Prostate Cancer Treatment & Management

Updated: May 22, 2020
  • Author: Gerald W Chodak, MD; Chief Editor: Edward David Kim, MD, FACS  more...
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Approach Considerations

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 [68] :

  • 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:

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

Metastatic prostate cancer is rarely curable. [69] 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.

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.


Localized Prostate Cancer

Whether one of the several different modalities used for treating localized prostate cancer offers survival benefits over the others remains controversial. The choice of definitive therapy has been suggested to make a significant difference in long-term survival in less than 10% of patients.

This means that most patients are cured either because the treatment was effective or because they had a non–life-threatening tumor and the treatment was unnecessary. The remainder of patients are not cured, either because they had unsuspected micrometastases or because the local therapy did not eradicate all of the malignant cells.

The AUA/ASTRO/SUO guidelines on clinically localized prostate cancer contain the following strong recommendations [68] :

  • Active surveillance as the best available care option for patients with very low-risk localized prostate cancer
  • Not to add androgen deprivation therapy (ADT) along with radiotherapy for low-risk localized prostate cancer, except to reduce the size of the prostate when using brachytherapy
  • Observation or watchful waiting for men with a life expectancy ≤5 years with low- or intermediate-risk localized prostate cancer
  • Radical prostatectomy or radiotherapy plus ADT as standard treatment options for patients with intermediate- or high-risk localized prostate cancer
  • Not to use primary ADT for high-risk localized prostate cancer unless the patient has both limited life expectancy and local symptoms

In a population-based cohort study of older patients with localized prostate cancer, Lu-Yao and colleagues found that primary ADT did not improve long-term overall or disease-specific survival. The study involved 66,717 men 66 years of age and older and was conducted in predefined geographical areas of the United States covered by the Surveillance, Epidemiology, and End Results (SEER) Program. [70]

The AUA/ASTRO/SUO guidelines also include the following recommendations, which are conditional or based on expert opinion [68] :

  • In most patients with low-risk localized prostate cancer, tissue-based genomic biomarkers have not shown a clear role in the selection of candidates for active surveillance.
  • Whole-gland cryotherapy may be considered in patients with low- or intermediate-risk localized prostate cancer who are not suitable for either radical prostatectomy or radiotherapy due to comorbidities but whose life expectancy is greater than 10 years and who have not previously undergone transurethral resection of the prostate. However, patients should be informed that this procedure has considerable adverse effects and survival benefit has not been shown in comparison with active surveillance.
  • Men with localized prostate cancer who are considering focal therapy or high-intensity focused ultrasound (HIFU) should be informed that these treatment options lack robust evidence of efficacy. Although HIFU is approved by the US Food and Drug Administration (FDA) for the destruction of prostate tissue, it is not approved explicitly for the treatment of prostate cancer.
  • Cryosurgery, focal therapy, and HIFU are not recommended for treatment of high-risk localized prostate cancer outside of a clinical trial.

One aspect of counseling that the AUA guidelines do not discuss is how to provide this information to patients. Rather than simply listing the potential adverse effects of each intervention, patients are likely to benefit from being given the odds of developing each complication and the odds that the treatment will result in recurrence of cancer, reduce the development of metastases, and improve overall survival.

A review of US Department of Veterans Affairs (VA) data by Loeb et al found that conservative management of low-risk prostate cancer increased significantly from 2005 to 2015. Over that decade, the use of conservative management in men younger than 65 years rose from 27% to 72%; in men 65 years or older, it rose from 35% to 79%. Conservative management consisted mostly of active surveillance; watchful waiting was more likely to be used in men older than 75 years and those with a higher PSA level and greater comorbidity. [71]

Active surveillance

Active surveillance differs from watchful waiting. With watchful waiting, patients forgo close follow-up and primary treatment. Instead, palliative treatment is provided if local or metastatic progression occurs, as indicated by symptoms. With active surveillance, the physician monitors the course of the disease over time and intervenes with treatment if the disease begins to progress.

Active surveillance is increasingly being recommended for men with very-low-risk disease (ie, T1c, 2 or fewer biopsy cores positive, no core with >50% involved, Gleason 3+3/grade group 1, and a PSA density < 0.15 ng/mL/g) or low-risk disease (T1-2a disease, a Gleason score of 2-6, and a PSA level below 10 ng/mL. The National Comprehensive Cancer Network (NCCN) notes that active surveillance is usually appropriate for men with very-low-risk and low-risk prostate cancer who have a life expectancy of 10 years or more. [72]

Progression of local disease may be indicated either by increased tumor volume or changes in the Gleason score. PSA doubling times are also being used, although some studies have questioned their reliability for this purpose.

The optimal management of men on active surveillance is evolving, although no randomized studies have yet been conducted. Monitoring typically consists of PSA testing every 3 months and repeat biopsy at 12- to 24-month intervals. Biopsy findings are the most important factor in deciding whether to pursue treatment. A rapid PSA level rise or patient choice can also prompt the physician to proceed to treatment. [73]

Tissue-based genomic biomarkers have not demonstrated a clear role in active surveillance.

Current NCCN recommendations for active surveillance (based on lower-level evidence) include the following [26] :

  • PSA no more often than every 6 mo unless clinically indicated
  • DRE no more often than every 12 mo unless clinically indicated
  • Repeat prostate biopsy no more often than every 12 mo unless clinically indicated

However, the NCCN recommends a repeat biopsy within 6 months of diagnosis if the initial biopsy included fewer than 10 cores. Repeat biopsies are not indicated in patients whose life expectancy is less than 10 years. [26]

Multiparametric magnetic resonance imaging (mpMRI) is a promising technique for prostate cancer surveillance. [74] MpMRI has a high negative predictive value for the detection of clinically significant prostate cancer, and may eliminate the need for frequent repeat biopsies in some cases; i tmay also be useful for selection of patients for active surveillance. [68]

Watchful waiting

Watchful waiting is typically recommended to patients of advanced age and to those who have significant, life-limiting comorbidities or a life expectancy of less than 10 years. These patients will most likely experience worse quality of life if their cancer is treated than if they wait for disease progression. They have a very high chance of dying from another cause, and treatment of their prostate cancer could actually worsen comorbid (eg, cardiac) disease and hasten death.

In a 2009 study—the largest US study since the advent of PSA screening—Lu-Yao et al found that the prostate cancer–specific 10-year survival rate in patients managed with watchful waiting was 94%. Median age at diagnosis of the patients in this study was 78 years. [56]

Lu-Yao et al noted that outcomes in these patients, who were diagnosed from 1992-2002, were better than outcomes in patients diagnosed in the 1970s and 1980s. Possible explanations for the improvement include additional lead times, overdiagnoses related to PSA testing, grade migrations, and/or advances in medical care.

Radical prostatectomy versus watchful waiting

Since 1990, only 2 randomized studies comparing radical prostatectomy and watchful waiting have been conducted in men with clinically localized disease. In the first one, which was done in Sweden and included only a small percentage of cases diagnosed by screening PSA (3-5%), overall mortality at 15 years was 46.1% in the surgery group, compared with 52.7% in the watchful waiting group. [68, 75]

Prostate cancer mortality was 14.6% versus 20.7%, respectively, meaning that 1 cancer death was prevented for every 18 men treated with surgery. [75] In a subsequent analysis of the data, however, no mortality benefit was seen in men over 65 years.

Similarly, a 2008 research summary by the Agency for Healthcare Research and Quality (AHRQ) concluded that men with clinically localized prostate cancer detected by methods other than PSA testing who were treated with radical prostatectomy had fewer deaths from prostate cancer, marginally fewer deaths from any cause, and fewer distant metastases, than did men who underwent watchful waiting. [76]

As in the Swedish study, the AHRQ report noted that the advantage of radical prostatectomy with regard to lower cancer-specific and overall mortality rates appears to be limited to men younger than 65 years. The advantage was unrelated to baseline PSA level or histologic grade. The AHRQ found insufficient evidence to determine whether radiation or hormone therapy results in fewer deaths or cancer progressions than does watchful waiting. [76]

The AHRQ also pointed out that radical prostatectomy, radiation therapy, and hormone therapy result in more long-term adverse effects than watchful waiting. These include sexual, urinary, and bowel problems. [77]


Unlike the above reports, the Prostate Intervention Versus Observation Trial (PIVOT), the only such randomized study performed in screened men, showed no statistically significant difference between radical prostatectomy and watchful waiting with respect to either all-cause mortality (47% versus 49.9%, respectively) or prostate cancer–specific mortality (5.8% versus 8.4%, respectively) after a median follow-up of 10 years. PIVOT included 731 men aged 75 years or younger with localized prostate cancer, a PSA level below 50 ng/mL, and a life expectancy of at least 10 years. [28]

A subgroup analysis of PIVOT revealed a statistically significant reduction in overall mortality in men with a PSA greater than 10 ng/mL at diagnosis (61 of 126 men vs 77 of 125 men) but not in men with a PSA of 10 ng/mL or less (110 of 238 men vs 101 of 241 men). These results must be interpreted carefully, however. Age (< 65 vs ≥65 years), Gleason score, comorbidity, race, and performance score did not affect the efficacy of either treatment. [28]

Longer-term follow-up data from PIVOT confirmed the initial observation that for men with low-risk early-stage prostate cancer, surgery does not reduce the risk for death compared with observation. The 19.5-year cumulative incidence of death with surgeryversus observation was 61.3% versus 66.8%, respectively (hazard ratio [HR], 0.84; P = 0.06). Quality-of-life analysis in PIVOT subjects found that urinary incontinence and erectile and sexual dysfunction were each greater with surgery than with observation. [29]

Vascular-targeted photodynamic therapy

Vascular-targeted photodynamic therapy is an investigational technique being studied in Europe. In this technique, a light-responsive drug (padeliporfin) is infused intravenously; optical fibers are inserted into the prostate transcutaneously, to cover the desired treatment zone; and laser light is then used to activate the drug.

 A phase 3 randomized controlled trial in patients with low-risk, localized prostate cancer (Gleason grade 3) found that at a mean follow-up interval of 24 months, disease progression had occurred in 58 of the 206 men in the vascular-targeted photodynamic therapy group compared with 120 of the 207 men in the active surveillance group (28% versus 58%, respectively; adjusted risk ratio 3.67, P < 0.0001). [78]

The most common grade 3–4 adverse effects in the study were prostatitis, acute urinary retention, and erectile dysfunction, which occurred at similar rates (< 1% to 2%) in the vascular-targeted photodynamic therapy group and the active surveillance group. The most common serious adverse event in the vascular-targeted photodynamic therapy group, retention of urine occurred in 15 patients but resolved within 2 months in all cases. [78]



Radiation Therapy

External-beam radiation therapy

Radiation therapy also offers the potential for curative treatment of localized prostate cancer. It may be delivered in the form of external-beam radiation therapy (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). Higher-dose-rate therapy using stereotactic guidance is being used despite lack of data on long-term survival or complication rates.

In general, after 2 years, the quality-of-life profile for IMRT and surgery are similar, although radiation therapy does pose a slightly higher risk of persistent fecal urgency and incontinence of gas. [79]

Proton-beam therapy is theoretically an excellent modality for EBRT, providing an ideal dose distribution. In a phase 2 study in patients with organ-confined prostate cancer, Nihei et al found that acute, transient grade 2 rectal and bladder toxicity developed in 0.7% and 12% of patients, respectively, who underwent proton-beam therapy; at 2 years, late grade 2 or greater rectal and bladder toxicity developed in 2% and 4.1% of patients, respectively. [80]

A study of radiation therapy for primary prostate cancer treatment by Sheets et al found that, compared with patients undergoing conformal therapy, patients who received IMRT had less gastrointestinal (GI) morbidity and fewer hip fractures and were less likely to undergo additional cancer treatments. They were, however, more likely to develop erectile dysfunction. Patients who received proton therapy had more GI morbidity than did patients receiving IMRT and were more likely to undergo GI procedures. [81]

In a multi-center study, Briganti et al found that early salvage radiation therapy is comparable to adjuvant radiation therapy for improving biochemical recurrence–free survival in pT3pN0 prostate cancer patients after radical prostatectomy. Early salvage radiation therapy may reduce the overtreatment associated with adjuvant radiation therapy without compromising disease control in these patients. [82]

Complications of EBRT include cystitis, proctitis, enteritis, impotence, urinary retention, and incontinence. Rates depend on the total dose and the technique used.

A systematic review and meta-analysis of radiation therapy for prostate cancer found that 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. [83]


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. [84] 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. [85]

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. [86]

In a study by Pisansky et al of 1489 intermediate-risk prostate cancer patients, disease-specific survival in patients who underwent 28 weeks of preradiation total androgen suppression (TAS) was not significantly different from that achieved in patients with only 8 weeks of TAS prior to radiation therapy. [87]

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. [87]

Radiation therapy versus surgery

The 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. [77] 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 look at 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 quality of life complicate comparison using uncontrolled studies.


Non–Organ-Confined Disease

When imaging studies provide clear evidence of non–organ-confined disease (eg, seminal vesicle or periprostatic involvement), the treatments offered may vary. Typically, some combination of modalities is involved.

Survival of men with locally advanced prostate cancer (T3-4N0M0) is improved by combining external radiation with androgen ablation for 6 months. If brachytherapy is used, it is often combined with EBRT and ADT, although studies demonstrating an improved outcome with combined radiation are also lacking. Because of the aggressive nature of these tumors, active surveillance is an option only in highly selected patients with life expectancies of less than 5 years.

Radical prostatectomy

Historically, radical prostatectomy for clinical stage T3 prostate cancer at initial presentation was not considered beneficial, because of the increased probability of incomplete resection of the cancer, the likelihood of micro-metastatic disease, and increased morbidity. For patients with T3a disease, however, current National Comprehensive Cancer Network guidelines recommend radical prostatectomy plus pelvic lymph node dissection as an option for initial therapy. [26]

Adjuvant therapy

Radical prostatectomy followed by adjuvant radiation is also an option, but the rate of adverse effects with this approach is higher than with external radiation and hormone therapy. In addition, proof is lacking as to whether it offers comparable survival to radiation and hormone therapy.

Neoadjuvant hormone therapy has been used to clinically down-stage patients before surgery; however, all randomized studies to date have failed to show a significant benefit in either disease recurrence or survival. See Neoadjuvant Androgen Deprivation in Prostate Cancer for more information on this topic.

One small, randomized study found that in men undergoing radical prostatectomy who had lymph node metastases detected, the addition of continuous androgen deprivation improved survival. However, it is unknown whether this combination also improves survival for T3-T4, N0 disease. [88]

In this study, Messing et al reported on results in 98 patients who underwent radical prostatectomy and lymphadenectomy and were found to have metastatic prostate cancer in the excised lymph nodes. Patients were randomized to receive immediate hormone blockade or to undergo observation. At a median follow-up of 7 years, the survival rate in the hormone blockade group was superior to that in the observation group (85% vs 65%, respectively).

This result becomes more impressive when only deaths from prostate cancer are considered (94% vs 68% survival rate, respectively). Not unexpectedly, the use of early hormone blockade was associated with a higher rate of grade I/II hematologic, genitourinary, and constitutional (eg, weight gain) toxicities.

The study by Messing et al supports the use of early hormone blockade in the setting of regionally advanced disease (ie, node-positive). However, quality of life may be compromised unless patients are carefully selected to balance the risks and benefits of therapy.

Unfortunately, the Messing study does not address the potential benefit of postoperative locoregional therapy (ie, radiation therapy). The benefit of radiation therapy following radical prostatectomy has been demonstrated in certain high-risk patients (eg, those with positive surgical margins) but not in men with node-positive disease.

Androgen ablation

Reports from the Memorial Sloan-Kettering Cancer Center suggest that long-term survival rates (ie, ≥15 y) are essentially zero in the setting of synchronous nodal involvement at diagnosis. In this group of patients, hormone blockade with or without EBRT is used. Patients in whom non–organ-confined disease is suspected or confirmed but metastases are absent typically receive radiation therapy with hormone manipulation (LHRH agonist or antagonist treatment). The effect of chemotherapy in this setting has not been well studied.

Several phase 3, randomized clinical trials have assessed the value of total androgen blockade in the treatment of patients with non–organ-confined disease. In each of these trials, patients exhibited longer disease-free intervals and PSA control of disease when total androgen suppression is used either during or after radiation therapy treatment. Few data suggest that the improved biochemical control of disease translates to improved survival, however.

A study by Bolla et al demonstrated increased survival with hormone blockade in conjunction with EBRT. [89] The authors reported 5-year disease-free survival rates of 74% with combination therapy versus 40% for EBRT alone. Moreover, overall 5-year survival rates improved, favoring patients who received 3 years of LHRH agonist treatment (78% vs 62%).

A subsequent study by Bolla et al found that when androgen suppression is given in combination with radiation therapy, 6 months of androgen suppression provides inferior survival compared with 3 years of androgen suppression. [90] These data suggest the importance of prolonged androgen ablation therapy in combination with EBRT.

Similarly, a meta-analysis by Bria et al suggests that the combination of androgen suppression and radiation therapy significantly decreases recurrence and mortality in patients with localized prostate cancer, without affecting toxicity. [91]

In men with high-risk prostate cancer managed with long-term ADT, including radiotherapy as part of initial treatment improved outcomes in a recent randomized study. During a median follow-up of 10.7 years, 118 of 439 patients treated with hormone therapy alone died of prostate cancer, compared with 45 of 436 patients treated with combination therapy (P< .0001). In the hormone-therapy-only group, the 10-year and 15-year prostate-cancer-specific mortality rates were 18.9% and 30.7%, compared with 8.3% and 12.4% in the combination therapy group. [92]

The AHRQ concluded that in high-risk patients (as defined by PSA levels >10 ng/mL or Gleason score >6), adding androgen ablation to EBRT may decrease overall and disease-specific mortality. [76] In contrast to Bria et al, however, the AHRQ found that the combination increases adverse effects. [76]

Androgen ablation commonly begins several months before radiation is initiated and continues for several months or years afterward. However, the optimum sequencing of androgen blockade and radiation therapy remains unclear. So far, the best results have occurred with 3 years of therapy, but those studies were performed when lower doses of radiation were used without IMRT techniques. Additional studies would be needed using higher doses of radiation to determine whether the same benefit would occur.

ADT produces a range of adverse effects, but these symptoms usually diminish or disappear after the hormone therapy is discontinued. However, awareness and treatment of the various side effects of this therapy are important for a man’s quality of life and for reducing the morbidity of this therapy.

Testosterone replacement therapy

In contrast to the established role of ADT, one study has demonstrated benefit of testosterone replacement therapy (TRT) in selected patients with prostate cancer. 

In a study of 824 patients who underwent robot-assisted radical prostatectomy (RARP) for the primary treatment of prostate cancer, Towe et al gave TRT for postoperative recovery of sexual function to the subset of patients (n = 152, 18%) who had low preoperative levels of free testosterone. Patients remained on TRT throughout follow-up or until biochemical recurrence. Surprisingly, after a median follow-up of 3.1 years, TRT was associated with a 53% relative reduction in risk for biochemical recurrence. In addition, TRT prolonged the time to recurrence by a median of 1.5 years (P = 0.005). [93]


Management of Advanced and Metastatic Disease

A rise in PSA after radical prostatectomy to greater than 0.2 ng/mL or three consecutive PSA increases after radiation therapy are evidence of impending disease progression. 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. [94]

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 after 2 years following local treatment than if it occurs before 2 years.

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

Guidelines from the Naitonal Comprehensive Cancer Network (NCCN) [26] and the European Association of Urology [95] provide recommendations for treating patients with advanced prostate cancer in whom local therapy has failed.

Therapeutic options include the following:

  • LHRH agonists - Available in 1-month, 3-month, 6-month, and once-yearly depots
  • LHRH antagonist - Available in a 1-month depot
  • Complete androgen blockade - LHRH agonist or antagonist with an oral antiandrogen
  • Nonsteroidal antiandrogen monotherapy
  • Bilateral orchiectomy

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. Intermittent hormone therapy, which has been studied in men with nonmetastatic disease, does enable some men to minimize their adverse effects without affecting overall survival, even though prostate cancer mortality is slightly higher.

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.

Although administering an antiandrogen just prior to starting the LHRH agonist can reduce the risk of a flare response, it does not completely eliminate that risk. One advantage of LHRH antagonist therapy is the avoidance of a flare response and a more immediate drop in testosterone than with LHRH agonists.

For full discussion, see Metastatic and Advanced Prostate Cancer.


Investigational therapies

Investigational therapies for recurrent prostate cancer include high-intensity focused ultrasound (HIFU) and gene therapy. [96] Other options include cellular immunotherapy, [97] tumor vaccines, or vaccination with tumor- or prostate-specific proteins such as PSA.

High-intensity focused ultrasound

HIFU is an acoustic ablation technique that uses ultrasound waves to destroy prostate tissue. Like cryotherapy, this is a transperineal procedure that does not involve ionizing radiation. (Among several cryotherapy studies that are currently under way is a multicenter national trial comparing the effectiveness of cryotherapy with HIFU.)

HIFU has been available since 1993 in Canada, Europe, and Mexico but is not yet approved for use by the US Food and Drug Administration (FDA). Patients who undergo the procedure require a catheter for about 10 days after therapy. Although urologists from the United States perform the procedure in Mexico and the Dominican Republic, patients should be counseled that the cure rates with this technique have not been proved, nor has the incidence of side effects been determined. [98]

Radiolabelled prostate-specific membrane antigen 

Treatment with prostate-specific membrane antigen 617 that is radiolabelled with lutetium-177 (177Lu–PSMA-617) is a promising approach to metastatic castration-resistant prostate cancer that has progressed after standard treatments. In this technique, after a screening PSMA and FDG-PET/CT to confirm high PSMA expression in the metastatic cells, the 177Lu–PSMA-617 is injected intravenously; the PSMA-16 binds with high affinity to PSMA, and the attached 177Lu then delivers high doses of beta particles to the metastatic cells. As beta particles travel only 1 millimeter, radiation exposure to normal cells is minimized.

Early studies of treatment with 177Lu–PSMA-617 have reported high response rates, low toxic effects, and pain reduction. [99, 100]  In an Australian trial, 22 of 49 patients (44.9%) showed a decline of ≥ 50% in PSA levels, and most adverse events were grade I (predominantly, dry mouth and transient nausea). [100]


Androgen Suppression in Advanced and Metastatic Disease

Androgen deprivation is considered the primary approach to the treatment of metastatic prostate cancer. However, ADT has been found to be palliative, not curative. 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.

Early versus delayed treatment

In the years following the introduction by Huggins and Hodges of hormone therapy for prostate cancer, [101] 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. [102]

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. [103, 104]

Intermittent androgen suppression

Intermittent androgen suppression has been assessed in prospective, randomized studies as a possible means of minimizing the side effects of ADT. Crook et al found that intermittent androgen suppression was noninferior to continuous therapy with respect to overall survival. [105] 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. [106]

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 androgen deprivation therapy 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, a 10% higher relative risk for death). Intermittent therapy was associated with better erectile function and mental health at month 3 but not thereafter. [107]

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. [108]  

Combined androgen blockade

Combined androgen blockade (CAB; also known as maximal androgen blockade [MAB]) recognizes the 5-10% contribution of adrenal androgens to total body testosterone. The concept was originally studied by Huggins and then by Labrie and colleagues after the development of medications that allowed CAB to be accomplished pharmacologically rather than surgically. [109, 110]

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. [111]

One explanation for many of the negative studies is the antiandrogen withdrawal phenomenon, in which a tumor that has started to grow despite antiandrogen treatment regresses when antiandrogen treatment is stopped. This phenomenon was highlighted by the advent of PSA testing; it was observed that when the PSA increased in a patient who was receiving antiandrogen treatment, withdrawing the antiandrogen resulted in a decline in PSA in 20-40% of patients, with some also having objective improvement.

The antiandrogen withdrawal phenomenon apparently results from alterations in the tumor’s androgen receptor, which causes the antiandrogen to stimulate growth. The phenomenon was not known at the time the studies were conducted. Since the study protocols called for continuing the antiandrogen until objective progression occurred, many men may have been made worse by not stopping the antiandrogen sooner. [109]

Although meta-analyses have shown that overall improvement in survival with antiandrogen treatment is small, it remains the best option for maximizing survival. Current American Society of Clinical Oncology (ASCO) guidelines recommend either orchiectomy or an LHRH agonist for initial hormonal management of androgen-sensitive, metastatic, recurrent, or progressive prostate cancer. However, the guidelines state that CAB should be considered in these patients. [112]

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. Giving the antiandrogen for only 1-3 months reduces, but does not eliminate, the risk of a flare response; instead, the antiandrogen should continue to be given unless PSA progression occurs.

If the PSA level begins to rise in a patient who is receiving CAB, the antiandrogen should be discontinued before other therapy is initiated. Generally, 1-2 months are needed following antiandrogen withdrawal to see whether the patient will improve. The optimal interval varies with different antiandrogens.

Androgen suppression plus docetaxel

Early results from a randomized, controlled study of 790 men with hormone-sensitive metastatic prostate cancer indicated that patients treated with the chemotherapy drug docetaxel at the beginning of standard hormone therapy with androgen deprivation therapy (ADT) have improved survival compared with those treated with hormone therapy alone. [113]

Patients were treated with either ADT alone or ADT combined with docetaxel, every 3 weeks for 18 weeks. Patients who received docetaxel had a significant improvement in overall 3-year survival, as compared with those treated with ADT alone (69.0% vs. 52.5%). In patients with a high extent of metastatic disease, 3-year survival rates were 63.4% for ADT plus docetaxel treatment versus 43.9% for ADT alone. [113]

Androgen suppression plus abiraterone

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 3 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. [114]

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. [114]

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. [115]

Adverse effects of androgen suppression

Surgical and medical castration lead to a number of side 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. [116]

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, patients should be evaluated for risk factors for these diseases before prescribing these agents. [117]

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. [118]

In a study of the bone density differences between African-American and Caucasian men who were receiving androgen deprivation therapy 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. [119]

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. [120, 121]

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, zoledronic acid [Reclast] and denosumab [Prolia], have been approved to treat osteoporosis secondary to androgen deprivation. These drugs are given along with supplemental vitamin D and calcium. Both agents are associated with a low incidence of osteonecrosis of the jaw.

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%) [122]

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. [123]


Radiation Therapy in Metastatic Disease

In a study of men with newly diagnosed metastatic prostate cancer, treatment with prostate radiation and androgen deprivation therapy (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). [124]

In patients with metastatic prostate cancer, radiation is also applied for palliative purposes. It is used in patients with castrate-resistant disease 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. [125]

Radium-223 dichloride (Xofigo), formerly alpharadin, is an alpha–particle-emitting radioactive therapeutic agent that was approved by the FDA in May 2013. [126] It is approved for men with castration-resistant prostate cancer (CRPC), symptomatic bone metastases, and no known visceral metastatic disease. Approval was based on the 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. [127, 128, 129] The multinational 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).


Surgical Management of Metastatic Disease

There is no evidence that radical prostatectomy conveys any benefits to patients with documented metastatic disease. 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.


Management of Castrate-Resistant Prostate Cancer

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.

Nonchemotherapy options that provide palliation and improve quality of life include the following:

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

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


Therapeutic options for patients with castrate-resistant prostate cancer have changed significantly in the past 7 years, beginning with the approval of docetaxel chemotherapy. Two randomized studies have shown that this drug improves survival. [130] 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). [131] 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. [132]

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. [133]

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

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. [113]

In the phase 3 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. [134]


Sipuleucel-T is a therapeutic vaccine that was approved by the FDA in April 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. [26]

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. [135] 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. [135]

Abiraterone acetate

Abiraterone acetate (Zytiga), an inhibitor of androgen biosynthesis, was approved by the FDA in April 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. [136] 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. [137]

Men receiving abiraterone also had a significantly longer time to PSA progression, a longer progression-free survival, and a higher PSA response. The side effects occurring more frequently in the treated group were related to decreased mineralocorticoid effects and included hypertension, fluid retention, and hypokalemia. [137]

An ultramicronized abiraterone tablet (Yonsa) was approved in May 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.

In December 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. [138]


Enzalutamide acts by inhibiting the binding of androgens to the androgen receptor and inhibits translocation of the androgen receptor into the nucleus. The results of a large, randomized trial showed a median overall survival period of 18.4 months in the enzalutamide group, versus 13.6 months in the placebo group. [139]

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. [139]

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. Patients in the group had Median progression-free survival was significantly longer with enzalutamide than bicalutamide (15.7 versus 5.8 months; 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. [140]

In July 2018, the FDA approved an expanded indication for enzalutamide in CRPC to include patients with nonmetastatic disease. Approval was based on the PROSPER trial. In the 1401-patient trial, enzalutamide decreased the risk for distant metastasis or death by 71% (hazard ratio, 0.29; 95% confidence interval, 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). [141]


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. [142]


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 (hazard ratio, 0.28; 95% confidence interval [CI], 0.23 - 0.35). [143] .

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 doubled within 10 months or less following treatment, despite hormone therapy. [143]


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

Approval was based on the phase 3 ARAMIS 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. Among men with nonmetastatic, castration-resistant prostate cancer, metastasis-free survival was significantly longer with darolutamide than with placebo. [144]


Rucaparib, a PARP (poly ADP-ribose polymerase) inhibitor, was approved by the FDA in May 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 an objective response rate (ORR) of 44% from the multicenter, single arm TRITON2 clinical trial. The confirmatory TRITON3 trial is ongoing. [145]  


Another PARP inhibitor, olaparib, was approved in May 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 3 clinical trial. Results showed olaparib significantly reduced risk of disease progression or death by 66% (HR 0.34, P < 0.0001) compared with abiraterone or enzalutamide. [146]

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.

As of October 2012, and 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.

On September 11, 2014 the FDA expanded the approved use of enzalutamide for the 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 enzalutamide reduced the risk of radiographic progression or death by 83% versus placebo, while significantly reducing the risk of death by 29%. [147]

Without formal studies to guide recommendations, either drug may be used next, although enzalutamide does not require prednisone, and for that reason it may be most suitable. 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.


Bone Protection in Metastatic Disease

Use of a bone-protective therapy is an important aspect of managing men with metastatic disease. Two agents are now approved for this indication: zoledronic acid, a bisphosphonate, and denosumab, an antibody that inhibits osteoclastic activity in bone. 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.

Zoledronic acid is administered as an intravenous infusion. Denosumab is administered subcutaneously. 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). [148]

Vitamin D and calcium should be taken as supplements with this therapy. In addition, patients should be monitored regularly for hypocalcemia.


Palliative Therapy

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.


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 occasions, 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.


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.


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. [149]

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. [150] 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. [151]

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. [10, 11]

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. [152]

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. [13] 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. [153]



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.


Long-Term Monitoring

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 discussed below.


Watchful waiting

Patients on watchful waiting are treated only if they develop symptomatic progression of their disease. No curative therapy is administered. A digital rectal examination (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 [154] )

  • 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. [155] 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.

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 new 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 [156, 157] :

  • 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

  • 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