumor progression and metastasis. Most prostate cancers (90%) are adenocarcinomas.

Rarely, cancers may arise from the urothelial lining of the prostatic urethra. These are not prostatic adenocarcinomas but are treated as urothelial cancers. 

Squamous cell carcinomas constitute less than 1% of all prostate carcinomas. In many cases, prostate carcinomas with squamous differentiation arise after radiation or hormone treatment.

Of prostate cancer cases, 70% arise in the peripheral zone, 15-20% arise in the central zone, and 10-15% arise in the transitional zone. Most prostate cancers are multifocal, with synchronous involvement of multiple zones of the prostate, which may be due to clonal and nonclonal tumors.

Local spread and metastasis

When these cancers are locally invasive, the transitional-zone tumors spread to the bladder neck, while the peripheral-zone tumors extend into the ejaculatory ducts and seminal vesicles. Penetration through the prostatic capsule and along the perineural or vascular spaces occurs relatively late.

The mechanism for distant metastasis is poorly understood. Cancer spreads to bone early, often without significant lymphadenopathy. 

Natural history

Undiagnosed prostate cancer that does not affect survival has been frequently described. Incidental, unsuspected prostate cancers have been noted in 25-40% of prostate specimens when the bladder and prostate are removed for male bladder cancers.[11] Latent prostate cancer has been described in numerous autopsy studies across several countries. Pooled analysis of several studies suggest that the prevalence of incidental prostate cancer at autopsy doubles for approximately every 14 years of life, with most of these cancer being of low Gleason grade.[12]

Taken together, the prevalence of indolent prostate cancer combined with the lethality of some cases would suggest a spectrum of prostate cancer ranging from cancer that men die with and that which men die from. Indeed, a pooled analysis of several natural history evaluations would suggest that low-grade (Gleason 5-6) disease requires 10-15 years of lead time to develop into aggressive disease while higher-grade disease is associated with poor disease-specific mortality at 10 years if left untreated.[13] It should be noted that Gleason 5 disease is no longer considered cancer.

With the advent of prostate cancer screening in the 1990’s, several epidemiologic evaluations have demonstrated a significant stage migration and improvements in prostate cancer mortality and thus the natural history, though with the caveat of overtreatment.[14, 15, 16] This is discussed in greater detail in Workup/Prostate Cancer Screening. 

Internationally, the incidence of prostate cancer varies by more than 50-fold, with the highest rates being in North America, Australia, and northern and central Europe and the lowest rates being in southeastern and south-central Asia and northern Africa.[1, 17]

Occurrence and mortality in the United States

In the United States, prostate cancer is the most common noncutaneous cancer in men. An estimated one in six White men and one in five Black men will be diagnosed with prostate cancer in their lifetime, with the likelihood increasing with age. The American Cancer Society estimates that 288,300 new cases of prostate cancer will be diagnosed in 2023. Prostate cancer is rarely diagnosed in men younger than 40 years, and it is uncommon in men younger than 50 years.[2]

Between 1989 and 1992, incidence rates of prostate cancer increased dramatically in the United States, probably because of earlier diagnoses in asymptomatic men as a result of the increased use of serum PSA testing. In addition, the incidence of organ-confined disease at diagnosis increased because of PSA testing and standard digital rectal examination. After 1992, incidence rates declined markedly, decreasing from over 230 per 100,000 population to 97 per 100,000 population in 2014.[18] Subsequently, however, rates began rising; the incidence increased by 3% annually from 2014 through 2019.[2]

Advanced disease accounts for a growing percentage of new prostate cancer cases. A review of almost 800,000 cases of prostate cancer diagnosed from 2004–2013 found that although the incidence of low-risk prostate cancer decreased from 2007-2013 to 37% less than that of 2004, the annual incidence of metastatic prostate cancer during those years increased to 72% more than that of 2004. The increase in metastatic prostate cancer was greatest (92%) in men aged 55–69 years.[19] In 2015–2019, incidence rates for regional and distant prostate cancer increased by 4-6% per year.[20]

Prostate cancer mortality rates began to decline in the early 1990s, in all racial and ethnic populations, decreasing from 39.3 per 100,000 persons in 1991 to 18.6 per 100,000 in 2020.[18] However, in 2015-2019, the decline in death rates slowed for Black and Hispanic men and ceased for White and Asian American/Pacific Islander men.[20] The American Cancer Society estimates that 34,700 men will die of prostate cancer in 2023.[2]

Age-related demographics

Prostate cancer incidence increases as men age; as many as 60% of men over 65 years of age may be diagnosed with prostate cancer.[17] Prostate cancer is most often diagnosed in men aged 65-74 years; median age at diagnosis is 66 years.[18]

However, men as young as 17 years are experiencing an increasing incidence of prostate cancer in much of the world, including the United States, according to data from the Surveillance, Epidemiology, and End Results (SEER) program and the Institute for Health Metrics and Evaluation (IHME) Global Burden of Disease (GBD) database. These younger patients frequently present with more advanced cancer and have worse survival than middle-aged and older men. Worldwide, the incidence of prostate cancer has increased in men ages 15 to 40 years at a steady rate averaging 2% per year since 1990. In the United States, this age group was more than 6 times more likely than older men to have distant disease at diagnosis.[21]

Racial demographics

In the United States, the incidence rate of prostate cancer is 70% higher in Black versus White men, and the prostate cancer mortality rate in Black men is 2-4 times higher than in every other racial and ethnic group.[20] Worldwide, the incidence is highest in Blacks and Caribbean men of African descent, followed by Whites, Hispanics, and finally Asian men living in their native countries. Prostate cancer incidence is highest in countries with the highest socioeconomic index.[22]

A cohort study of 7.8 million Veterans Affairs patients found that despite the equal access to care in this setting, incidence rates of localized and advanced prostate cancer were nearly twice as high in Black (African American) veterans as in White ones. Of the veterans with localized prostate cancer, Blacks were younger than Whites (median age, 63 vs 65 years) and had higher prostate-specific antigen levels (> 20 ng/mL) at the time of diagnosis. However, outcomes were similar in patients who received the same treatment, with lowered risk of metastasis.[23]

Risk factors

Well-established risk factors for prostate include ethnicity, age, and country of residence. Additional risk factors include family history and genetic predisposition. For men with a family history (1 or more first-degree relatives) of breast cancer, the risk of prostate cancer diagnosis increases by 21%, and lethality increases by 34% compared with those without such history. Similarly, a family history of prostate cancer increases risk by 68% and lethality of disease by 72%, with a general trend favoring increases in risk according to earlier cancer onset in families.[24] These associations have led to the identification of several germline mutations associated with hereditary prostate cancer, including HOXB13,BRCA1, BRCA2, DNA mismatch repair genes, ATM, CHEK2, PALB2, NBN, and RAD51D.[25]

Discovery of these mutations has led to recommendations for the consideration of genetic testing for men with family histories that strongly suggest the presence of these mutations and men with metastatic castrate-resistant prostate cancer.[25, 26] In men referred for genetic testing, about 20% will have a known genetic variation while only 63% will have a significant family history that would guide genetic testing decision making.[27] BRCA1/2 and ATM mutations have been found in significantly higher rates for men with lethal prostate cancer.[28] Overall, genetic testing remains a novel and developing area of prostate cancer research, but may ultimately inform screening, risk stratification, treatment aggressiveness, and (where currently applied) targeted systemic therapy for advanced disease.[29]

An examination of cancer histories of 198 Lynch syndrome families, including probands and their first- through fourth-degree relatives, found that men with Lynch syndrome have a 2-fold higher risk of prostate cancer compared with the general population. Of the 4127 men involved in the study, 97 had prostate cancer. Median age at diagnosis was 65, with 11.5% diagnosed before age 50. The cumulative risk of prostate cancer for men with Lynch syndrome was 6.3% at age 60 and 30% at age 80, versus a population-wide risk of 2.6% and 17.8%, respectively.[30]

Several additional risk factors are associated with either prostate cancer incidence but with lower levels of evidence, or conflicting evidence. Both increased body mass index (BMI) and additional components of the metabolic syndrome (eg, hyperinsulinemia, waist circumference) have been variably associated with both increased prostate cancer incidence and possibly increased recurrence after definitive therapy.[31, 32, 33, 34, 35]

Increasing evidence suggests that the gut and genitourinary microbiome play a role in prostate cancer.[36] Banerjee et al found that the microbiome signature (viral, bacterial, fungal, and parasitic elements) in prostate cancer samples differed from the microbiome signature in benign prostate hyperplasia controls. These authors also identified three distinct prostate cancer–specific microbiome signatures that correlated with different cancer grades, stages, and scores.[37]

Hurst et al identified bacteria in urine collected after digital rectal examination and in secretions from prostatectomy samples and reported an association between the presence of bacteria and prostate cancer risk; the percentage of urine samples positive for bacteria rose from 17% in patients with low-risk prostate cancer to 100% of those with high-risk disease. In addition, the presence of five specific anaerobic genera, including three novel bacteria, was associated with aggressive prostate cancer risk.[38]

Tobacco smoking, nutritional supplementation and/or deficiency, activity, and dietary components have also demonstrated variable association with prostate cancer incidence and/or mortality.[39] Supplementation with selenium and vitamin E were prospectively evaluated for the prevention of the prostate cancer in the SELECT trial, which demonstrated an increase in prostate cancer cases for those given vitamin E only and no effect of selenium supplementation.[40] The effect observed for vitamin E was not seen in other studies.[41] The significant heterogeneity surrounding these risk factors suggests that further, nuanced evaluation is required before they can be classified as risk factors for prostate cancer or prostate cancer severity.

The most important and established indicators of prognosis for prostate carcinoma include the Gleason grade, the extent of tumor volume, and the presence of capsular penetration or margin positivity at the time of prostatectomy. High-grade prostate cancer, particularly the percentage of Gleason grades 4 and 5 that are present, is associated with adverse pathologic findings and disease progression. Conversely, low-grade prostate tumors are infrequently dangerous.

According to Surveillance, Epidemiology, and End Results (SEER) data from 2012 to 2018, 5-year relative survival for men with localized and regional prostate cancer is 100%, but is 32.3% for distant disease.[18] In a review of 11,521 patients treated with radical prostatectomy at 4 academic centers from 1987 to 2005, Eggener et al reported an overall 15-year prostate cancer–specific mortality rate of 7%. High-grade cancer and seminal vesicle invasion were the prime determinants of prostate cancer–specific mortality.[42]

Despite the steady decline in the incidence of newly diagnosed metastatic prostate cancer and microscopic lymph node metastasis, from 20% in the 1970s to 3.4% in the 1990s, the risk of extra-prostatic disease in patients with clinically localized disease remains high at approximately 30%. Depending on the PSA value, pathologic stage, and histologic grade of the tumor, approximately 30% of clinically localized prostate cancers are estimated to progress, despite initial treatment with intent to cure.

The Cancer of the Prostate Risk Assessment (CAPRA) score for predicting prognosis is calculated on the basis of the following:

• PSA level
• Gleason score
• Percentage of biopsy cores positive for cancer
• Clinical tumor stage
• Age at diagnosis

In a study of 10,627 men with clinically localized prostate cancer who underwent primary radical prostatectomy, radiation therapy, androgen deprivation monotherapy, or watchful waiting/active surveillance, and had at least 6 months of follow-up after treatment, Cooperberg et al found that the CAPRA score was accurate for predicting metastases, cancer-specific mortality, and all-cause mortality.[43]

In a multivariate analysis, biochemical recurrence and disease-specific mortality were much higher in men who were smokers at the time of diagnosis versus those who had never smoked. A higher number of pack-years was associated with significantly increased risk for prostate cancer mortality but not for biochemical recurrence. Men who had quit smoking 10 years prior to diagnosis—or who had quit more recently but smoked for < 20 pack-years—had prostate cancer–mortality risks much like those of men who had never smoked.[44]

In a retrospective study at Johns Hopkins Medical Center in Baltimore, a greater connection between cigarette smoking and risk of prostate cancer recurrence was identified in men who had been treated with radical prostatectomy.[45] Without prospective studies, however, these relationships remain hypothetical.

In an analysis of two large cohort studies of health professionals, researchers found a significantly increased risk for melanoma among men with prostate cancer. In 42,372 participants in the Health Professionals’ Follow-Up Study, a history of prostate cancer was independently associated with an increased risk for melanoma (hazard ratio, 1.83). This association was confirmed in an analysis of 18,603 participants in the Physicians’ Health Study (hazard ratio, 2.17).[46]

Transitional cell carcinoma (TCC), prostatic stroma invasion, regardless of whether it represents primary or secondary involvement, is associated with poor prognosis (it is staged as pT4a bladder cancer). In contrast, prostatic involvement solely by cancer in situ (CIS) has no bearing on the staging of bladder cancer, although it may have implications for intravesical therapy.[47, 48, 49, 50, 51, 52]  The 5-year survival rate has ranged from 50% to 100% for patients with prostatic urothelium CIS alone and from 20% to 60% for patients with prostatic stroma invasion, independent of bladder tumor stage.[47, 48, 49, 50, 51, 53, 52]

Molecular prognostic markers

Several prognostic tests have been shown to aid in determining the risk of harboring aggressive disease for patients with localized prostate cancers. This is an area of rapid change. Consensus regarding the applicability of different markers based on clinical scenarios remains elusive. Lamy and colleagues have published a detailed review of prognostic biomarkers used for management of localized prostate cancer.[54] For discussion of markers utilized in the post-surgery or metastatic setting, see Metastatic and Advanced Prostate Cancer.

With the advent of PSA screening, and in the absence of level I studies comparing the various options, a greater number of men require education about prostate cancer and how it is diagnosed, staged, and treated. Such education allows patients to make informed decisions about screening and, in men diagnosed with prostate cancer, to select the most appropriate treatment. Up-to-date information is available through the National Cancer Institute and the American Cancer Society, as well as Prostate Videos.com.

For patient education information, see Prostate Cancer.

Currently, the majority of prostate cancers are identified in patients who are asymptomatic. Diagnosis in such cases is based on elevation of the prostate-specific antigen (PSA) level on a screening study or findings on digital rectal examination (DRE). In addition, prostate cancer can be an incidental pathologic finding when tissue is removed during transurethral resection to manage obstructive symptoms from benign prostatic hyperplasia.

Symptoms of local disease

In the pre-PSA era, patients with prostate cancer commonly presented with symptoms that included urinary complaints or retention, back pain, and hematuria. Currently, with PSA screening, most prostate cancers are diagnosed at an asymptomatic stage. When symptoms do occur, diseases other than prostate cancer may be the cause. For example, urinary frequency, urinary urgency, and decreased urine stream often result from benign prostatic hyperplasia.

Symptoms of advanced disease

Advanced prostate cancer results from any combination of lymphatic, hematogenous, or contiguous local spread. Skeletal manifestations are especially common because prostate cancer has a strong predilection for metastasizing to the bone.

Manifestations of metastatic and advanced prostate cancer may include the following:

• Weight loss and loss of appetite
• Anemia
• Bone pain, with or without pathologic fracture
• Neurologic deficits from spinal cord compression
• Lower extremity pain and edema due to obstruction of venous and lymphatic tributaries by nodal metastasis

Uremic symptoms can occur from urethral obstruction caused by local prostate growth or retroperitoneal adenopathy secondary to nodal metastasis.

Physical examination (ie, digital rectal examination [DRE]) alone cannot reliably differentiate benign prostatic disease from cancer. Consequently, a biopsy is warranted to establish a diagnosis. Unfortunately, false-negative results often occur, so multiple biopsies may be needed before prostate cancer is detected.

If cancer is suspected, determining whether the disease is localized or extends outside the capsule is important for planning treatment. Obliteration of the lateral sulcus or involvement of the seminal vesical often indicates locally advanced disease.

Findings in patients with advanced disease may include the following:

• Cancer cachexia
• Bony tenderness
• Lower-extremity lymphedema or deep venous thrombosis
• Adenopathy
• Overdistended bladder due to outlet obstruction

Neurologic examination, including determination of external anal sphincter tone, should be performed to help detect possible spinal cord compression. Findings such as paresthesias or wasting are uncommon, however.

Digital rectal examination

The DRE is examiner-dependent, and serial examinations over time are best. A nodule is suspicious for malignancy and warrants evaluation. In addition, findings such as asymmetry, a difference in texture, and bogginess are important clues and should be considered in conjunction with the PSA level. Change in texture over time also suggests the need for a biopsy.

Cysts or stones cannot be accurately differentiated from cancer based on DRE findings alone. Therefore, maintain a high index of suspicion for noncancerous disorders if the DRE results are abnormal.

If cancer is detected, the DRE findings form the basis of clinical staging of the primary tumor (ie, tumor [T] stage in the tumor-node-metastases [TNM] staging system). In current practice, most patients diagnosed with prostate cancer have normal DRE results but abnormal PSA readings.

Currently, most cases of prostate cancer are identified by screening in asymptomatic men. Digital rectal examination (DRE) and prostate-specific antigen (PSA) evaluation are the two components used in prostate cancer screening. Transrectal ultrasonography (TRUS) has been associated with a high false-positive rate, making it unsuitable as a screening tool, but it has an established role in directing prostatic biopsies.

In patients whose screening shows elevated PSA levels or abnormal DRE findings, National Comprehensive Cancer Network (NCCN) guidelines strongly recommend multiparametric magnetic resonance imaging (MRI) of the prostate, if available, as the initial diagnostic test. Patients whose MRI results indicate low suspicion for prostate cancer can be followed up with PSA/DRE in 6 to 12 months, while those with high suspiction for prostate cancer should undergo prostate biopsy.[7]

Needle biopsy of the prostate is indicated for tissue diagnosis. Biopsy techniques include 12-core sampling guided by transrectal ultrasonography (TRUS), MRI-targeted biopsy, or both combined.[9] Pathologic evaluation of the biopsy specimen permits calculation of the Gleason score, which is used to help determine prognosis.

Blood studies beyond PSA offer little useful information for men with newly diagnosed early-stage prostate cancer. For men with advanced disease, a chemistry profile (including serum creatinine and liver function tests) is warranted. Acid and alkaline phosphatase measurements do not provide helpful information in most cases.

Urinalysis should be performed. If results are abnormal (ie, indicating the presence of hematuria or infection), further workup is warranted before planning cancer therapy.

For staging, computed tomography (CT) and/or MRI of the abdomen/pelvis are performed in a risk-stratified approach. Chest radiography is no longer a routinely advisable staging test for prostate cancer, though it may be of use in patients with prostatic ductal adenocarcinoma. 

In patients with a family history of high-risk germline mutations (eg, BRCA 1/2, Lynch mutation), a suspicious family history, or intraductal carcinoma on prostate biopsy, NCCN guidelines recommend germline testing, preferably with pre-test genetic counseling. If a genetic mutation is identified, the NCCN recommends post-test genetic counseling.[58]

Prostate-specific antigen (PSA) testing with or without digital rectal examination (DRE) are the two components used in prostate cancer screening. Transrectal ultrasonography (TRUS) has been associated with a high false-positive rate, making it unsuitable as a screening tool, although it has an established role in directing prostatic biopsies.

A systematic review and meta-analysis that included 7 studies with 9,241 patients who underwent both DRE and prostate biopsy found that DRE performed by primary care physicians has poor diagnostic accuracy in screening for prostate cancer. The sensitivity of DRE in that setting was estimated to be 0.51, with a specificity of 0.59 and a positive predictive value of 0.41.[59]

The screening debate

Since the introduction and widespread adoption of screening men for prostate cancer using PSA, the rate of metastatic disease at presentation (de novo) has declined by 50%, and the rate of death from prostate cancer has declined by 70%.[60] However, PSA screening also led to the increased detection and the somewhat exuberant treatment of prostate cancer at increasingly early stages, and it became abundantly clear that the benefit of early prostate cancer detection must be balanced with the risk for the potential overtreatment of early-stage prostate cancer.

Both surgery and radiation therapy are associated with morbidity, including diminished erectile function and incontinence. This has prompted multiple evaluations of prostate cancer screening, including the Prostate, Colorectal, Lung, and Ovarian (PLCO) screening trial,[61] the European Randomized Study of Screening for Prostate Cancer (ERSPC),[62] and the Göteborg trial.[63]

The PLCO was conducted in the United States. Patients were randomized between 1993-2001 to either annual PSA screening with a DRE for 6 years or usual care. The screening cohort included 38,340 men and the usual care cohort included 38,343 men. After a median of 15 years of follow-up, there was no reduction in prostate cancer mortality.[61] Only 2.7% of men died from prostate cancer. Of note, this study was plagued by crossover. Overall, the rate of screening for at least one PSA test during the study was 99% for the intervention arm and 86% for the control arm. Many have argued that this study demonstrates no difference between screening and opportunistic screening; however, the difference between the two has questionable clinical significance, and this study really just evaluated screening compared with screening.

The ERSPC trial, conducted across centers in 8 European countries and similar in design to the PLCO trial, enrolled 72,891 men in the PSA screening arm and 89,352 men in the control arm. After 13 years of follow-up, there was a significant reduction in prostate cancer–related mortality for the PSA screening; the number needed to invite for screening to prevent 1 death was 781 men and the number needed to treat was 27.[62] Some elements of PSA screening existed prior to trial enrollment and at several centers. The extrapolated PSA testing contamination (ie, testing of asymptomatic men in the control arm) in this study was significantly lower than in the PLCO trial (30%).[64]

Finally, the Göteborg screening study represents the smallest population of men with the least amount of PSA contamination and the longest follow-up. Men aged 50-64 who had not had prior PSA testing were randomized to PSA screening or standard care. At 18 years of follow-up, to prevent one prostate cancer-related mortality,  the number needed to invite was 231 and the number needed to diagnose was 10.[63] For perspective, with breast cancer screening, for which the United States Preventive Services Task Force (USPSTF) has granted a grade B recommendation, the number needed to treat to prevent one death from breast cancer is around 414 and the number needed to invite for screening is around 1200 .[65, 66]

In 2012, the USPSTF recommended against all prostate cancer screening, on the basis of less mature data from PSA screening trials.[67] Many primary care societies amended their prostate cancer screening guidelines to reflect the USPSTF decision; thus, screening decreased among access points to urology clinics.

This recommendation resulted in a significant decrease in the annual incidence of prostate cancer diagnosed and an increase in the incidence of metastatic disease at the time of diagnosis in men older than 50 years of age. Decreasing incidence was observed for patients with low-risk as well as high-risk disease.[68] Emerging evidence suggests that these trends were also associated with worse survival.[69] The USPSTF guidance was amended in 2018, such that the USPSTF now provides a grade C recommendation for individualized prostate cancer screening for men aged 55-69 and a grade D rating for prostate cancer screening for men 70 years or older.[70]

Currently, the American Cancer Society (ACS),[71] American Urological Association (AUA), European Association of Urology,[72] and the National Comprehensive Cancer Network (NCCN)[7] provide authoritative guidelines regarding prostate cancer screening. The specifics are addressed in the table below. Each body recommends an estimation of life expectancy as a component of both screening and treatment. Earlier screening is generally recommended in men with a family history of prostate cancer, those of African-American ancestry, and those with a personal or family history of high-risk germline mutations such as those associated with DNA damage repair, including BRCA1/2 and ATM. DRE is not as sensitive as PSA and is not mandated by many of the guidelines panels.

Repeated PSA testing occurs at differing intervals and the PSA threshold for biopsy is generally considered on a continuum. Of note, there is no PSA value threshold that can be used to rule out prostate cancer, and PSA testing should be repeated at least once after initial elevation

Evaluation of the competing risks for patient comorbidity and shared decision regarding both screening and treatment is of paramount importance. Shared decisions require collaboration between the care provider and patient to ensure that patient preference is accounted for in the decision-making process. This is especially important in patients with comorbid conditions and limited life expectancy.

In a cohort study evaluating survival 10 years after prostate cancer diagnosis, prostate cancer–specific mortality occurred in only 3% and 7% of patients with low and intermediate-risk disease, respectively, and in 18% of those with high-risk disease. However, 10-year mortality for men with more than three comorbid conditions was 26%, 40%, and 71% for age groups < 60, 61-74, and > 75 years, respectively.[73] Similar associations were noted in the PIVOT trial (see Treatment) and exemplify the need to balance cancer treatment, personal preference, and life expectancy.[69]

Table 2. Prostate cancer screening recommendations from 4 major organizations (Open Table in a new window)

A study

When PSA testing was first developed, the upper limit of normal for PSA was thought to be 4 ng/mL. However, subsequent studies have shown that no PSA level guarantees the absence of prostate cancer. As the PSA level increases, so does the risk of this disease. When the PSA is 1 ng/mL, cancer can be detected in about 8% of men if a biopsy is performed. With a PSA level of 4-10 ng/mL, the likelihood of finding prostate cancer is about 25%; with a level above 10 ng/mL, the likelihood is much higher.[74]

Although cancer may be present even when the PSA level is less than 1 ng/mL, experts do not recommend a biopsy unless the PSA is higher (unless there is a suspicion on DRE or other modality). Some use 2.5 ng/mL as the cutoff, while others wait until it is 3 ng/mL or greater.

The European Randomized Study of Screening for Prostate Cancer (ERSPC) applied a PSA cutoff value of 3 ng/mL or higher as an indication for lateralized sextant biopsy.[75] For men with an initial PSA value of less than 3 ng/mL, the risk of developing aggressive prostate cancer and death has been found to significantly increase with PSA values in the 2-2.9 ng/mL range, although the overall risk of aggressive prostate cancer–related death remains limited.[76]

A review of data from the Surveillance, Epidemiology, and End Results (SEER) system of men with newly diagnosed prostate cancer from 2004 to 2006 by Shao et al found that most patients with a PSA threshold below 4.0 ng/mL had low-risk disease but underwent aggressive local therapy. Shao et al suggested that in the absence of the ability to distinguish indolent from aggressive cancers, lowering the biopsy threshold might increase the risk of overdiagnosis and overtreatment.[77]

A review by Preston and colleagues concluded that PSA levels in midlife correlate with future risk of lethal prostate cancer. The study population consisted of men who had PSA levels measured on enrollment in Physicians' Health Study, when they were 40-59 years old. In men with baseline PSA levels in the >90th percentile, versus those with levels at or below the median, the odds ratios for developing lethal prostate cancer (by age at baseline measurement) were as follows[78] :

• Age 40-49 years: 8.7
• Age 50-54 years: 12.6
• Age 55-59 years: 6.9

A variety of approaches have been proposed for improving the accuracy of PSA for detecting prostate cancer. These include assessment of the velocity of PSA level increase and the percentage of free PSA.

See Prostate-Specific Antigen Testing for a complete discussion of this topic.

PSA velocity

PSA velocity is an important concept. To calculate velocity, at least 3 consecutive measurements on specimens drawn over at least 18-24 months should be used. Guidelines from the NCCN suggest that PSA velocity be considered in the context of the PSA level.[7] The following PSA velocities are suspicious for cancer:

• PSA velocity of 0.35 ng/mL/y, when the PSA is ≤2.5 ng/mL
• PSA velocity of 0.75 ng/mL/y, when the PSA is 4–10 ng/mL

However, a study by Vickers et al in 2011 called into question the concept of PSA velocity. In this study, PSA velocity cut points with a comparable specificity to PSA level cut points had a lower sensitivity, particularly for high-grade and clinically significant prostate cancer. The researchers concluded that “PSA velocity added little to the predictive accuracy of high PSA levels or positive DRE and would substantially increase the number of men recommended for a biopsy.”[79] This controversy has not been resolved.

Bound versus free PSA

The measurement of bound and free PSA can help to differentiate mildly elevated PSA levels due to cancer from elevated levels due to benign prostatic hyperplasia. Free PSA is calculated as a percentage of total PSA; the lower the percentage of free PSA, the higher the likelihood of cancer. For example, cancer is found at prostate biopsy in only 8% of men with greater than 25% free PSA, but in more than half of those with less than 10% free PSA.

The percentage of free PSA is generally used as an additional factor in making an informed recommendation for or against biopsy in patients with a PSA level of 4-10 ng/mL. Typically, a free PSA above 25% is considered normal. Some experts recommend a biopsy when the free PSA is less than 18%; others advise a cutoff of 12%.

Free PSA percentage is most useful in men with very large glands and in patients in whom 1 biopsy result has already been negative. In healthy men with a PSA level of 4-10 ng/mL, many experts recommend biopsy without the additional free-PSA test. 

The diagnosis of screening-detected prostate cancer is confirmed by prostate biopsy. For several decades, prostate biopsy has been performed via a transrectal approach utilizing ultrasound guidance (TRUS). Initial prostate biopsies followed a sextant (6 core) protocol and were utilized in the many of the early studies regarding prostate cancer screening. However, over time, it became apparent that the sensitivity of a 6-core prostate biopsy was suboptimal. Optimization of prostate biopsy protocols demonstrated the value of obtaining 12 cores of prostate tissue in predetermined prostatic regions primarily targeting the peripheral zone, where most prostate cancers arise.[80]

In spite of these improvements, ultrasound-guided prostate biopsies fail to identify 20-30% of cancers and undergrade others.[81] Transrectal prostate biopsy is associated with several potential drawbacks. Complications include rectal bleeding, hematuria, hematospermia, pain, urinary tract infection (UTI), lower urinary tract symptoms, acute urinary retention, and transient erectile dysfunction. Most notably, sepsis requiring hospitalization occurs in 0.5-4% of cases, depending on antimicrobial administration practices.[82]

Transperineal prostate biopsy has demonstrated promise in reducing several of the risks associated with transrectal biopsy. In a cohort of 1,287 patients undergoing transperineal prostate biopsies under local anesthesia, the rate of complications was notably low, with only 1.6% of patients developing urinary retention, one patient with a culture-confirmed UTI, and no episodes of sepsis. Cancer was detected in 49.8% of patients, with 30% of patients overall harboring clinically significant prostate cancer; moreover, 9.7% of cancers detected were located only in the anterior zone, a zone not normally sampled in transrectal biopsy templates.[83]

A similar study in 3,000 men undergoing transperineal biopsy demonstrated similar rates of complications, including UTI in < 1% of patients and acute urinary retention in 6.7% of patients, with complication rates increasing when the number of biopsies increased from 12 to 24.[84] Overall, detection rates for clinically significant prostate cancer are similar between TRUS and transperineal biopsies.[85]

Finally, the utilization of magnetic resonance imaging (MRI) to assess for lesions concerning for prostate cancer has recently gained significant traction in several clinical scenarios, including the following:

• Prior to prostate biopsy
• Active surveillance
• Surgical or local therapy planning
• Patients with a prior negative prostate biopsy and persistently elevated PSA

Lesions in the prostate that are detected on MRI are assigned Prostate Imaging–Reporting and Data System (PI-RADS) scores, based on location within the prostatic zones utilizing multiple MRI sequences. The images from the MRI are then overlaid on the images obtained using the ultrasound probe and the lesions of interest are targeted for biopsy. Each PI-RADS score is associated with the probability of detecting clinically significant ande role of prostate MRI and MRI-targeted biopsy in patients with a negative biopsy.[86, 87, 8]

For men with an elevated PSA and no prior biopsy, the detection rates of clinically significant prostate cancer do not significantly vary with MRI-guided biopsy compared with TRUS biopsy alone; however, the omission of a biopsy for patients with a negative MRI might lead to decreased detection of clinically insignificant prostate cancer and low rates of missing clinically significant prostate cancer.[88]

These findings have been further confirmed in the PRECISION trial, in which MRI at the time of initial prostate biopsy demonstrated noninferiority to standard TRUS biopsy, with findings suggestive of superiority.[89]  The combintion of MRI-targeted prostate biopsy with TRUS-guided sampling is also being studied.[9]

The role of MRI in the surveillance of men with low-risk prostate cancer is currently being evaluated, with mixed results and a consistent suggestion that a targeted biopsy should not be omitted.[90, 91, 92]

See Transrectal Ultrasonography of the Prostate for a discussion of TRUS and prostate biopsy, as well as Imaging in Prostate Carcinoma and Techniques of Local Anesthesia for Prostate Procedures and Biopsies.

Although the change in glandular architecture represented by the Gleason score is currently the most widely used histologic parameter, it is not the only histologic change that can be observed in prostate cancers. Indeed, notable changes in cell and nuclear morphology, DNA ploidy, neuroendocrine differentiation, and vascularity can be observed and may have prognostic significance.

There is a continuum from normal prostatic epithelium to invasive carcinoma. Precursor lesions to carcinoma may include prostatic intraepithelial neoplasia (PIN) and atypical small acinar proliferation (ASAP). (See the images below.)

Prostate cancer. Micrograph of high-grade prostatic intraepithelial neoplasia

Prostate cancer. Adenocarcinoma around a small nerve (center). Courtesy of Thomas M. Wheeler, MD.

Prostate cancer. Small focus of adenocarcinoma on needle biopsy on right side of slide (normal glands on left side). Courtesy of Thomas M. Wheeler, MD.

Prostate cancer. Immunohistochemical stains showing normal basal cells (brown) in a benign gland with no basal cells in malignant glands (on right side with no brown staining). Malignant glands show increased expression of racemase (red cytoplasmic stain). Courtesy of Thomas M. Wheeler, MD.

The architecture of the gland remains normal but the epithelial layers become multi-layered and crowded. At a cellular level, the nucleus becomes large and nucleoli are visible. The term PIN is becoming less used in favor of atypical small acinar proliferation (ASAP), which is proliferation of usually small acini with features suggestive of but not diagnostic of cancer.

Clinical studies suggested that PIN predates a carcinoma by 10 or more years. This concept is less accepted in the modern era. PIN as a precursor of cancer has been replaced by ASAP. The identification of ASAP in prostate biopsy specimens warrants further searching for concurrent invasive carcinoma, with up to 30% having cancer identified on subsequent biopsy specimens. Repeat biopsies within 3-6 months are recommended for patients with ASAP cases but PIN is treated as a benign finding.

See Precancerous Lesions of the Prostate for a complete discussion of this topic.

Transitional cell prostate carcinoma

Transitional cell carcinoma (TCC) of the prostate is carcinoma of urothelial origin with a pathology that involves prostatic tissue. Primary prostatic TCC is very rare and involves the entire prostatic urethra, particularly near the verumontanum, the large prostatic duct, and nearby acini. Secondary prostatic TCC mainly involves the bladder neck or posterior prostatic tissue; it results from direct pagetoid spread of urothelial cancer in situ (CIS) or direct pathologic invasion of bladder urothelial carcinoma.

Extensive involvement of the prostatic duct and acini may appear as areas of luminal necrosis and periductal fibrosis. In cases of prostatic stroma invasion, there are irregular areas of induration and fibrosis.

Primary prostatic papillary urothelium carcinoma is characterized by papillary growth lined by urothelial cells of multiple layers with mild to severe cytologic atypia. Endophytic growth pattern with involvement of superficial suburethral tissue and ductal spread may occur.

Urothelial cancer in situ (CIS) may involve the prostatic urethra, the prostatic duct, and the acini. The vast majority of cases arise synchronously with bladder urothelial neoplasia or from pagetoid spread from the bladder neck. CIS is characterized by partial or complete replacement of urethra or duct by highly atypical urothelial cells; these cells have pleomorphic nuclei, coarse chromatin, and frequent mitoses or apoptosis. There may be large areas of well-defined nests of CIS as a result of CIS's extension into prostatic acini. Periductal fibrosis or fibrosis of the acini, as well as chronic inflammation, may be evident.[93]

Invasion of urothelial carcinoma into prostatic stroma is characterized by irregular nests, clusters, or single atypical cells that infiltrate into dense prostatic tissue. Two well-recognized pathways of invasive carcinomas have been described: (1) invasive carcinoma arising from the prostatic urethra and duct, which is often associated with CIS within the prostatic duct or acini, and (2) prostatic stroma invasion, in which bladder cancer penetrates from posterior periprostatic soft tissue or the bladder neck. Focal invasion of superficial lamina propria has also been reported to occur in association with prostatic urethra CIS.

Once detected on biopsy, prostate cancer is assigned a grade and stage followed by a risk group for consideration of further therapy. Prostate cancer grading has traditionally been performed according to the Gleason Grading system, a two-number system in which the first number is assigned to the predominant focus of tumor and the second assigned to the second more predominant pattern; each is graded on a scale of 1-5 and the sum of the two constitutes the overall grade.[94] Generally, the cut-off for prostate cancer starts with Gleason grade 3+3 cancer.

In 2010, the International Society of Urological Pathology (ISUP) modified the Gleason Grading system to a 5-grade system in which grade group 1 encompasses Gleason 3+3 disease, and Gleason 3+4 is stratified into a different grade than Gleason 4+3 (see the Table below).[95]

Table 3. International Society of Urological Pathology (ISUP) grading system (Open Table in a new window)

The tumor-node-metastasis (TNM) staging system of the American Joint Committee on Cancer (AJCC) is used to stage prostate cancer. The current revision of the AJCC system, which took effect in January 2018, also uses both the Gleason score and the grade group for staging.[96]  See Prostate Cancer Staging.

Clinical staging is combined with grading and clinical parameters (such as PSA, PSA density, and volume of cancer in biopsy cores) to formulate clinical risk groups. Many groups have assigned risk stratification tools in this area, however, the NCCN risk stratification is discussed in this article. In the NCCN approach, risk group is assigned on the basis of clinical and pathologic features; in turn, risk grouping guides additional evaluation with imaging studies, such as bone imaging and pelvic and/or abdominal imaging. Risk group and in some cases family history guide the use of germline testing, and risk group along with life expectancy guides the use of molecular biomarker analysis of the tumor.[58] In the NCCN guidelines, clinical risk calculators such as the PCPT or ERSPC calculators are utilized to determine the risk of lymph node involvement.[97]

Advanced imaging utilizing multiple radiotracers is currently being evaluated for localized prostate cancer staging, but it has not yet been standardized for clinical practice and staging and is beyond the scope of this article.[98]

Therapy is primarily determined by life expectancy and patient goals. For very low risk disease, therapy distinction is based on life expectancy < 10 years, 10-20 years, or > 20 years. For low risk and both categories of intermediate risk disease, this distinction is made at 10 years. For high and very high risk disease, this cut-point is 5 years or based on symptoms from advanced disease. NCCN guidelines provide initial therapy recommendations based on risk category and life expectancy.[58]

Transitional cell carcinoma (TCC)

TNM staging of TCC involving the prostate depends on the primary site.

Prostatic TCC secondary to bladder TCC

If prostatic stroma invasion is present, it is staged as pT4a bladder cancer, regardless of whether there is contiguous invasion of the prostatic urethra, prostatic duct, or acini or direct, penetrating invasion of the bladder. If the prostate is involved only by cancer in situ (CIS), the stage of bladder tumor depends on the depth of invasion into the bladder, independent of the amount and location of the CIS.

Primary prostatic urethra urothelial carcinoma

The tumor is staged according to the depth of invasion and the degree of involvement of the prostate, as follows:

• Ta - Noninvasive, papillary carcinoma
• Tis - Urethral CIS
• T1 - Invasion of subepithelial connective tissue
• T2 - Involvement of the prostatic stroma
• T3 - Invasion beyond the prostatic capsule or bladder neck
• T4 - Invasion of adjacent organs

Models have been developed that combine the clinical stage (as determined by DRE findings), Gleason score, and PSA level in an attempt to better predict which men have organ-confined cancer, as opposed to those who may have local extension. In addition, these models can be used to predict the time to biochemical failure and the time to the development of clinical metastatic disease in patients with rising PSA levels.

These models have been adapted to personal-computer and handheld-computer platforms and can be used with ease in clinical practice. One such program can be downloaded free of charge from the Prostate Nomogram section of the Memorial Sloan-Kettering Cancer Center Web site. The Partin tables, updated by experts at Johns Hopkins in 2013, are another excellent nomogram for predicting prostate cancer spread and prognosis. Updates to the tool were based on a study of 5629 men who underwent radical prostatectomy and staging lymphadenectomy between 2006 and 2011. The updated tables show that certain categories of men who were previously not thought to have a good prognosis (eg, those with a Gleason score of 8) actually can be cured with surgery.[99]

The Cancer of the Prostate Risk Assessment (CAPRA) score is calculated from the PSA level, the Gleason score, the percentage of biopsy cores positive for cancer, the clinical tumor stage, and the patient age at diagnosis. In a large cohort of patients with clinically localized prostate cancer, the CAPRA score proved accurate for predicting metastases, cancer-specific mortality, and all-cause mortality. No patient with a CAPRA score of 0 reached either metastasis or mortality endpoints, but each single-point increase in the CAPRA score was associated with increasing risk.[100]

From the results of the Prostate Cancer Prevention Trial (PCPT), an online risk calculator was created.[6] The information needed includes age, PSA score, ethnicity, family history, positive or negative DRE findings, and positive or negative prior biopsy findings. After those values are entered, the calculator predicts the chances for no, low-grade, and high-grade prostate cancer. The intent is to help guide treatment decision-making. See the PCPT prostate cancer risk calculator.

Whitmore-Jewett classification

The Whitmore-Jewett classification divides prostate cancer into 4 stages, A-D, as follows:

• Stage A - Tumor is present, but not detectable clinically
• Stage B - The tumor can be felt on physical examination but has not spread outside the prostatic capsule
• Stage C - The tumor has extended through the capsule
• Stage D- The tumor has spread to other organs

The Whitmore-Jewett classification is no longer widely used, as prostate cancer does not necessarily progress in a sequential manner. However, further stratification of stage D by Crawford and Blumenstein[101] has been thought to improve classification and understanding of a subset of patients who have hormone-insensitive prostate cancer. The staging is as follows:

• Stage D1 - Involvement of pelvic lymph nodes
• Stage D1.5 - Rising PSA level after failure of local therapy (ie, biochemical failure)
• Stage D2 - Metastatic disease to bone and other organs
• Stage D2.5 - Rising PSA after nadir level
• Stage D3 - Castrate-resistant prostate cancer
• Stage D3.5 - Sensitive to hormones
• Stage D4 - Insensitive to hormones

Molecular/genetic characteristics

The molecular and genetic features of prostatic TCC are similar to those of bladder TCC. Common cytogenetic abnormalities are chromosomal losses (2q, 5q, 8p, 9p, 9q, 11p, 18q) and gains (1q, 5p, 8q, 17q). Many oncogenes (Her2/neu, H-ras, EGFR, cyclin, and MDM2) and tumor suppressor genes (p53, RB, and PTEN) have been implicated in the tumorigenesis.[102]

In a review of 42 biopsies, Varinot and colleagues found HOXB13 expression was negative or weakly positive in individuals with carcinomas of urothelial origin, and positive in patients with prostatic carcinoma. They concluded that HOXB13 was a marker for prostatic origin of a carcinoma with good sensitivity (89%) and very good specificity (100%) and had the potential to be a diagnostic aide when poorly differentiated or neuroendocrine tumors were encountered.[103]

Immunohistochemistry

The immunoprofile of prostatic transitional cell carcinoma (TCC) is identical to that of bladder carcinoma. Tumors are positive for cytokeratin (CK) 7 (90%), p63 (87%), thrombomodulin (79%), CK20 (61%), high–molecular weight CK (HMWCK) 34βE12 (59%), CK5/6 (55%), and uroplakin III (55%).[104]

Treatment of prostate cancer varies by disease stage. See the image below.

Prostate cancer. Diagram illustrates the progression of prostate cancer and associated treatment options.

Current guidelines on localized prostate cancer from the American Urological Association (AUA)/American Society for Radiation Oncology (ASTRO) Society of Urologic Oncology (SUO) strongly recommend that selection of a management strategy incorporate shared decision making and explicitly consider the following[105] :

• Cancer severity (risk category)
• Patient values and preferences
• Life expectancy
• Pretreatment general functional and genitourinary symptoms
• Expected post-treatment functional status
• Potential for salvage treatment

Standard treatments for clinically localized prostate cancer include the following:

• Watchful waiting
• Active surveillance
• Radical prostatectomy
• Radiation therapy

Metastatic prostate cancer is rarely curable.[106] Management of these cases typically involves therapy directed at relief of particular symptoms (eg, palliation of pain) and attempts to slow further progression of disease.

Comparisons between treatments for prostate cancer are complicated by the stage-migration and lead-time bias associated with the adoption of prostate-specific antigen (PSA)–based screening and the resultant increase in the detection of small, clinically localized cancers. In addition, treatment selection has become more complicated as options have increased.

Surgical treatment currently includes nerve-sparing techniques, laparoscopic procedures, robotically-assisted procedures, and the classic retropubic prostatectomy and perineal prostatectomy. There is oncologic equipoise of robotic and retropubic prostatectomy.

Multiple forms of radiation therapy are currently available. These include the following:

• Conventional radiation therapy
• Three-dimensional (3-D) conformal radiation therapy
• Intensity-modulated radiation therapy
• Temporary and permanent brachytherapy
• Proton-beam radiation
• Stereotactically guided radiation

Hormone therapy for prostate cancer is also known as androgen deprivation therapy (ADT). It may consist of surgical castration (orchiectomy) or medical castration. Agents used for medical castration include luteinizing hormone–releasing hormone (LHRH) analogues or antagonists, antiandrogens, and other androgen suppressants.

The first patient-driven international prostate cancer quality-of-life study, the Europa Uomo Patient Reported Outcomes Study (EUPROMS), found that except for active surveillance, all treatments for prostate cancer may negatively affect quality of life—especially continence and sexual function—and that for many men these effects may be greater than previously thought. EUPROMS gathered data from 2,943 European men from 25 countries who had been treated for prostate cancer 6 years previously, on average.[107]

Urinary incontinence was most affected by radical prostatectomy. Fatigue scores were twice as high with radiotherapy as with surgery, and three times as high with chemotherapy. Both radiotherapy and radical prostatectomy had a severe impact on sexual function—radiotherapy more than radical prostatectomy. Overall, 50% of respondents reported that loss of sexual function (including the ability to have an erection or reach orgasm) was a big (28%) or moderate (22%) problem. The best quality-of-life scores were achieved in patients whose prostate cancer was discovered in an early, curable stage.[107]

To view a multidisciplinary tumor board case discussion, see Memorial Sloan Kettering e-Tumor Boards: Unfavorable Intermediate-Risk Prostate Cancer.

Standard treatments for clinically localized prostate cancer include watchful waiting, active surveillance, radical prostatectomy, and radiation therapy. Whether any one of those modalities offers survival benefits over the others remains controversial.

Watchful waiting

Watchful waiting, defined as observation for prostate cancer without definitive local therapy, has been evaluated in several key studies.

In the Prostate cancer Intervention Versus Observation Trial (PIVOT), conducted through the US Department of Veterans Affairs from 1994-2020, 731 men with localized prostate cancer were randomized to radical prostatectomy or observation.[108] Initially, there was no difference in survival, but at 22.1 years of follow-up, 68% of men assigned to surgery versus 73% of men assigned to observation had died; mean survival was 1 year longer in the surgical arm. This effect was greatest in men with intermediate-risk disease.[69]

However, a significantly higher-than-anticipated portion of patients in each arm of PIVOT died from competing causes (ie, not prostate cancer). The degree of competing risk in the PIVOT trial was higher than in approximately 90% of patients seen in clinical practice, limiting the generalizability of the PIVOT results.[109]

In the Veterans Administration Cooperative Urological Research Group (VACURG) trial comparing observation with surgery for non-PSA-screening–detected prostate cancers in 111 patients, minimal to no difference was found in survival at 23 years. The statistical power of this study was limited by the small number of patients involved.[110]

The Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) trial provides the most robust data comparing watchful waiting with surgery for non-PSA–detected prostate cancers. After 23.6 years of follow-up in 695 men there was a 12% absolute reduction in the risk of prostate cancer– related death for men undergoing surgery and a gain of 2.9 years in life expectancy.[111]

While these studies demonstrate a modest improvement favoring local therapy for non–screening-detected prostate cancer, they also demonstrated that many men might suffer from overtreatment of prostate cancer. This led to the development of active surveillance as a management modality.

Active surveillance

Active surveillance (AS) for prostate cancer encompasses continued monitoring of men with very low, low, and some favorable intermediate-risk prostate cancers after the initial diagnosis.[112] The goal is to delay potential curative intervention if needed without missing the window for a cure. Surveillance generally includes continued PSA monitoring at set intervals, confirmatory prostate biopsy, and repeat prostate biopsies at predetermined time points (generally at least 12-24 months apart). Monitoring with multiparametric magnetic resonance imaging (mpMRI) has also been used as part of AS.[113] No single AS strategy is currently recommended, and the time to discontinue AS has not been established; however, AS is recommended by numerous international organizations.[114]

Several long-term cohort studies of AS, with varying inclusion criteria, have demonstrated the consistent safety of AS. Overall, 27-53% of patients in the large studies have undergone definitive therapy, while the rates of metastasis (0.12-6%) and prostate cancer–related mortality (0-1.5%) have been low.[115]

For example, the randomized, controlled ProtecT trial, which compared AS with both surgery and radiotherapy in patients with primarily low-risk prostate cancer, demonstrated that for patients with low-risk prostate cancer, mortality from cancer is low at 10 years, and AS appears as safe as an immediate intervention. Overall, < 1% of patients died from prostate cancer over the study time period. Disease progression was significantly higher in the AS arm than in the intervention arms and about half of the patients in the AS arm went on to receive surgery or radiation therapy.[116] After 15 years of follow-up, prostate cancer–specific mortality remained low regardless of the treatment assigned.[117]

Definitive local therapy

Definitive local therapy for prostate cancer generally involves either surgical removal or irradiation of the prostate, with or without removal or irradiation of the draining pelvic lymph nodes. No head-to-head, randomized, prospective trials comparing radiation with surgery have been conducted, so data for each are generally extrapolated. Patient-centered decision making generally takes into account the differences in short- and long-term adverse effects associated with the different forms of therapy.

Radiation therapy is delivered either from an external source, via implanted radioactive seeds (brachytherapy), or a combination of both, with or without concurrent androgen deprivation therapy (ADT) for a set period of time. It is important to note that radiation therapy delivery methods, fractionation, and dosing have continued to evolve over time. This article will not review the technical differences between therapies; however, at present, 3-dimensional conformal radiation therapy and intensity-modulated radiation therapy with high-dose (hypofractionated) therapy are generally utilized. Proton-beam therapy as well as brachytherapy through a variety of seed types may also be considered.[118]

The approach for radiation therapy is primarily determined by risk stratification, as discussed in detail below. Current radiation therapy protocols generally consider the addition of 4-36 months of ADT (castration), based on risk stratification. The selection of modality is generally driven by disease characteristics, differences in adverse effects, and patient preference. National Comprehensive Cancer Network (NCCN) and European Urology Association (EUA) guidelines regarding risk-stratified therapy are presented in the guidelines section. 

In general, radiation therapy and surgery have similar effects on quality of life. Radiation therapy adverse events can be modulated by the type of radiation utilized. In general, both surgery and radiation pose risks of erectile dysfunction and bladder neck contracture. Surgical therapy is associated with immediate operative risks (eg, pain, infection), erectile dysfunction, and persistent incontinence.[119, 120, 121]

Radiation therapy is uniquely associated with a higher risk of persistent fecal urgency and incontinence of gas, secondary malignancy in the radiation field, and hemorrhagic cystitis.[122, 123, 124] A systematic review and meta-analysis of radiation therapy for prostate cancer found that external beam radiation therapy (EBRT), but not brachytherapy, was consistently associated with increased odds for a second malignancy of the bladder, colon, and rectum. Absolute rates were low, however: 0.1-3.8% for bladder, 0.3-4.2% for colorectal, and 0.3-1.2% for rectal cancers.[125]

Surgical therapy

In general, surgical therapy for prostate cancer involves the removal of the prostate, seminal vesicles, and the draining pelvic lymph nodes (when risk indicates removal) with re-anastomosis of the bladder to the urethra. Historically, prostatectomy has been performed via open surgical approaches, including perineal, suprapubic, retropubic, infrapubic, transrectal, ischiorectal, and sacral.[126, 127] Over time, however, radical retropubic prostatectomy (RRP) became the gold standard for prostate cancer surgery, and those other approaches were largely abandoned.[128]

Since the introduction of the robotic surgical platform at around the turn of the 21st century, robotic prostatectomy (RP) has rapidly become an established modality, increasing from 67% of prostatectomies in 2010 to 85% in 2013.[129, 130] RP has consistently demonstrated oncologic safety equivalent to that of RRP, with decreased blood loss favoring RP. Refinement of RP with techniques for sparing the peri-prostatic nerves, bladder neck, and space of retzius, as well as continued evaluation and understanding of anatomy, have led to improved outcomes with respect to erectile function, continence, and surgical margin positivity.[131, 132, 133, 134]

Given the continued innovation in this area, with new robotic platforms and approaches, specific rates of complications and surgical margin positivity are now user and approach dependent and should be reviewed with patients by the performing surgeon. Generally speaking, outcomes after prostatectomy for patients with low- and intermediate-risk disease are favorable. Of patients with high-risk disease undergoing prostatectomy, approximately 25-50% will experience disease recurrence over 10 years, while 1 in 4 may experience disease-related mortality. However, those statistics generally derive from retrospective series and show significant heterogeneity.

Radiation therapy

Radiotherapy also offers the potential for curative treatment of localized prostate cancer. It may be delivered in the form of EBRT or brachytherapy (ie, the insertion of radioactive seeds into the prostate gland). EBRT techniques include 3-dimensional conformal radiation therapy (3D-CRT) and intensity-modulated radiation therapy (IMRT) with hypofractionation.

Brachytherapy

In 2011, the American Society for Radiation Oncology (ASTRO) and the American College of Radiology (ACR) issued a practice guideline for transperineal permanent brachytherapy of prostate cancer. These guidelines established standards for the safe and effective performance of brachytherapy for patients with organ-confined prostate cancer.[135] See External Beam Radiation therapy in Prostate Cancer and Brachytherapy (Radioactive Seed Implantation Therapy) in Prostate Cancer for more information on these topics.

Radiation therapy plus androgen ablation therapy

Androgen ablation has been shown to improve survival in men with localized disease who are treated with external radiation. D’Amico et al reported higher overall survival with the combination of radiation therapy and 6 months of ADT in men with intermediate-risk prostate cancer. Median follow-up was 7.6 years.[136]

A study by Jones et al found that for patients with stage T1b, T1c, T2a, or T2b prostate cancer and a PSA level of 20 ng/mL or less, short-term ADT increased overall survival in intermediate-risk—but not low-risk—men. The 10-year rate of overall survival was 62% with combination therapy, versus 57% with radiation therapy alone; 10-year disease-specific mortality was 4% and 8%, respectively. In this study, ADT was given for 4 months, starting 2 months before radiation therapy.[137]

In a study by Pisansky et al of 1489 intermediate-risk prostate cancer patients, disease-specific survival was not significantly different whether total androgen suppression (TAS) was given for 8 weeks or for 28 weeks prior to radiation therapy.[138] Patients in the study were randomized to 8 or 28 weeks of TAS with LHRH agonist, along with a daily nonsteroidal antiandrogen, prior to radiation treatment. This was followed in both groups by an additional 8 weeks of androgen suppression, administered concurrently with radiotherapy.

Pisansky and colleagues found that the 10-year disease-specific survival rate in the study was 95% in the 8-week treatment group and 96% in the 28-week treatment group. The 10-year disease-free survival rates in the 8- and 28-week groups were 24% and 23%, respectively, and the 10-year cumulative incidences of clinical and biochemical relapse were 57% and 60%, respectively.[138]

Taken together, radiation therapy is generally given for 4-36 months, depending on the risk group of the patient. 

Radiation therapy versus surgery

In 2014, the Agency for Healthcare Research and Quality (AHRQ) found insufficient evidence to determine whether any type of radiation therapy results in fewer deaths or cancer recurrences than radical prostatectomy does in patients with clinically localized prostate cancer.[139]  The importance of dose escalation in disease control complicates the extraction of meaningful conclusions from current radiation therapy treatments (eg, 3D-CRT, IMRT).

Brachytherapy has also been compared with surgery in the management of early-stage disease. Direct comparisons (ie, prospective, randomized trials) are not readily available, but preliminary data from most centers suggest that permanent prostate implants yield comparable local control and biochemical disease-free rates.

Valid comparisons of surgery and radiation therapy are impossible without data from randomized studies that track long-term survival rather than PSA recurrence. Variation in radiation techniques and dosage administered; the variable use of androgen ablation, which improves survival in intermediate- and high-risk disease; and the variable impact on the quality of life complicate comparison using uncontrolled studies.

Radiation as adjuvant or salvage therapy after surgery

Several randomized trials have evaluated the use of adjuvant radiation therapy to the prostatic bed following surgery for patients at high risk of recurrence (generally those with positive surgical margins or with seminal vesical invasion). Those include EORTC 22911,[140] SWOG 8794,[141]  ARO 96-02/AUO AP 09/95,[142] and FinnProstataX,[143] as well as the ongoing RAVES, GETUG-AFU 17, and RADICALS-RT studies. Recent research has further highlighted the role of early salvage radiation therapy (PSA < 0.5) with concomitant ADT for those with biochemical recurrence after prostatectomy, to avoid overtreatment associated with adjuvant radiotherapy. This is reflected in the current AUA/ASTRO guidelines.[144]

Emerging therapies

Several emerging therapies for the management of localized prostate cancer are gaining traction, though they are not yet routinely recommended for that purpose. These include whole-, hemi-, and partial-gland ablative therapies such as cryoablation, high-intensity focused ultrasound (HIFU), and photodynamic therapy.[145] They are generally utilized in patients with low-risk prostate cancer. Long-term safety and efficacy data remain largely elusive.[146, 147, 148, 149, 150]

However, on 4-year follow-up of the prospective, randomized PCM301 trial in men with low-risk prostate cancer, cancer progression rates (overall and by grade) were significantly lower in patients who underwent partial gland ablation with vascular targeted photodynamic therapy (n=207) versus those who underwent active surveillance (n=206). Consequently, fewer patients in the ablation cohort required conversion to radical therapy (24%, vs 53% in the surveillance cohort; hazard ratio 0.31, 95% confidence interval 0.21-0.46).[151]

AUA/ASTRO/SUO guidelines on advanced prostate cancer separate management considerations into the following four disease states, which encompass the entire continuum of advanced prostate cancer[152] :

1. Biochemical recurrence without metastatic disease, after exhaustion of local treatment options
2. Metastatic hormone-sensitive prostate cancer
3. Non-metastatic castration-resistant prostate cancer
4. Metastatic castration-resistant prostate cancer

These disease states are defined by the following:

• Primary tumor status
• Presence or absence of distant disease on imaging (metastatic versus nonmetastatic)
• Testosterone levels (noncastrate versus castrate)
• Prior chemotherapy exposure ^[153]

Biochemical recurrence without metastatic disease after exhaustion of local treatment options 

Biochemical recurrence is defined as a rise in PSA to 0.2 ng/mL and a confirmatory value of 0.2 ng/mL or greater following radical prostatectomy,  or a rise of 2 ng/mL or more above the nadir PSA after radiation therapy. Not all men who have a rising PSA will develop metastases, and for that reason not all such men require treatment. The risk of metastases and death depend on the patient’s Gleason score, the length of time between the nadir PSA and the onset of the PSA’s rise, and the PSA doubling time.[154]

Patients who have PSA (biochemical) failure following radical prostatectomy and have no evidence of metastatic disease have the options of watchful waiting, radiation therapy, or hormone ablation as salvage therapy. Similarly, patients who have PSA failure following radiation therapy have the following options:

• Watchful waiting
• Brachytherapy
• Prostatectomy
• Cystoprostatectomy
• Cryotherapy
• Hormone ablation

The pretreatment Gleason score, clinical stage, PSA level, and percentage of positive core biopsy results have been found to be reliable predictors of failure following local therapy. Unfortunately, no means of identifying recurrences limited to the pelvis is reliable. Although a Gleason grade of 7 or less is associated with a better prognosis than a grade of 8 or more, the survival likelihood associated with a rise in the PSA level is greater if the rise occurs more than 2 years after local treatment than if it occurs less than 2 years afterward.

The decision algorithm for the initiation of treatment for biochemical failure is controversial. Factors to consider include the following:

• Type of local therapy previously instituted (if any)
• Patient's life expectancy
• Intention and likelihood of cure
• Risk for increased morbidity
• Patient's quality of life

For patients with a rising PSA after failure of local therapy and no demonstrated metastatic disease by conventional imaging, the AUA recommends observation or enrollment in a clinical trial. A balance between disease control and minimization of the toxicity and intolerance of the treatment is difficult to maintain. Androgen blockade, while able to limit disease progression and reduce urinary outlet obstruction, produces a number of adverse effects. Unlike treatment of men with a biochemical recurrence following prostatectomy, where early salvage radiation with or without adjuvant ADT remains the preferred treatment strategy, there are currently no systemic treatments with proven efficacy in men without metastatic disease who are not candidates for additional local therapy.

Two large observational studies have assessed the question of salvage systemic therapy in this population, and neither found an advantage for earlier treatment in terms of metastasis or survival.[155, 156] Initiation of ADT is not recommended in the absence of visible metastases for men who have completed maximal local therapy, but if it is used, intermittent ADT may be offered instead of continuous ADT.

An open-label trial by Crook et al in 1,386 patients with a PSA rise to > 3 ng/mL more than 1 year following primary or salvage radiation for localized prostate cancer found that at a median follow-up of 6.9 years, there was no difference in survival between intermittent versus continuous ADT (median 8.8 versus 9.1 years, (HR= 1.02; 95% CI, 0.86 to 1.21). There was also no difference in prostate cancer–specific survival (hazard ratio [HR]=1.18; 95%CI 0.90 to 1.55). Intermittent therapy was associated with better scores for hot flashes (P < 0.001), desire for sexual activity (P < 0.001), and urinary symptoms (P=0.006) compared with continuous therapy.[157]

In this study, intermittent therapy consisted of an 8-month treatment cycle. At the end of the 8-month cycle, treatment was discontinued if there was no evidence of clinical disease progression, the PSA level was < 4 ng/mL and did not increase more than 1 ng/mL. The PSA threshold to reinitiate the next cycle of ADT was 10 ng/mL.[157]

Androgen deprivation is considered the primary approach to the treatment of metastatic prostate cancer. However, androgen deprivation therapy (ADT) has been found to be palliative, not curative.[158] Prior to the development of newer therapies, overall survival for patients with metastatic prostate cancer ranged from 24-36 months. In recent years, however, several new therapies have been approved that prolong survival in men whose disease progresses on ADT. In patients with metastatic hormone-sensitive prostate cancer (mHSPC), castrate levels of testosterone (< 50 ng/dL) may be achieved with LHRH analogues, gonadotropin-releasing hormone (GnRH) antagonists, or orchiectomy. These treatments are considered equivalent in cancer control, although they have never been compared in large randomized controlled trials.

Combined androgen blockade

Combined androgen blockade (CAB) recognizes the 5-10% contribution of adrenal androgens to total body testosterone. Considerable controversy has surrounded this approach despite a total of 27 prospective randomized studies. Most of these studies showed no benefit from CAB, but 3 showed significant 3-6 month increases in survival with the use of an LHRH agonist combined with an antiandrogen.[159]  

Current AUA guidlines note that first-generation antiandrogens (bicalutamide, flutamide, nilutamide) should not be offered in combination with LHRH agonists in patients with mHSPC, except to block testosterone flare. The addition of an antiandrogen to LHRH agonist treatment can minimize the risk of the flare response (ie, temporary rise in testosterone levels) that can occur with LHRH treatment. There is limited evidence of the clinical utility of this approach. As opposed to LHRH agonists alone, GnRH antagonists and orchiectomy as monotherapy have a rapid onset of action and avoid a testosterone flare, making them useful in situations needing rapid hormone ablation such as impending spinal cord compression.

Early versus delayed treatment

In the years following the introduction by Huggins and Hodges of hormone therapy for prostate cancer,[160]  early institution of such treatment was recommended, based on comparison with historical controls. Later, the Veterans Administration Cooperative Urology Research Group (VACURG) studies resulted in the recommendation to defer hormone therapy until symptomatic progression occurred; this was thought to avoid the promotion of early androgen resistance in prostate tumors.[161]

Subsequently, the controversy of the appropriate timing of ADT was renewed because of the advent of an LHRH antagonist and LHRH agonists. Laboratory studies demonstrated that early hormone therapy does not confer early resistance. Moreover, clinical trials found that it provided significantly longer survival with fewer complications (eg, pathologic fractures, spinal cord compression, ureteral obstruction) than did deferred treatment.[162, 163]

Intermittent androgen suppression

Intermittent androgen suppression has been assessed in prospective, randomized studies as a possible means of minimizing the side effects of ADT. As previously discussed, Crook et al found that intermittent androgen suppression was noninferior to continuous therapy with respect to overall survival.[157]  In a Spanish study, a greater number of cancer deaths in the intermittent treatment arm was balanced by a greater number of cardiovascular deaths in the continuous treatment arm.[164]

In both studies, intermittent therapy resulted in better quality of life. Indeed, this benefit might be more pronounced than was seen in these studies, because the testosterone level does not return to baseline in about one third of men on intermittent therapy.

However, survival in men with metastatic hormone-sensitive prostate cancer may be shorter when ADT is given intermittently rather than continuously, according to a large study of 770 men treated with intermittent therapy and 765 men treated with continuous therapy, who were followed for a median of almost 10 years (average survival, 5.1 vs 5.8 years, respectively—a 10% higher relative risk for death). Intermittent therapy was associated with better erectile function and mental health at month 3 but not thereafter.[165]

National Comprehensive Cancer Network (NCCN) guidelines advise that for men with nonmetastatic prostate cancer, intermittent ADT is considered as safe as continuous ADT. The NCCN recommends that intermittent ADT be considered in men with metastatic disease.[58]

Addition of androgen pathway–directed therapy or chemotherapy

mHSPC remains incurable. While ADT, with or without nonsteroidal antiandrogens, has been the backbone of mHSPC treatment for many decades, ADT alone is no longer considered sufficient treatment for mHSPC. In the past 5 years, multiple studies have shown that additional therapy with either docetaxel or androgen pathway–directed therapy (abiraterone acetate plus prednisone, apalutamide, enzalutamide) significantly extends overall and progression-free survival. 

Androgen suppression plus abiraterone acetate with prednisone

In February 2018, the FDA approved abiraterone acetate (Zytiga) in combination with prednisone for patients with metastatic high-risk castration-sensitive prostate cancer, based on findings from the LATITUDE trial. In this double-blind, placebo-controlled, phase III trial in 1199 men with metastatic, castration-sensitive prostate cancer, the addition of abiraterone acetate and prednisone to ADT significantly increased overall survival and radiographic progression-free survival. Median overall survival was significantly longer in the abiraterone group versus the placebo group (not reached vs. 34.7 months). Median radiographic progression-free survival was 33 months in the abiraterone group versus 14.8 months in the placebo group.[166]

In addition, the abiraterone group had significantly better outcomes in all secondary end points, including the time until pain progression, next subsequent therapy for prostate cancer, initiation of chemotherapy, and prostate-specific antigen progression (P< 0.001 for all), along with next symptomatic skeletal events.[166]

In the STAMPEDE trial, the addition of abiraterone acetate and prednisolone at the initiation of primary ADT was associated with a 71% relative improvement in the time to treatment failure, which translated into a 37% difference in overall survival. Three-year survival rates were 83% with combination therapy versus 76% with ADT alone, and treatment failure–free survival rates at 3 years were 75% vs 45%, respectively. STAMPEDE included 1917 men with newly diagnosed, locally advanced or metastatic prostate cancer, or relapsed disease with high-risk features.[167]

Androgen suppression plus enzalutamide

In the open-label, randomized, phase III ENZAMET trial,1125 men were randomized to receive testosterone suppression plus either open-label enzalutamide (160 mg daily) or standard care with a nonsteroidal antiandrogen (bicalutamide, nilutamide, or flutamide). The primary end point was overall survival (OS). With a median follow up of 34 months, there were 102 deaths in the enzalutamide group versus 143 deaths in the standard care group (HR= 0.67; 95%CI 0.52 to 0.86; P= 0.002). Kaplan-Meier estimates of OS at 3 years were 80% in the enzalutamide group and 72% in the standard care group.[168]

In the double-blind, phase III ARCHES trial, conducted in 1150 men with mHSPC, the risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT compared with placebo plus ADT (hazard ratio, 0.39; 95% CI, 0.30 to 0.50; P < 0.001; median not reached vs 19.0 months). The benefit of enzalutamide extended to patients with low-volume disease and/or prior docetaxel therapy.[169]

Both enzalutamide and apalutamide do present a small risk of seizures, so patients with a seizure disorder should instead choose a regimen such as abiraterone acetate plus prednisone or docetaxel.

Androgen suppression plus docetaxel

Since 2015, two clinical trials demonstrated the benefits of adding docetaxel chemotherapy to ADT for mHSPC patients.The phase III E3805/ CHAARTED trial (ChemoHormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) randomized 790 patients with mHSPC to six cycles of docetaxel plus ADT or ADT alone. Intended to enroll only patients with high disease burden, defined by the presence of visceral metastases (a bone metastasis burden beyond the axial skeleton) or a high number of lesions, the trial was later amended to enroll patients with low disease burden as well. At a median follow-up of 53.7 months, the median OS was 57.6 months for the chemohormonal therapy arm versus 47.2 months for ADT alone (HR=0.72; 95%CI 0.59 to 0.89; P= .0018). This benefit was most apparent and significant among patients with high disease burden and was maintained in these patients at 54-month follow up. However, patients with low disease burden had no survival benefit after docetaxel addition[170] . 

Similar survival outcomes were seen with the docetaxel and docetaxel plus zoledronic acid arms in the large multicenter multi-arm MRC STAMPEDE (Medical Research Council Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) trial, which enrolled 2,962 patients with metastatic, nodal, or high- risk localized disease. At a median follow up of 43 months, median OS was 71 months for ADT alone compared with 81 months for standard of care plus zoledronic acid plus docetaxel (HR=0.78; 95%CI 0.66 to 0.93; P=0.006).[171]

Like many chemotherapy agents, docetaxel has a significant toxicity profile that needs consideration. In the STAMPEDE trial, the most frequently reported adverse events in the docetaxel group included febrile neutropenia (15%), general disorder (including lethargy, fever, asthenia—7%), and gastrointestinal disorder (including diarrhea, abdominal pain, constipation, vomiting—8%).[171]  

Relugolix

Relugolix is the first oral androgen deprivation therapy approved by the FDA for advanced prostate cancer. It is a gonadotrophin-releasing hormone (GnRH) receptor antagonist that decreases gonadotropin release (ie, luteinizing hormone, follicle stimulating hormone), thereby decreasing the downstream production of testosterone by the testes in men. 

Approval of relugolix was based on the HERO clinical trial (n = 622). In HERO, sustained testosterone suppression at 48 weeks was achieved in 96.7% of relugolix-treated patients compared with 88.8% with leuprolide. Risk of major adverse cardiovascular events was 54% lower with oral relugolix compared with leuprolide injections.[172]

Eventually, almost all metastatic prostate cancers become resistant to androgen ablation. In patients with castrate serum testosterone levels (less than 50 ng/dL), castrate-resistant prostate cancer is defined as 2-3 consecutive rises in PSA levels obtained at intervals of greater than 2 weeks and/or documented disease progression based on findings from computed tomography (CT) scan and/or bone scan, bone pain, or obstructive voiding symptoms.

Rarely, a rise in PSA may reflect failure of LHRH treatment to control testosterone secretion, rather than the development of castrate-resistant disease. Therefore, the testosterone level should be measured when the PSA rises. If the serum testosterone level exceeds castrate levels, changing the antiandrogen therapy may drop the PSA and delay the need for other therapy.

Prior to the development of the most recent therapies, the median time to symptomatic progression after a rise in the PSA level of more than 4 ng/mL was approximately 6-8 months, with a median time to death of 12-18 months. Since then, however, the latter figure has increased.

Little information is available about the impact of maintaining hormone suppression when androgen-independent progression occurs, but the general consensus among specialists is that the treatment should continue. The reasoning is that tumor cells are still hormone sensitive and may grow faster if the testosterone is permitted to rise.

Non-chemotherapy options that provide palliation and improve quality of life include the following:

• Megestrol
• Nonsteroidal antiandrogens
• Corticosteroids
• Ketoconazole
• Radiation therapy
• Bisphosphonates
• Suramin
• Estrogen

None of those have been shown to improve survival, although few of them have been properly assessed for that endpoint.

A subset of men who have developed castration-resistant prostate cancer will have a rising PSA, but no visible metastatic disease on conventional imaging. In these patients a PSA doubling time of ≤10 months is associated with a high risk of developing metastatic disease or dying from prostate cancer.[173] Along with serial PSA measurements at 3-6 month intervals, patients should undergo convential imaging every 6-12 months to assess for metastatic disease.

In patients with castration-resistant prostate cancer treated with enzalutamide prior to chemotherapy in the PREVAIL trial, radiographic progression occurred in 24.5% of patients without PSA progression, suggesting that routine imaging can identify a significant portion of patients who would otherwise not be identified.[174] The AUA/ASTRO/SUO guidelines stratify treatment decisions based on risk for developing metastatic disease. Patients with a PSA doubling time ≤10 months are deemed high risk and should be offered apalutamide, darolutamide, or enzalutamide with continued ADT.

Docetaxel

Therapeutic options for patients with castration-resistant prostate cancer have changed significantly, beginning with the approval of docetaxel in 2004. Two randomized studies have shown that this drug improves survival.[175]  In the Southwestern Oncology group trial SWOG 99-16, median survival was 2 months longer with docetaxel plus estramustine than with mitoxantrone plus prednisone (17.5 vs 15.6 months).[176]  Gastrointestinal and cardiovascular side effects were more common in the group receiving docetaxel, however.

In the TAX 327 trial, median survival was 16.5 months in patients given mitoxantrone, 17.4 months in those given weekly docetaxel, and 18.9 months in those given docetaxel every 3 weeks. All 3 groups also received prednisone.[177]  A follow-up analysis confirmed these findings, with median survival of 16.3 months in the mitoxantrone arm, 17.8 months in the weekly docetaxel arm, and 19.2 months in the every-3-weeks arm.[178]

Other therapies now approved for androgen-independent prostate cancer include the following:

• Sipuleucel-T (Provenge)
• Abiraterone acetate (Zytiga, Yonsa)
• Enzalutamide (Xtandi)
• Cabazitaxel (Jevtana)
• Mitoxantrone
• Apalutamide (Erleada)
• Rucaparib (Rubraca)
• Olaparib (Lynparza) 
• Niraparib/abiraterone (Akeega)

As previously mentioned, early results from a randomized, controlled trial indicated that in patients with hormone-sensitive metastatic prostate cancer, those who are treated with docetaxel at the beginning of standard hormone therapy with ADT have improved survival compared with those treated with hormone therapy alone.[170]

In the phase III COMET-1 study, the tyrosine kinase inhibitor cabozantinib did not significantly improve overall survival compared with prednisone in heavily treated patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressive disease after docetaxel and abiraterone and/or enzalutamide. Cabozantinib had some activity in improving bone scan response, which was the secondary trial end point. However, grade 3 to 4 adverse events and discontinuations because of adverse events were higher with cabozantinib than with prednisone.[179]  

Lutetium Lu 177 vipivotide tetraxetan

Lutetium Lu 177 vipivotide tetraxetan is indicated for the treatment of men with prostate-specific membrane antigen (PSMA)-positive, metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. It is a radioligand therapeutic agent. The active moiety is the radionuclide lutetium-177, which is linked to a moiety that binds to PSMA, a transmembrane protein expressed in prostate cancer, including mCRPC. Upon binding to PSMA-expressing cells, the lutetium-177 delivers beta-minus radiation to the cells, as well as to surrounding cells, inducing DNA damage that can lead to cell death. 

Approval was based on the phase 3 VISION trial. Compared with patients receiving standard care (n = 196), patients who received lutetium Lu 177 vipivotide tetraxetan plus standard care (n = 581) had significantly prolonged imaging-based progression-free survival (median, 8.7 vs 3.4 months; P < 0.001) and overall survival (15.3 vs 11.3 months; P < 0.001).[180]   

Sipuleucel-T

Sipuleucel-T is a therapeutic vaccine that was approved by the FDA in 2010 for asymptomatic or minimally symptomatic prostate cancer with metastases resistant to standard hormone treatment. The National Comprehensive Cancer Network supports its use in men with good performance status, a life expectancy of more than 6 months, no hepatic metastases, and no or minimal symptoms.[58]

Sipuleucel-T must be prepared individually for each patient. To create Sipuleucel-T, peripheral blood mononuclear cells, including antigen-presenting cells (APCs), are extracted from the patient using leukapheresis and are incubated with prostatic acid phosphatase, an antigen expressed in prostate cancer tissue. The product, which now contains activated APCs, is then reinfused into the patient.

An updated report of a randomized, placebo-controlled study by Kantoff et al showed median survival of 25.8 months versus 21.7 months and a survival probability at 36 months of 32.1% versus 23% in the sipuleucel-T and placebo arms, respectively.[181]  The study included a crossover design, which means the true benefit is likely to be higher. A subset analysis found that survival in men with a PSA level below 22 ng/mL was 13 months longer in the sipuleucel-T group than in the control group.

One aspect of sipuleucel-T treatment that has made its acceptance difficult is that it does not appear to produce either a PSA or an objective disease response; the benefit is limited to overall survival. Consequently, other therapies can be instituted after the sipuleucel-T treatment regimen has been completed.

Adverse events that have been reported more often with sipuleucel-T than with placebo include chills, pyrexia, headache, influenzalike illness, myalgia, hypertension, hyperhidrosis, and groin pain. The majority of these were low grade and resolved within 1-2 days.[181]

Abiraterone acetate

Abiraterone acetate (Zytiga), an inhibitor of androgen biosynthesis, was approved by the FDA in 2011 for use in combination with prednisone for the treatment of patients with mCRPC who have received prior chemotherapy containing docetaxel. Abiraterone blocks CYP17A1, an enzyme that is important in the synthesis of testosterone by the adrenal gland and by prostate cancer cells. This results in blocking all testosterone production.

Approval of abiraterone was based on the results of a randomized, controlled trial that showed improved survival in 1195 patients with castrate-resistant prostate cancer who were treated with this combination.[182]  More recently, a large, international, randomized trial found a median overall survival period of 15.8 months in men receiving abiraterone, compared with 11.2 months in the placebo group.[183]

Men receiving abiraterone also had a significantly longer time to PSA progression, a longer progression-free survival, and a higher PSA response. The adverse  effects occurring more frequently in the treated group were related to decreased mineralocorticoid effects and included hypertension, fluid retention, and hypokalemia.[183]

In 2012 the FDA expanded the approved use of abiraterone to treatment of men with late-stage (metastatic), castrate-resistant prostate cancer prior to receiving chemotherapy. The expanded indication was based on a study in which patients who received abiraterone had a median overall survival period of 35.3 months, compared with 30.1 months for patients receiving placebo, and had better radiographic progression–free survival.[184]

An ultramicronized abiraterone tablet (Yonsa) was approved in 2018 for mCRPC in combination with methylprednisolone. The ultramicronized formulation may be administered with or without food, whereas the original tablet formulation (Zytiga) must be administered 1 hour before or 2 hours after meals. 

Niraparib/abiraterone 

Niraparib/abiraterone (Akeega) is a fixed-dose combination of a poly (ADP-ribose) polymerase (PARP) inhibitor (niraparib) and an antiandrogen (abiraterone) for deleterious or suspected deleterious BRCA-mutated mCRPC. It is given with prednisone.

Approval was based on the phase 3 MAGNITUDE trial, a randomized, placebo-controlled trial with 423 patients, 225 (53%) of whom had BRCA gene mutations. In the subgroup with a BRCA mutation, radiographic progression-free survival was a median of 19.5 months vs 10.9 months (P = 0.0007). The subgroup with non-BRCA homologous recombination repair mutations did not demonstrate a significant improvement in radiographic progression-free survival.[185]  

Enzalutamide

Enzalutamide acts by inhibiting the binding of androgens to the androgen receptor and inhibits translocation of the androgen receptor into the nucleus. A stage III trial in 1199 men with castration-resistant prostate cancer after chemotherapy showed median overall survival of 18.4 months in the enzalutamide group versus 13.6 months in the placebo group. Patients receiving the active drug also had a higher PSA and quality-of-life response and a longer time to PSA progression, longer radiographic progression-free survival, and longer time to first skeletally-related event. Fatigue, diarrhea, and hot flashes were more common in the enzalutamide group. Seizures were reported in five patients (0.6%) receiving enzalutamide.[186]

Enzalutamide proved superior to bicalutamide in the TERRAIN clinical trial, a double-blind, randomized phase II study in 375 asymptomatic or minimally symptomatic men with prostate cancer progression on ADT. Median progression-free survival was significantly longer with enzalutamide than bicalutamide (15.7 versus 5.8 months; hazard ratio [HR], 0.44; P< 0.0001). However, 68% of patients in the enzalutamide group and 88% of those in the bicalutamide group discontinued their assigned treatment before study end, mainly due to progressive disease.[187]

In  2018, the FDA approved an expanded indication for enzalutamide in CRPC to include patients with nonmetastatic castration-resistant prostate cancer. Approval was based on the PROSPER trial. In the 1401-patient trial, enzalutamide decreased the risk for distant metastasis or death by 71% (HR, 0.29; 95% confidence interval [CI], 0.24 - 0.35; P < 0.0001), with a median metastasis-free survival of 36.6 compared with 14.7 months in the placebo group (an improvement of 21.9 months).[188]

In 2019, FDA approval was further expanded to include metastatic castration-sensitive disease. Approval was based on the ARCHES trial, in which median radiographic progression-free survival was not reached (NR) in the enzalutamide arm, compared with 19.4 months in the placebo arm.[189]

Cabazitaxel

Cabazitaxel is another taxane that acts as a microtubular inhibitor. In a study of 755 men with mCRPC that had progressed despite docetaxel treatment, the median overall survival period was 15.1 months in patients receiving cabazitaxel, versus 12.7 months in those receiving mitoxantrone. Median progression-free survival was also longer with cabazitaxel. Both groups also received prednisone. The most common clinically significant grade 3 or higher adverse events with cabazitaxel were neutropenia and diarrhea. Febrile neutropenia was also more common with cabazitaxel.[190]

Apalutamide

Apalutamide, an androgen receptor inhibitor, was approved by the FDA in February 2018 for treatment of nonmetastatic castration-resistant prostate cancer. The FDA based its approval on safety and efficacy data from the phase 3 SPARTAN (Selective Prostate Androgen Receptor Targeting With ARN-509) trial, in which median metastasis-free survival (the primary endpoint), was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (P < 0.001). That translated into a 72% reduction in the relative risk for metastasis or death with apalutamide (HR, 0.28; 95% CI, 0.23 - 0.35).[191] .

In the SPARTAN trial, 806 men were randomized to receive treatment with apalutamide (240 mg per day) and 401 to receive placebo; all participants also received hormone therapy, either gonadotropin-releasing hormone analogue therapy or surgical castration. All the participants had undergone previous definitive treatment, either surgery or radiotherapy, for prostate cancer, but their PSA scores had doubled within 10 months or less following treatment, despite hormone therapy.[191]

Darolutamide

Similar to apalutamide, darolutamide was approved for patients with nonmetastatic castration-resistant prostate cancer.

Approval was based on the phase IIARAMIS trial which evaluated metastasis-free survival, with the presence of metastasis determined by independent central review of radiographic imaging every 16 weeks. Patients (n=1509) received either darolutamide or placebo while continuing androgen-deprivation therapy. In the planned primary analysis, the median metastasis-free survival was 40.4 months with darolutamide, as compared with 18.4 months with placebo. Darolutamide was also associated with benefits to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event. In men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo.[192]

Rucaparib

Rucaparib, a PARP inhibitor, was approved by the FDA in 2020 for mCRPC associated with a deleterious BRCA mutation (germline and/or somatic) in patients who have been treated with androgen receptor–directed therapy and taxane-based chemotherapy. Accelerated approval was based on findings from the multicenter, single-arm TRITON2 clinical trial, in which the final results included an objective response rate (ORR) of 46% in the BRCA mutation subgroup; patients with other DNA damage repair gene alterations also experience clinical benefit. The confirmatory TRITON3 trial is ongoing.[193]  

Olaparib 

Another PARP inhibitor, olaparib, was approved in 2020 for deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated mCRPC that progressed after treatment with enzalutamide or abiraterone. Approval was supported by the PROfound phase III clinical trial, in which olaparib significantly reduced risk of disease progression or death by 66% (HR 0.34, P < 0.0001) compared with abiraterone or enzalutamide.[194, 195]

Final analysis of PROfound results confirmed the benefit of olaparib in this setting. The median duration of overall survival in patients with at least one alteration in BRCA1, BRCA2, or ATM (n=245) was 19.1 months with olaparib and 14.7 months with control therapy (HR for death, 0.69; 95% confidence interval [CI], 0.50 to 0.97; P=0.02). In patients with at least one alteration in any of the other 12 prespecified genes (n=142), the median duration of overall survival was 14.1 months with olaparib and 11.5 months with control therapy. Substantial crossover from the control group to olaparib (86 of 131 patients) occurred; adjusted for crossover, the HR for death was 0.55 (95% CI, 0.29 to 1.06) in the overall population.[196]

Drug sequencing for androgen-independent prostate cancer

The availability of the above new agents presents a challenge for physicians and patients, who must decide on the best sequence and timing for each of them. So far, no studies have been done to determine the best approach. Studies in progress are likely to result in some change to the sequencing of these drugs.

Excluding cost considerations, men with asymptomatic or minimally symptomatic progressive disease can start with immunotherapy using sipuleucel-T; since no objective responses are expected, patients can then be given abiraterone acetate. Men with mCRPC can be treated with enzalutamide prior to receiving chemotherapy.[197]

Without formal studies to guide recommendations, either enzalutamide or abiraterone acetate may be used first before chemotherapy. Enzalutamide does not require prednisone and for that reason it may be more suitable. However, results of a retrospective study slightly favored the abiraterone-to-enzalutamide sequence in men with mCRPC, in terms of progression-free but not overall survival.[198] Hopefully, studies will be done to determine whether men are better off receiving either enzalutamide or abiraterone first or second. Men showing progression on those drugs should then be offered docetaxel followed by cabazitaxel.

For full discussion, see Metastatic and Advanced Prostate Cancer.

In a study of men with newly diagnosed metastatic prostate cancer, treatment with prostate radiation and ADT led to substantially longer survival compared with treatment with ADT alone. In the study, which included 6,382 men, combination therapy yield superior median survival (55 v 37 months) and 5-year overall survival (49% versus 33%) (P < 0.001).[199]

In patients with metastatic prostate cancer, radiation is also applied for palliative purposes. It is used in patients with castration-resistant prostate cancer (CRPC) with painful bone metastases, in patients at risk for fracture, and in patients with impending spinal cord compression.

A meta-analysis of the use of radioisotopes to relieve pain from bone metastases found that over 1-6 months, pain may be reduced without an increase in analgesic use; however, severe effects such as leukocytopenia and thrombocytopenia frequently surface.[200]

Radium-223 dichloride (Xofigo), formerly alpharadin, is an alpha particle–emitting radioactive therapeutic agent that was approved by the FDA in 2013 for use in men with CRPC, symptomatic bone metastases, and no known visceral metastatic disease.[201] Approval was based on the multinational ALSYMPCA trial (ALpharadin in SYMptomatic Prostate CAncer), which is the first randomized phase III trial to demonstrate improved survival of CRPC with a bone-seeking radioisotope.[202]

The ALSYMPCA trial was conducted in 19 countries and included 921 patients with prostate cancer that had progressed with symptomatic bone metastases and no known visceral metastases. The trial was halted early after a planned interim analysis found a survival benefit in favor of radium-223. Updated analysis has demonstrated a 3.6-month survival advantage compared with placebo (14.9 vs 11.3 months, respectively).

Physicians have suggested that the benefits seen from radiation to the prostate point to the benefits of local therapy, raising the question of whether radical prostatectomy might have the same results. Trials are ongoing, and at present the use of surgery should be considered investigational and conducted only within the context of a trial. However, transurethral resection is sometimes needed in men who develop obstruction secondary to local tumor growth. Bilateral orchiectomy can be used to produce androgen deprivation in patients with widely advanced and metastatic prostate cancer.

Since the introduction of LHRH agonist and antagonist therapies, surgical intervention has been practiced less often. An indication for immediate bilateral orchiectomy is spinal cord compression, because it avoids the potential flare response that can occur during the first 3 weeks of treatment with an LHRH agonist.

Surgical and medical castration lead to a number of adverse effects, including the following, that can have a significant impact on a man’s quality of life:

• Anemia
• Breast enlargement
• Cognitive impairment
• Decreased libido
• Decreased muscle mass
• Erectile dysfunction
• Fatigue
• Fractures
• Gastrointestinal tract disturbances
• Gynecomastia
• Hot flashes
• Osteoporosis
• Metabolic syndrome
• Pulmonary edema
• Psychological changes
• Weight gain

In addition, in men with prostate cancer receiving ADT, lean body mass decreases significantly after 12-36 months of treatment.[203]

Uncertainty remains about the impact of androgen ablation on cardiovascular morbidity and mortality. However, the combination of weight gain and anemia in men with asymptomatic cardiovascular disease could adversely affect survival in some cases.

The FDA has advised that manufacturers of gonadotropin-releasing hormone (GnRH) agonists, which are approved for palliative treatment of advanced prostate cancer, must add safety warnings about the increased risk of diabetes and certain cardiovascular diseases (eg, myocardial infarction, sudden cardiac death, stroke) in men receiving these medications. The FDA notes that although the risk for these complications appears to be low, physicians should evaluate patients for risk factors for these diseases before prescribing these agents.[204]

Patients receiving GnRH agonists should be actively monitored for diabetes and cardiovascular disease and treated when possible. Periodic measurement of fasting glucose, cholesterol, triglycerides, and blood counts should be performed. In addition, the package inserts for all LHRH medications recommend periodically measuring serum testosterone, because levels above 50 ng/dL do occur and may adversely affect long-term survival.

Long-term androgen blockade for prostate cancer may also increase a patient’s risk for colorectal cancer. An observational study by Gillessen et al of men with prostate cancer—identified through the Surveillance, Epidemiology, and End Results (SEER) database of the National Cancer Institute—found that after adjustment for confounding variables such as age, socioeconomic status, and the use of radiation therapy, the rate of colorectal cancer was 30-40% higher in men treated with androgen blockade than in those who were not.[205]

In a study of the bone density differences between African-American and Caucasian men who were receiving ADT for prostate cancer, Morgans et al found that African-American men had a greater hip bone mineral density and tended to have fewer prevalent vertebral fractures than Caucasian men. However, African-American men experience a decrease in bone mineral density similar to that of Caucasian men despite a lower baseline risk for osteoporosis and fracture.[206]

Acute kidney injury

In a case-control analysis of more than 10,000 men with prostate cancer, ADT was significantly associated with an increased risk for acute kidney injury (AKI). Current use of any ADT more than doubled the risk for AKI, compared with such risk in patients who had never undergone ADT. The risk was especially heightened for combination therapies and estrogens.ref197}

In the study, researchers reviewed data from the UK Clinical Practice Research Datalink on 10,250 men newly diagnosed between 1997 and 2008 with nonmetastatic prostate cancer. The overall incidence rate of AKI in the study population was 5.5 per 1000 person-years, compared with 1.8 per 1000 person-years in the general population. The odds of developing AKI with current ADT use, compared with that for persons who never used the therapy, were highest during the first year of treatment. The odds decreased with longer durations but remained statistically significant for up to 3 years, as well as for 3 years and beyond.

Bone protection in patients receiving androgen blockade

Two drugs, the bisphosphonate zoledronic acid and the RANKL inhibitor denosumab, have been approved to treat osteoporosis secondary to androgen deprivation. Zoledronic acid is administered as an intravenous infusion. Denosumab is administered subcutaneously. These drugs are given along with supplemental vitamin D and calcium. Patients should be monitored regularly for hypocalcemia. Both agents are associated with a low incidence of osteonecrosis of the jaw. Both drugs delay the risk of skeletally-related events by relieving bone pain, preventing fractures, decreasing the need for surgery and radiation to the bones, and lowering the risk of spinal cord compression.

A double-blind, placebo-controlled, multicenter study in men with primary or hypogonadism-associated osteoporosis found that over a 14-month period, treatment with zoledronic acid reduced the risk of vertebral fractures by 67%. New morphometric vertebral fracture occurred in 1.6% of men taking zoledronic acid and in 4.9% taking placebo. Patients receiving zoledronic acid had significantly higher bone mineral density and lower bone-turnover markers. However, the rate of myocardial infarction was higher in the treatment group (1.5% vs 0.3%).[207]

A double-blind, placebo-controlled, multicenter study in men undergoing ADT for nonmetastatic hormone-sensitive prostate cancer found that patients receiving denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5% vs 3.9% with placebo). Patients receiving denosumab also had significant increases in bone mineral density in the total hip, femoral neck, and distal third of the radius.[208]

In a double-blind, randomized, comparative trial performed in men with hormone-refractory disease, the time to first skeletally-related event was significantly longer with denosumab than with zoledronic acid (20.7 mo vs 17.1 mo, respectively). Hypocalcemia was more common in the denosumab group than in the zoledronic acid group (13% vs 6%, respectively). Osteonecrosis of the jaw occurred infrequently in both groups (2% vs 1%, respectively).[209]

Despite the availability of new therapies, most men with metastatic prostate cancer will eventually experience progression of disease. For these patients, palliative care is important, and early consultation with hospice may provide for a smoother transition.

The combination of mitoxantrone and prednisone is an approved treatment for symptoms of metastatic disease but does not improve survival. Bone pain due to metastatic disease requires narcotics, awareness of fractures, and, possibly, palliative radiation.

Urinary retention

Urinary retention may occur secondary to urethral strictures, bladder outlet obstruction, or a blood clot. Cystoscopy or a retrograde urethrogram should be performed to identify the cause. Strictures can be either dilated or treated endoscopically. Outlet obstruction can be managed by transurethral resection. Ureteral obstruction due to lymphadenopathy may be treated with a ureteral stent or percutaneous nephrostomy.

Long-term urinary retention or malignant urinary obstruction due to untreated prostate cancer can lead to chronic renal failure, which manifests as uremic symptoms and an elevated serum creatinine level. Patients on watchful-waiting protocols are at risk for this if they are not closely monitored.

Hematuria

This may manifest as a small element of prostate venous bleeding or it may lead to large clots. Hematuria is more common in patients who have undergone radiation therapy.

Vigorously irrigate the bladder with copious amounts of fluid to remove all evidence of clots. Sterile water is best because it helps to lyse the clot. Use care, however, because absorption of the fluid may occur in situations in which prostatic venous channels are open.

Prostatic bleeding may be treated first with transurethral resection and cauterization. If that is unsuccessful, medications can be attempted. Androgen ablation can be tried if not already in use. Otherwise, aminocaproic acid and megestrol may help some men.

Urinary incontinence

Incontinence from bladder spasm or irritation is common immediately after various prostate treatments. While patients have urinary catheters in place, oxybutynin, tolterodine, belladonna and opium suppositories, and phenazopyridine (Pyridium) may be used to decrease symptoms.

Patients with incontinence secondary to radical prostatectomy or radiation may benefit from placement of a urinary sphincter. In rare cases, urinary diversion may be considered.

Rectal complications

Although uncommon, a urethrorectal fistula may occur after surgery or radiation. Manage the fistula with urinary and fecal diversion using appropriate treatment options.

Rectal bleeding and tenesmus are observed in patients treated with radiation. Steroid enemas and in some cases focal cauterization can alleviate the problem.

Fractures

Patients receiving ADT and those with bone metastasis should receive preventive therapy for fractures. Patients diagnosed with impending paralysis due to spinal cord compression or patients with pathologic fractures should be immediately hospitalized and treated emergently with spinal cord decompression, steroids, and orchiectomy or an LHRH antagonist.

Consultation with a radiation oncologist should be obtained for palliative radiation therapy for bone metastases, for locally extensive tumors, and, on an emergent basis, for spinal cord compression. Consultations with a neurosurgeon for spinal cord compression and an orthopedic surgeon for pathologic fractures are appropriate. Consultation with a medical oncologist may also be considered for chemotherapy when a patient with metastatic disease begins to show disease progression on hormone therapy.

Follow-up is not standardized; however, practitioners use general guidelines that are derived mainly from publications report outcomes on various methods of treatment. In addition, the NCCN, an alliance of 19 cancer centers, publishes follow-up guidelines for the various treatment modalities.

Followup by primary care physicians

The American Cancer Society has released evidence- and expert-based guidelines for the management of prostate cancer survivors by primary care physicians (PCPs), a response to the fact that as the number of men surviving prostate cancer has increased, reliance on PCPs for their care has grown as well. The guidelines address promotion of healthy lifestyles, surveillance for disease recurrence, screening for second primary cancers, and evaluation and management of adverse physical and psychosocial effects caused by the disease and its treatment. Recommendations include the following[210] :

• Oncologists should provide PCPs with treatment summaries, as well as recommendations for posttreatment follow-up

• Serum prostate-specific antigen (PSA) levels should be assessed every 6-12 months during the first five years of follow-up and then should be rechecked annually

• Patients should undergo an annual digital rectal examination (DRE)

• Patients undergoing androgen deprivation therapy (ADT) should be periodically monitored for treatment-associated anemia, but routine anemia therapy for asymptomatic patients receiving ADT is not necessary

• Owing to the risks for metabolic syndrome, obesity, and bone loss and fracture associated with ADT, baseline assessments of calcium and vitamin D levels and bone-density scanning should be performed in men undergoing this treatment, and patients should receive dietary counseling, supplements (if needed), and other therapeutic interventions

• Physicians should, during routine care, inquire about the patient’s ability to function sexually; treatment options for sexual dysfunction include phosphodiesterase type 5 (PDE-5) inhibitors

• Patients may suffer from depression and anxiety as a result of sexual dysfunction or bowel and urinary problems, necessitating a counseling referral

Watchful waiting

Patients on watchful waiting are treated only if they develop symptomatic progression of their disease. No curative therapy is administered. A DRE and PSA test are performed periodically to determine when a bone scan and CT scan might be warranted and if hormone therapy is necessary. The results can also be used to determine when bone-directed treatments are appropriate to avoid serious morbidity.

Radical prostatectomy

PSA testing is performed every 3-4 months for the first 2 years after radical prostatectomy, every 6 months for the third and fourth years, and yearly thereafter. DRE has not been shown to offer any added advantage in the detection of local recurrence beyond PSA testing, but most physicians continue to do it.

Radiation therapy

In patients who have been treated with EBRT, DRE and PSA are performed every 3-6 months for 5 years and then annually thereafter. Evidence is lacking that periodic prostate biopsies following radiation therapy are beneficial.

After brachytherapy, PSA testing is performed every 3-6 months for 2 years and then annually thereafter. Here too, no studies have proved that there is a benefit to performing a prostate biopsy unless the PSA begins to rise and the patient is considered a candidate for salvage prostatectomy.

Biochemical recurrence

A biochemical recurrence (ie, measurable PSA) is considered to have occurred following radical prostatectomy if the PSA level is greater than 0.2 ng/mL or is above the minimal detectable level of the assay. For example, using ultrasensitive PSA assays, a cutoff of 0.01 ng/mL or 0.05 ng/mL can be used.

The definition of a biochemical recurrence following radiation is more complex, and significant debate still surrounds this topic. Options for determining biochemical recurrence include the following:

• 2-3 consecutive rises in the PSA level following a nadir (ASTRO definition)
• Rise of 2 ng/mL or more above the nadir PSA level (Phoenix definition) ^[211]
• An absolute cutoff of 0.2, 0.5, or 1 ng/mL

Biochemical recurrence should prompt closer follow-up and consideration of alternative therapies. When the PSA level begins doubling every 10-12 months or reaches some minimal level ranging from 10-20 ng/mL, imaging studies may be performed, as follows:

• Bone scan
• CT scan of the abdomen and pelvis
• Potentially, transrectal ultrasonography–guided rebiopsy of the prostate or prostatic fossa in patients treated with radical prostatectomy
• ProstaScint scan

The ProstaScint scan is most commonly used in patients who have biochemical recurrence without evidence of metastases and who may be candidates for EBRT. The ProstaScint scan is especially useful for identifying localized recurrence and lymphatic spread.

Other imaging studies include positron emission tomography (PET) scanning and magnetic resonance imaging (MRI) spectroscopy. PET scanning uses cancer metabolism to illuminate cancer spread to other organs. MRI spectroscopy combines anatomic information with metabolic activity to detect residual cancer in the gland.

Multiparametric MRI (mpMRI) may have a role in detecting clinically significant prostate cancer in men with elevated PSA levels.[212] Recommendations on a standardized method for the conduct, interpretation, and reporting of prostate MRI for cancer detection and localization have been agreed on, using formal consensus methods.

Possible preventive measures for prostate cancer include lifestyle modification and chemoprevention with 5-alpha-reductase inhibitors (5-ARIs). Use of 5-ARIs, however, has proved problematic. Lifestyle measures such as weight loss in obese patients and physical activity can be recommended unequivocally because of their multiple benefits.

Lifestyle measures

Diets associated with a reduced risk of prostate cancer in epidemiologic studies are composed mainly of vegetables, fruits, grains, and fish. Tomatoes (because of their lycopene content), broccoli, green tea, and soy have all been hypothesized to be beneficial.

Increased risk has been shown with high-fat diets, excessive intake of estrogens and phytoestrogens, and the consumption of burned or charred foods. Obesity appears to be the diet-related factor most strongly associated with prostate cancer, so overall energy intake is important.

Because a high-fat diet is linked with a higher incidence of prostate cancer, a low-fat diet may be beneficial for men at high risk of developing prostate cancer (ie, those with a positive family history, African Americans) and for patients undergoing treatment for advanced prostate cancer. However, no prospective studies have proved that dietary modification provides a benefit.

Nutritional supplements also have not proved beneficial in research studies. The Physicians' Health Study II, a long-term, randomized, controlled trial involving male physicians, found that neither vitamin E nor vitamin C supplementation reduced the risk of prostate or other cancers.[213]

Similarly, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), a randomized placebo-controlled trial involving 35,533 relatively healthy study participants from 427 US sites, found that neither selenium nor vitamin E (alone or in combination), at the doses and formulations used, prevented prostate cancer.[214] See Prostate Cancer and Nutrition for more information on this topic.

Physical activity appears to lower prostate cancer risk. A meta-analysis by Liu et al found a small, but significant, association between physical activity and prostate cancer in men aged 20-45 years.[215]

Improving diet and increasing physical activity to reduce prostate cancer risk will also reduce cardiovascular risk. This is a significant benefit, as cardiovascular disease is the cause of death in many men with prostate cancer.

5-alpha-reductase inhibitors

The 5-ARIs, approved by the FDA for benign prostatic hyperplasia (BPH) and alopecia, include finasteride (Proscar, Propecia) and dutasteride (Avodart, Jalyn).

The use of 5-ARIs to prevent prostate cancer was studied in 2 large, randomized, controlled trials, the Prostate Cancer Prevention Trial (PCPT) and the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. In both of these studies, men taking dutasteride or finasteride had a decreased incidence of prostate cancer overall, but they also had an increased incidence of high-grade prostate cancer over participants who received placebo.[216, 217]

PCPT randomized almost 19,000 men in the United States at low risk of prostate cancer to receive either finasteride or placebo for the primary prevention of prostate cancer over a 7-year period. Although there was a significant reduction in the risk of prostate cancer, this benefit was observed only for low-grade disease, while there was an increase in the risk of Gleason grade 7-10 disease.[218] Several subsequent analyses of the data suggest that the risk of higher-grade disease was associated with increased cancer detection owing to prostate volume decreases rather than direct effects of the medication.[219]

The REDUCE trial evaluated dutasteride for the primary prevention of prostate cancer in 6,700 men at a slightly higher risk of prostate cancer than the PCPT trial and over 4 years of follow-up. Dutasteride treatment was associated with an overall reduction in low-grade prostate cancer diagnosis but no increase in higher-grade disease.

Because both trials demonstrated a reduction in the risk of low-risk prostate cancer only, and both medications have potential adverse effects, neither one is currently recommended for prostate cancer prevention. Some evidence does suggest that, for men on these medications, a rising PSA level might be more sensitive for the detection of clinically relevant prostate cancer.[220]

The American Society of Clinical Oncology (ASCO) Health Services Committee (HSC), the ASCO Cancer Prevention Committee, and the American Urological Association Practice Guidelines Committee jointly convened a panel of experts who used the results from a systematic review of the literature to develop evidence-based recommendations on the use of 5-ARIs for prostate cancer chemoprevention.[221]

The panel concluded that asymptomatic men with a PSA level of 3 ng/mL or less who are undergoing regular PSA screening or who are planning to undergo such screening annually may be aided by a discussion of the benefits of using 5-ARIs for prostate cancer prevention and of the risks associated with the drugs, such as the development of high-grade prostate cancer.

On June 9, 2011, the FDA announced revisions to the prescribing information for 5-ARIs to include a warning regarding a possible increased risk of high-grade prostate cancer with these agents.[222] The revised prescribing information recommends that prior to initiating therapy with 5-ARIs, an appropriate evaluation be performed to rule out other urologic conditions, including prostate cancer, that might mimic BPH. Finasteride and dutasteride were denied approval for prostate cancer prevention.

In contrast, a 2012 placebo-controlled study of dutasteride on prostate cancer progression in men with low-risk disease who chose to be followed up with active surveillance found that at 3-year follow-up, 38% of men in the dutasteride group and 48% of controls had prostate cancer progression. No prostate cancer–related deaths or metastatic disease occurred; 5% of patients in both groups experienced cardiovascular adverse events. The investigators concluded that dutasteride could be a beneficial supplement to active surveillance.[223]

Guidelines on the following aspects of prostate cancer have been published:

• Screening ^{[7, 74, 224, 225, 226, 227, 228]}
• Prostate biopsy, risk stratification, and staging ^{[58, 227, 228]}
• Genetic testing ^{[58, 105]}
• Initial workup ^[58]
• Management of clinically localized prostate cancer ^{[58, 105, 227, 228, 229]}
• Management of castration-sensitive prostate cancer ^{[58, 152, 227, 228]}
• Management of castration-resistant prostate cancer ^{[58, 152, 227, 228]}

For summaries of these guidelines, see Prostate Cancer Guidelines.

The goals of pharmacotherapy for prostate cancer are to induce remission, reduce morbidity, and prevent complications. Agents used include the following:

• Androgen antagonists
• Gonadotropin-releasing hormone (GnRH) agonists
• GnRH antagonists
• Bisphosphonates
• Antifungal agents
• Chemotherapeutic agents
• Corticosteroids
• Immunologic agents
• Poly(ADP)-ribose polymerase (PARP) inhibitors
• Radiopharmaceuticals

Class Summary

GnRH agonists provide medical castration in patients with prostate cancer. They are used early and late in the course of the disease.

GnRH agonists bind to the GnRH receptors on pituitary gonadotropin-producing cells, causing an initial release of luteinizing hormone (LH) and follicle stimulating hormone (FSH) and consequently a rise in testosterone levels for a few weeks. However, sustained use of these agents causes a decrease in the production of LH and FSH, which in turn leads to a decrease in testosterone production in the testes, reducing testosterone to castrate levels or to below the castrate threshold (50 ng/dL).

Leuprolide (Lupron Depot, Lupron Depot-Ped, Eligard)

Leuprolide is indicated as palliative treatment for advanced prostate cancer when orchiectomy or estrogen administration is not indicated or is unacceptable to the patient. It is a potent inhibitor of gonadotropin secretion when given continuously in therapeutic doses.

Leuprolide can be administered as a depot at doses of 3.75 mg every 4 weeks, 11.25 mg every 12 weeks, or 30 mg every 24 weeks. Lupron should be administered intramuscularly, and Eligard should be administered subcutaneously.

Triptorelin (Trelstar, Trelstar Mixject)

Triptorelin is indicated for palliative treatment of advanced prostate cancer. The recommended dosage is 3.75 mg intramuscularly once every 4 weeks, 11.25 mg intramuscularly once every 12 weeks, or 22.5 mg intramuscularly once every 24 weeks.

Triptorelin is a synthetic decapeptide agonist analogue of GnRH. It decreases LH and FSH secretion when administered long-term and thus decreases testosterone and estrogen levels. The serum testosterone concentration drops to a level typically seen in surgically castrated men.

Histrelin (Vantas, Supprelin LA)

Histrelin is indicated for the palliative treatment of advanced prostate cancer. It is available in a 50 mg subcutaneous implant designed to provide continuous release of histrelin at a nominal rate of 50-60 mcg/day over 12 months. This agent is not active when given orally. The recommended dose is 1 implant inserted subcutaneously every 12 months.

Histrelin is a potent inhibitor of gonadotropin secretion. It desensitizes the responsiveness of pituitary gonadotropin, which in turn causes a reduction in testicular steroidogenesis.

Goserelin (Zoladex)

Goserelin is used in the palliative treatment of advanced prostate cancer. It is available as a 3.6 mg and 10.8 mg subcutaneous implant. The usual dose is 3.6 mg every 4 weeks or 10.8 mg every 12 weeks.

Goserelin is a synthetic decapeptide analogue of GnRH that inhibits pituitary gonadotropin secretion if administered long-term. Like other GnRH agonists, goserelin provides a medical castration that deprives hormonally-dependent tumors of testosterone or estrogen. Decreased testosterone production leads to a decrease in prostatic size and improves associated symptoms.

Class Summary

Antiandrogens bind to androgen receptors and competitively inhibit their interaction with testosterone and dihydrotestosterone. Unlike medical castration, antiandrogens do not decrease LH levels and androgen production; testosterone levels are normal or increased. Antiandrogens are not commonly used as monotherapy. Rather, these agents are generally used in combination with a GnRH agonist.

Antiandrogen therapy appears to be less effective than medical or surgical castration, except possibly in patients without overt metastases (M0).[230]

Abiraterone (Yonsa, Zytiga)

Abiraterone is indicated in combination with corticosteroids for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) and metastatic high-risk castration-sensitive prostate cancer (CSPC). Two products are available (tablet or ultramicronized tablet) with different dosage regimens.

Abiraterone is an androgen biosynthesis inhibitor that inhibits 17-alpha-hydroxylase/C17,20-lyase (CYP17); this enzyme is expressed in testicular, adrenal, and prostatic tumor tissues and is required for androgen biosynthesis.

Niraparib/abiraterone (Akeega)

Fixed-dose combination of a poly (ADP-ribose) polymerase (PARP) inhibitor (niraparib) and antiandrogen (abiraterone) given with prednisone for deleterious or suspected deleterious BRCA-mutated mCRPC. 

Bicalutamide (Casodex)

Bicalutamide is indicated for the treatment of stage D2 metastatic carcinoma of the prostate, in combination with an LHRH analogue. It is a nonsteroidal androgen receptor inhibitor that competitively inhibits the action of androgens by binding to cytosol androgen receptors. The usual dosage is 50 mg orally once daily in the morning or evening.

Flutamide

Flutamide is approved by the US Food and Drug Administration (FDA) for use in combination with LHRH agonists for the management of locally confined stage B2-C and stage D2 metastatic prostate cancer. The usual dosage is 250 mg every 8 hours. The antiandrogenic effects of flutamide are mediated by the inhibition of the uptake and/or nuclear binding of testosterone and dihydrotestosterone by prostatic tissue. Flutamide-induced inhibition of androgens at the cellular level complements the castration effects of LHRH agonists.

Nilutamide (Nilandron)

Nilutamide is not suitable for inducing chemical castration since, by blocking the feedback mechanism for control of testosterone secretion, it increases testosterone concentrations. Instead, it is indicated for use in combination with surgical castration for the treatment of metastatic prostate cancer (stage D2). The initial dose is 300 mg once daily for 30 days. The maintenance dose for nilutamide is 150 mg once daily.

Enzalutamide (Xtandi)

Androgen receptor inhibitor; competitively inhibits androgen binding to androgen receptors; also inhibits androgen receptor nuclear translocation and interaction with DNA resulting in decreased proliferation and induced cell death.

Major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide. It is indicated for treatment of nonmetastatic or metastatic castration-resistant prostate cancer (mCRPC). It is also approved for metastatic castration-sensitive prostate cancer (mCSPC).

Apalutamide (Erleada)

Androgen receptor (AR) inhibitor that binds directly to the ligand-binding domain of the AR. Inhibits AR nuclear translocation, inhibits DNA binding, and impedes AR-mediated transcription. This results in decreased tumor cell proliferation and increased apoptosis, leading to decreased tumor volume. It is indicated for nonmetastatic, castration-resistant prostate cancer (nmCRPC) and also for metastatic castration-sensitive prostate cancer (mCSPC).

Darolutamide (Nubeqa)

Darolutamide is an androgen receptor (AR) inhibitor. Darolutamide competitively inhibits androgen binding, AR nuclear translocation, and AR-mediated transcription. Keto-darolutamide, a major metabolite, exhibited similar in vitro activity to darolutamide. In addition, darolutamide functioned as a progesterone receptor (PR) antagonist in vitro. Darolutamide decreased prostate cancer cell proliferation in vitro and tumor volume in mouse xenograft models of prostate cancer. It is indicated for patients with nonmetastatic castration-resistant prostate cancer.

Relugolix (Orgovyx)

Indicated for advanced prostate cancer. Blocking GnRH receptors decreases the release of gonadotropins (ie, luteinizing hormone, follicle stimulating hormone), thereby decreasing the downstream production of testosterone by the testes in men. Available as an oral tablet. 

Degarelix (Firmagon)

Degarelix is a GnRH receptor antagonist indicated for patients with advanced prostate cancer. A single dose of degarelix 240 mg causes a decrease in the plasma concentrations of LH and FSH and subsequently of testosterone. Degarelix is effective in achieving and maintaining testosterone suppression below the castration level of 50 ng/dL. Unlike GnRH agonists, degarelix does not cause any short-term increase in testosterone; testosterone suppression to castrate concentrations is achieved within 1-3 days of administration.

The initial dose is 240 mg subcutaneous injection (given as 2 injections of 120 mg at a concentration of 40 mg/mL). The maintenance dose is 80 mg subcutaneous injection (at a concentration of 20 mg/mL) every 28 days. The first maintenance dose should be given 28 days after the starting dose.

Class Summary

Antimicrotubule chemotherapy agents such as docetaxel and cabazitaxel have demonstrated improvements in overall survival in patients with metastatic, castrate-resistant prostate cancer.

Docetaxel (Docefrez, Taxotere)

Docetaxel is indicated in combination with prednisone for the treatment of patients with androgen-independent (hormone-refractory), metastatic prostate cancer. The usual dose is 75 mg/m2 every 3 weeks as a 1-hour infusion in combination with prednisone 5 mg orally twice daily.

Cabazitaxel (Jevtana)

Cabazitaxel is indicated in combination with prednisone for hormone-refractory, metastatic prostate cancer previously treated with a docetaxel-containing regimen. The usual dosage is 25 mg/m2 administered as a 1-hour intravenous infusion every 3 weeks in combination with oral prednisone 10 mg administered daily throughout cabazitaxel treatment. Dosage can be reduced to 20 mg/m2 if patients experience adverse reactions. Caution should be used, since neutropenic deaths and severe hypersensitivity reactions have been reported.

Class Summary

For symptomatic patients who cannot tolerate docetaxel, mitoxantrone may provide palliative benefit.[230] Mitoxantrone is a palliative treatment option for patients who may not be candidates for taxane-based regimens.

Mitoxantrone

Mitoxantrone is indicated as initial chemotherapy for the treatment of patients with pain related to advanced, hormone-refractory prostate cancer. This agent is a palliative treatment that improves quality of life in these cases but does not improve survival. It is given in combination with corticosteroids such as prednisone. The recommended dose is 12-14 mg/m2 given as a short intravenous infusion every 21 days.

Class Summary

Estramustine is a conjugate of an alkylating agent to estradiol. As a single agent, estramustine showed some activity in men with castrate-resistant prostate cancer, which led to its evaluation in various combination regimens.[231]

Estramustine (Emcyt)

Estramustine combines estradiol and nitrogen mustard. It is a relatively weak alkylating agent with weak estrogenic activity.

Estramustine is used in combination with vinblastine, etoposide, paclitaxel, docetaxel, mitoxantrone, or corticosteroids to achieve synergistic effects. It is indicated for palliative treatment of metastatic and/or progressive carcinoma of the prostate. The usual dose is 14 mg/kg/day given in 3 or 4 divided doses. Treat patients for 30-90 days before assessing the possible benefits of continued therapy. Therapy should be continued as a favorable response is seen.

Class Summary

Autologous cellular immunotherapy is designed to stimulate a patient’s own immune system to respond against the cancer. Sipuleucel-T was developed to induce an immune response targeted against prostatic acid phosphatase (PAP), an antigen that is expressed in most prostate cancers.

Sipuleucel-T (Provenge)

Sipuleucel-T is a cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic prostate cancer that is resistant to standard hormone treatment. It is an autologous treatment, and thus must be prepared individually for each patient.

The usual regimen consists of the administration of 3 complete doses, given at intervals of approximately 2 weeks. Each dose contains a minimum of 50 million autologous CD54+ cells activated with prostatic acid phosphatase (PAP), an antigen expressed in more than 95% of prostate cancers, and granulocyte-macrophage colony-stimulating factor (GM-CSF), an immune-cell activator, suspended in 250 mL of lactated Ringer solution.

Class Summary

Advanced stages of prostate cancer may exhibit dysregulation of DNA-damage repair (DDR) pathways. These tumors are sensitive to poly(ADP) ribose polymerase (PARP) inhibition.

Rucaparib (Rubraca)

Indicated for deleterious BRCA mutation (germline and/or somatic) associated metastatic castration-resistant prostate cancer (mCRPC) in patients who have been treated with androgen receptor directed therapy and a taxane-based chemotherapy.

Olaparib (Lynparza)

Indicated for deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) in adults who have progressed following prior treatment with enzalutamide or abiraterone.

Class Summary

In men with castrate-resistant prostate cancer and bone metastases, zoledronic acid is recommended to help prevent or delay disease-associated, skeletally related events. Skeletally related events can include pathologic fractures or spinal cord compression, which may require surgery or radiation therapy to bone.[232]

Zoledronic acid (Zometa)

Zoledronic acid is an intravenous bisphosphonate that is indicated for patients with documented bone metastases from solid tumors treated with standard chemotherapy. Prostate cancer should have progressed after treatment with at least 1 hormonal therapy. It inhibits bone resorption, possibly by acting on osteoclasts or osteoclast precursors, and thus reduces the risk of skeletally related events. Adverse effects include osteonecrosis of the jaw.

General dosing recommendations include administering 4 mg infused intravenously over no less than 15 minutes every 3 or 4 weeks for patients with a creatinine clearance (CrCl) of more than 60 mL/min. Treatment is continued for 9-15 months. Oral calcium supplementation of 500 mg and a multiple vitamin containing vitamin D 400 units daily are also recommended.

Class Summary

Antifungal agents such as ketoconazole produce a response similar to that of antiandrogens. These agents provide an alternative option that may produce clinical benefit if initial androgen deprivation therapy fails. These agents inhibit various cytochrome P-450 enzymes, including 11-beta-hydroxylase and 17-alpha-hydroxylase, which in turn inhibit steroid synthesis.

Ketoconazole

Ketoconazole is an imidazole broad-spectrum antifungal agent that acts on several of the P-450 enzymes, including the first step in cortisol synthesis, cholesterol side-chain cleavage, and conversion of 11-deoxycortisol to cortisol. It may inhibit adrenocorticotropic hormone (ACTH) secretion when used at therapeutic doses. Ketoconazole in dosages of 400 mg every 8 hours has been used in the treatment of advanced prostate cancer, although it is not FDA approved for this indication.

Class Summary

Monoclonal antibodies such as denosumab have been shown to decrease the incidence of skeletally related events (fractures, spinal cord compression, need for radiation therapy) in men with known bone metastases from prostate cancer.

Denosumab (Prolia, Xgeva)

Denosumab is a human immunoglobulin G2 (IgG2) monoclonal antibody that binds to the receptor activator of nuclear factor kappaB ligand (RANKL), which acts as the primary signal to promote bone removal. By inhibiting the development and activity of osteoclasts, denosumab decreases bone resorption and increases bone density.

Under the brand name Prolia, denosumab is indicated for increasing bone mass in men who are at high risk for fracture because they are receiving androgen deprivation therapy for nonmetastatic prostate cancer. In these patients the dosage is 60 mg subcutaneously every 6 months.

Under the brand name Xgeva, denosumab is indicated for the prevention of skeletally related events in men with bone metastases from prostate cancer. In these patients the dosage is 120 mg subcutaneously every 4 weeks.

With both indications, all patients should receive calcium supplementation of 1000 mg and at least 400 units of vitamin D daily.

Class Summary

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli. They are used in combination with agents such as mitoxantrone, abiraterone, and docetaxel.

Prednisone (Rayos)

Prednisone provides significant subjective palliation and reduces prostate-specific antigen (PSA) levels. Higher doses may be used in patients with spinal cord compression or cerebral edema.

Hydrocortisone (A-Hydrocort, Cortef, Solu-Cortef)

Hydrocortisone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability.

Dexamethasone (Dexamethasone Intensol)

Dexamethasone may provide palliative benefits in patients with prostate cancer. Dexamethasone can prevent or suppress inflammation and immune responses when administered at pharmacologic doses.

Class Summary

Radiopharmaceuticals may be considered for treatment of metastatic castration-resistant prostate cancer.

Radium-223 dichloride (Xofigo)

Radium-223 dichloride is an alpha–particle-emitting radiopharmaceutical. This heavy metal mimics calcium and forms complexes with the bone mineral hydroxyapatite at areas of increased bone turnover, such as bone metastases. The complexes cause the double-strand DNA breaks that are lethal to the prostate cancer cell at the site of increased bone turnover induced by the cancer. It is indicated for men with castration-resistant prostate cancer with symptomatic bone metastases and no known visceral metastatic disease.

Lutetium Lu 177 vipivotide tetraxetan (Pluvicto)

Indicated for the treatment of men with prostate-specific membrane antigen (PSMA)-positive, metastatic castration-resistant prostate cancer (mCRPC) who have been treated with androgen receptor (AR) pathway inhibition and taxane-based chemotherapy. It is a radioligand therapeutic agent. The active moiety is the radionuclide lutetium-177, which is linked to a moiety that binds to PSMA, a transmembrane protein expressed in prostate cancer, including mCRPC. Upon binding to PSMA-expressing cells, the lutetium-177 delivers beta-minus radiation to PSMA-expressing cells, as well as to surrounding cells, inducing DNA damage that can lead to cell death.