Metastatic and Advanced Prostate Cancer

Updated: Jul 19, 2018
  • Author: Martha K Terris, MD, FACS; Chief Editor: Edward David Kim, MD, FACS  more...
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Continuous advances have provided a new understanding of the diagnosis, staging, and treatment of metastatic and advanced prostate cancer. The earlier definition of advanced disease (bone metastasis and soft-tissue involvement) has also been improved.

Prostate cancer is the most commonly diagnosed cancer in men in the United States, and the second leading cause of cancer-related deaths. [1] Most prostate cancer–related deaths are due to advanced disease, which results from any combination of lymphatic, hematogenous, or contiguous local spread.

This article provides an overview of the current modalities available in the treatment of advanced prostate cancer, highlighting the following points:

  • Identification of the population at risk of developing advanced prostate cancer
  • Evolution of clinical staging and therapeutic options currently available to these patients
  • Controversies surrounding early versus delayed treatment and combined androgen blockade (CAB)
  • Definition and management of biochemical failure
  • Hormone-refractory prostate cancer

The most important and established prognosticators 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 presence of Gleason grades 4 and 5, is associated with adverse pathologic findings and disease progression. Conversely, low-grade prostate tumors can also be biologically aggressive.

Note the image below.

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

Patient education

Family counseling for a terminally ill patient with an anticipated poor outcome is crucial to avoid any unreasonable expectations from arising. In addition, any experimental treatment modalities must be clearly outlined, with risks and potential benefits.

For patient education information, see the Men's Health Center and the Cancer Center, as well as Prostate Cancer.

Further information

For more information, see the following:


Epidemiology of Advanced Prostate Cancer

Approximately 11.6% of men will develop prostate cancer in their lifetime, with the likelihood increasing with age; prostate cancer is most often diagnosed in men age 55 to 74 years, and the median age at diagnosis is 66 years. [2] Since the advent of prostate-specific antigen (PSA) screening, prostate cancer is being detected and treated earlier.

Overall, incidence rates of prostate cancer began declining in 2000. Acceleration in the decline began in  2008, when organizations began recommending against routine PSA screening; from 2009 to 2013, the incidence rate decreased by about 8% per year. [1]

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. [3]

At diagnosis, 79% of prostate cancer cases are localized; in 12%, the cancer has spread to regional lymph nodes, and 5% have distant metastasis. The 5-year relative survival rate for localized and regional prostate cancer is 100%, compared with 29.8% for metastatic cases. [2]

Since the early 1990s, prostate cancer death rates have been decreasing in men of all races and ethnicities. However, they remain more than twice as high in blacks as in any other group. [1] Prostate cancer tends to not only be more aggressive and progressive in black men, leading to advanced disease, but to also be of a higher grade at diagnosis. [4, 5] Death rates are also higher in men who have advanced-stage cancer, and men who are 75 to 84 years of age. [2]

The mortality rate associated with prostate cancer continues to increase in Europe and in countries such as Australia, Japan, and Russia.


Presentation of Advanced Prostate Cancer

Advanced prostate cancer results from any combination of lymphatic, blood, or contiguous local spread. Manifestations of metastatic and advanced disease may include the following:

  • Anemia
  • Bone marrow suppression
  • Weight loss
  • Pathologic fractures
  • Spinal cord compression
  • Pain
  • Hematuria
  • Ureteral and/or bladder outlet obstruction
  • Urinary retention
  • Chronic renal failure
  • Urinary incontinence
  • Symptoms related to bony or soft-tissue metastases

Treatment-related symptoms, such as rectal bleeding, gross hematuria, and urethrorectal fistula, which are sometimes associated with radiation therapy, should also be kept in mind.

Physical examination findings of adenopathy, lower-extremity edema, and bony tenderness may indicate metastatic disease. In addition, obliteration of the lateral sulcus or seminal vesical involvement found during rectal examination often indicates locally advanced disease.

Neurologic examination, including determination of external anal sphincter tone, should be performed to help detect possible spinal cord compression.


Prostate Cancer Staging

The Whitmore-Jewett classification of stages A-D is no longer widely used. Prostate cancer does not necessarily progress in a sequential manner.

TNM classification system

Currently, the accepted international tumor, node, metastasis (TNM) staging system pertaining to prostate cancer includes the extent of local disease (T), the status of regional lymph nodes (N), and distant metastasis (M).

Tumor staging is as follows:

  • Stage T1-2c – Organ-confined disease

  • Stage T3a – Extracapsular extension of the tumor

  • Stage T3b – Invasion of the seminal vesicle(s)

  • Stage T4 – Tumor fixed or tumor invading adjacent structures other than the seminal vesicles (eg, the bladder neck, external sphincter, rectum, levator muscles, and/or pelvic floor)

Lymph node involvement is staged as follows:

  • Stage NX – Regional lymph nodes not assessed

  • Stage N0 – No regional lymph node metastasis

  • Stage N1 – Regional lymph node(s) metastasis

Distant metastatic involvement staging consists of the following (if more than one site of metastasis is present, the most advanced category is used):

  • Stage M0 – No distant metastasis

  • Stage M1 – Distant metastasis

  • Stage M1a – Distant metastasis other than regional lymph nodes

  • Stage M1b – Metastasis to bone(s)

  • Stage M1c – Other site(s) with or without bone involvement

Crawford and Blumenstein classification system

The definition of stage D by Whitmore-Jewett was further stratified by Crawford and Blumenstein. [6] The additional stratification is thought to improve classification and understanding of a subset of patients who have hormone-insensitive prostate cancer. It is as follows:

  • Stage D1 – Involvement of pelvic lymph nodes

  • Stage D1.5 – Rising prostate-specific antigen (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 – Hormone-refractory prostate cancer

  • Stage D3.5 – Sensitive to hormones

  • Stage D4 – Insensitive to hormones


Differential Diagnosis

In most cases, the differential diagnoses of advanced prostate cancer do not present any difficulty; however, certain caveats must be considered.

Radiologic findings of bony metastases can mimic Paget disease of the bone. Although bony metastases are blastic in nature, lytic lesions can occur, resulting in pathologic fractures. Furthermore, osteoporotic fractures due to prolonged luteinizing hormone-releasing hormone (LHRH) therapy must be distinguished from pathologic fractures.

Neurologic manifestations should be underscored, and elderly patients with a history of prostate cancer who present to the emergency department with sudden onset of weakness of the legs should raise the suspicion of spinal cord compression, necessitating emergency treatment (spinal cord decompression). Similarly, although brain metastases with associated neurologic manifestations are rare, they do occur with enough frequency to deserve recognition.

Lymphomas can manifest as pelvic masses and bone lesions. Coexistence of lymphomas with prostate cancer has also been reported.

Transitional cell carcinoma and sarcoma of the prostate are more common in men who have undergone previous pelvic radiotherapy for prostate cancer than in men who have not. Likewise, squamous cell carcinoma of the prostate may be observed in men treated with hormonal therapy. All of these can present as a large pelvic mass with or without metastases.


Laboratory Studies

In cases of suspected advanced prostate cancer, the hematologic workup should include a complete blood count (CBC), liver function tests (LFTs), and a chemistry profile, including levels of serum creatinine, acid and alkaline phosphatase, and serum prostate-specific antigen (PSA), as well as a free-to-total PSA ratio. Any demonstration of abnormalities by these tests may warrant additional studies.

Note that not all patients with a relatively high-grade prostate cancer have elevated PSA levels, nor do elevated PSA levels always signify disease progression.

Urinalysis should be performed. If the results are abnormal (ie, indicating the presence of an infection), urinalysis should be followed by a urine culture, especially if the patient is symptomatic.

Histologic and molecular marker analyses

Certain molecular markers, such as E-cadherin, p53 and p21, deoxyribonucleic acid (DNA) ploidy analysis, human kallikrein 2, and microvessel density (histologic marker of tumor angiogenesis) are also being evaluated to help characterize disease progression.


Imaging Studies

Bone scanning

At initial presentation with prostate cancer, the value of a bone scan is limited in patients with a Gleason score of less than 7 and a prostate-specific antigen (PSA) level of less than 20ng/mL. Those with a Gleason grade of greater than 6 may be candidates for a bone scan, irrespective of their PSA level. A bone scan may be performed as a baseline for treatment response in patients with recurrent metastatic disease at high risk of having bony metastatic disease.

Regardless of these guidelines, a bone scan is indicated in patients with prostate cancer who have symptoms suggesting bony metastases. Activity in the bone scan may not be observed until 5 years after micrometastasis has occurred; therefore, negative bone scan results do not rule out metastasis. In biochemical failure, a follow-up bone scan usually has no value until the PSA level exceeds 30ng/mL.

Chest radiography

Chest radiography can be used as a baseline study or to help reveal rare pulmonary metastases in select cases.

CT and MRI

Abdominal or pelvic computed tomography (CT) scanning or magnetic resonance imaging (MRI) may reveal extracapsular extension, seminal vesical involvement, pelvic lymph node enlargement, liver metastases, and hydronephrosis (due to result of distal ureteral obstruction) in patients suspected of having locally advanced disease. Because the prostate-specific antigen (PSA) level does not always correlate with disease progression, repeat CT or MRI scans can help to determine the treatment response. [7]


ProstaScint scanning is used to reveal extraprostatic disease (ie, localized recurrence or lymphatic spread). [8] ProstaScint scans frequently yield false-negative results, but the specificity of these studies may be improved when they are combined with CT scanning or single-photon emission CT (SPECT) scanning. [9]

PET scanning

Fluciclovine F 18 (Axumin) was approved in May 2016 for PET imaging in men with suspected prostate cancer recurrence. Approval was based on a comparative trial with 11C-choline. Sensitivities for 11C-choline and fluciclovine F 18 were 32% vs 37%, specificities 40% vs 67%, accuracies 32% vs 38%, and positive predictive values (PPVs) 90% vs 97%. [10] In a second trial, the diagnostic performance of fluciclovine PET/CT in recurrent prostate cancer was superior to that of CT, and fluciclovine PET/CT provided better delineation of prostatic from extraprostatic recurrence. [11]


Biopsy and Histology


Transrectal ultrasonography (TRUS)-guided needle biopsy of the prostate is indicated for tissue diagnosis in patients who present with elevated prostate-specific antigen (PSA) levels or abnormal digital rectal examination findings. This study should be repeated, if indicated, to determine local recurrence. (See Techniques of Local Anesthesia for Prostate Procedures and Biopsies for more information.)

Histologic findings

Currently, the Gleason grading system is the most common classification used that helps to determine the histologic characteristics of prostate cancer. [12] A grade of 1-5 is assigned to the glandular architecture of the tumor. The sum of the most predominant grade and the second most common histologic pattern determines the Gleason score. Patients with a Gleason score of 6 or higher are likely to progress to advanced cancer (if they have not already done so), as are patients with a prostate-specific antigen (PSA) value of 10ng/mL or higher.


Treatment Overview

Discerning whether the patient has widely advanced disease versus locally advanced disease (clinical stage T3) assists in determining what treatment options are available.

Historically, systemic therapy for metastatic and advanced prostate cancer has involved androgen suppression. In metastatic disease, this palliative therapy has yielded a median progression-free survival of 18-20 months and an overall survival of 24-36 months. However, virtually all patients develop hormone-refractory disease.

Although hormone therapy is associated with significant responses, its curative potential is limited because of the inherent heterogeneity of prostate cancer and the inability of hormones to eradicate all prostate cancer clones, both the androgen-dependent and androgen-independent components.

Despite the steady decline in the incidence of newly diagnosed metastatic prostate cancer and microscopic lymph node metastasis, from 20% in the 1970s to 5% in 2013, the risk of extraprostatic disease in patients with clinically localized disease remains high, at 30-60%. Depending on the prostate-specific antigen (PSA) value, pathologic stage, and histologic grade of the tumor, approximately 50% of clinically localized prostate cancers are estimated to progress despite initial treatment with intent to cure. In some cases of hormone-refractory prostate cancer, the prostate cancer may continue to exhibit hormone dependence. Currently, it is not possible to predict whether these patients may benefit from androgen withdrawal versus continued hormone therapy.

Supportive inpatient care may be required for pain management in terminally ill patients with progressive prostate cancer in whom all measures have failed to elicit response.

Patients diagnosed with impending paralysis due to spinal cord compression or patients with pathologic fractures should be immediately immobilized until appropriate consultations are obtained.


Consultation with a radiation oncologist should be obtained for palliative radiation therapy for bone metastases and for locally extensive tumors and on an emergent basis for spinal cord compression. Also consider consultations with a neurosurgeon for spinal cord compression, an orthopedic surgeon for pathologic fractures, and a medical oncologist for chemotherapy.

Dietary recommendations

Because a high-fat diet is linked with a higher incidence of prostate cancer, a low-fat diet may be beneficial for patients at high risk of developing prostate cancer (namely those with positive family history, black males) and for patients undergoing treatment for advanced prostate cancer. [13] In addition, tomatoes, broccoli, green tea, soy, lycopenes, licorice root, selenium, and antioxidants have all been hypothesized to be beneficial.

However, the Physicians' Health Study II, a long-term, randomized, controlled trial involving male physicians, found that neither vitamin E nor C supplementation reduced the risk of cancer—prostate or otherwise. [14] 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. [15] (See also Prostate Cancer and Nutrition.)


Pharmacologic Agents in Prostate Cancer

Gonadotropin-releasing hormone (GnRH) analogues suppress ovarian and testicular steroidogenesis by decreasing luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels, whereas GnRH antagonists lower serum testosterone levels by suppressing LH and FSH.

Bisphosphonates are analogues of pyrophosphate that act by binding to hydroxyapatite in bone matrix, thereby inhibiting the dissolution of crystals. These agents prevent osteoclast attachment to the bone matrix and osteoclast recruitment and viability. [16]

Antiandrogens are used as combination agents to treat prostate cancer. Antifungal agents produce a response similar to that of antiandrogens. These drugs inhibit various cytochrome P-450 enzymes, including 11-beta-hydroxylase and 17-alpha-hydroxylase, which in turn inhibit steroid synthesis. The antiandrogen abiraterone (Zytiga) is a 17 alpha-hydroxylase/C17, 20-lyase inhibitor that was approved by the US Food and Drug Administration (FDA) in 2011 for use in combination with prednisone for treatment of metastatic castration-resistant prostate cancer (mCRPC) in patients who received prior chemotherapy containing docetaxel. [17]

An ultramicronized abiraterone tablet (Yonsa) was approved in May 2018 for CRPC 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 2012, the FDA expanded approval of abiraterone with prednisone for chemotherapy-naïve patients with mCRPC. Approval was based on the results of a study of 1088 men in which patients who received abiraterone had a median overall survival of 35.3 months compared with 30.1 months for those receiving the placebo. Abiraterone also improved radiographic progression-free survival (rPFS). The median rPFS was 8.3 months in the placebo group and had not yet been reached for patients treated with abiraterone at the time of analysis. [18]

In February 2018, the FDA further expanded the approval for abiraterone for men with metastatic high-risk castration-sensitive prostate cancer (mCSPC). The new approval was based on the results of the 1199-patient LATITUDE trial. In the trial, patients were randomly assigned to receive either abiraterone and prednisone daily, along with standard androgen-deprivation therapy (ADT), or ADT alone. At 30.4 months of median follow-up, overall survival was not estimable in patients who were treated with abiraterone compared with 34.7 months in those who received placebo. Median time to initiation of chemotherapy was also not reached in the abiraterone arm compared with 38.9 months in the placebo arm. [19]

Chemotherapy agents inhibit cell growth and proliferation. Prostate cancer has been considered essentially a chemoresistant disease because of the poor survival outcomes reported in earlier series. No single agent has resulted in an objective response rate of greater than 30%. Because of the availability of prostate-specific antigen (PSA) testing to monitor the disease, renewed interest has been generated in this regard, and clinical trials are being conducted.

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

Immunologic agents are used as an autologous cellular immunotherapy designed to stimulate a patient’s own immune system to respond against the cancer.


Radiation Treatment

For locally advanced prostate cancer (clinical stage T3), the accepted treatment recommendation is external beam radiotherapy (EBRT) as local treatment for cure. Brachytherapy may be added to EBRT. In addition, studies have suggested that the addition of androgen-deprivation therapy (ADT) yields improvement in progression-free survival in patients. [20]

The standard treatment consists of 2 months of ADT before and then EBRT throughout. Three-dimensional (3-D) conformal radiation therapy is available to increase the radiation delivered to the prostate while minimizing the exposure to the rest of the pelvis; namely, the bladder and rectum.

Zapatero et al found that using long-term androgen deprivation in conjunction with higher doses (>78Gy) of radiotherapy was associated with improved biochemical tumor control in high-risk patients. A Gleason sum of more than 7 and a pretreatment PSA level of more than 20ng/mL indicated a risk of PSA failure that was 6.8 times higher. [21]

In patients with metastatic prostate cancer, radiation is also applied for palliative purposes. It is used in patients with hormone-refractory disease with painful bone metastases and in patients with impending spinal cord compression.

Adverse effects of EBRT include cystitis, proctitis, enteritis, impotence, urinary retention, and incontinence.


Biochemical Failure and Recurrence

The most common presentation of advanced prostate cancer is a patient with a rising prostate-specific antigen (PSA) level in whom initial local therapy has failed.

Prognostic indicators

Generally, after a radical prostatectomy, the PSA level should be less than 0.2 ng/mL and, after radiation therapy, the level should be less than 0.5 ng/mL. [22] The definition of a rising PSA level is not consistent in the literature, but many agree that the occurrence of 2 consecutive PSA level elevations is considered biochemical failure. Other important prognostic indicators include the PSA velocity, time to PSA nadir, time to PSA recurrence, and pattern of PSA recurrence.

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, if the PSA level rise occurs after 2 years following local treatment, the associated survival likelihood is greater than if the rise occurs before 2 years.

Therapeutic options

The decision algorithm for initiation of treatment for biochemical failure is controversial. Certain factors to consider include the type of local therapy previously instituted (if any), the patient's life expectancy, the intention and likelihood of cure, the risk for increased morbidity, and the patient's quality of life.

No guidelines have been set for treating patients with advanced prostate cancer in whom local therapy has failed. A balance between disease control and minimization of the toxicity and intolerance of the treatment is difficult to maintain. Androgen-deprivation therapy (ADT), although able to limit disease progression and to reduce urinary outlet obstruction, produces adverse effects and increases the risk of anemia, hot flashes, gastrointestinal tract disturbances, loss of libido, impotence, osteoporosis, muscle wasting, gynecomastia, deep vein thrombosis, congestive heart failure, myocardial infarction, pulmonary edema, and psychological changes.

Therapeutic options include the following:

  • Luteinizing hormone-releasing hormone (LHRH) agonists – Offered in 1-month, 3-month, and once-yearly depots

  • Combined androgen blockade (CAB) – LHRH agonist with an oral antiandrogen

  • Monotherapy of nonsteroidal antiandrogens - Eg, bicalutamide

  • Gonadotropin-releasing hormone (GnRH) agonist

A study by Saad et al found that the risk of osteopenia, osteoporosis, and bone fractures caused by ADT can be mitigated by appropriate bisphosphonate therapy. [22] The decision to institute bisphosphonate therapy should be based on the risk of these complications on a case-by-case basis. Patients determined to be at risk for such complications should be educated about measures to reduce the risk, including lifestyle modifications that may benefit their general and bone health. [22]

Surrogate endpoints

Denham et al reported that the PSA doubling time and the time to biochemical failure can provide useful surrogate endpoints for prostate cancer–specific mortality, potentially meaning that the follow-up period in clinical trials can be significantly reduced. However, further studies are still needed. [23]

In a study, based on an evaluation of data from the Radiation Therapy and Oncology Group 92-02 randomized trial, Ray et al determined that distant metastasis and general failure of clinical treatment at 3 years may be candidates as surrogate endpoints for prostate cancer–specific survival at 10 years, potentially shortening the duration of clinical trials for prostate cancer. However, the investigators concluded that these endpoints still need to be validated in other datasets. [24]


Androgen-Deprivation Therapy

Considered to be the primary approach in the treatment of symptomatic metastatic prostate cancer, androgen-deprivation therapy (ADT) has been found to be palliative, not curative. Although this therapy can slightly improve the likelihood of survival, most men progress to hormone-refractory prostate cancer, also termed androgen-independent cancer. These patients have disease progression despite castration levels of ADT.

Combined androgen blockade (CAB) recognizes the 10% contribution of adrenal androgens to the total body testosterone. A gonadotropin-releasing hormone (GnRH) antagonist with a nonsteroidal antiandrogen is used concurrently for what was thought to be complete ADT. However, multiple randomized trials have shown conflicting findings regarding significant improvement in survival.

Labrie and colleagues described the concept of CAB, in which luteinizing hormone-releasing hormone (LHRH) accomplished medical castration and antiandrogens achieved peripheral blockade. Initially, the investigators reported improved response and survival rates. [25] Additional studies supported these findings.

However, a meta-analysis by the Prostate Cancer Trialists' Collaborative Group, which included 22 trials with a total of 5710 patients with advanced prostate cancer, found no statistically significant survival advantage with CAB. Medical castration and bilateral orchiectomy were included. The overall mortality rate was 56.3% in patients receiving CAB versus 58.4% in patients receiving medical or surgical castration alone. Estimated 5-year survival rates were 26.2% with CAB and 22.8% with castration alone. [26, 27] The current American Society of Clinical Oncology (ASCO) guidelines recommend castration alone with either an orchiectomy or GnRH agonist.

In May 2010, the US Food and Drug Administration (FDA) stated that a preliminary and ongoing analysis found that men receiving gonadotropin-releasing hormone (GnRH) agonists were at a small, increased risk for diabetes, heart attack, stroke, and sudden death. On October 20, 2010, the FDA announced that prescribing information for GnRH agonists would include new warnings describing the increased risk for heart disease and diabetes. [28]

GnRH agonists approved in the United States include leuprolide (Eligard, Lupron, Viadur), nafarelin (Synarel), triptorelin (Trelstar), histrelin (Vantas), and goserelin (Zoladex).

Intermittent androgen therapy

Intermittent androgen suppression is a well-established treatment offered to patients with advanced prostate cancer; however, it is not considered the standard of care. [25, 26] Some indications for androgen-withdrawal therapy include newly diagnosed metastatic disease, localized disease with high risk of systemic relapse, prostate-specific antigen (PSA) level rise during treatment, lack of tolerance for side effects, and biochemical failure after local therapy.

Intermittent androgen suppression may delay androgen-independent cancer and increase quality of life (ie, fewer issues regarding potency and libido). Ongoing research is investigating the utility of intermittent treatment.

J-CAPRA risk prediction model

Cooperberg et al built and validated a model—the Japan Cancer of the Prostate Risk Assessment (J-CAPRA)—for risk prediction in patients receiving primary ADT for prostate cancer. [29] J-CAPRA is scored from 0 to 12 based on the Gleason score, PSA level, and clinical stage. J-CAPRA predicted progression-free survival with a c-index of 0.71 among 13,740 men in a US registry and predicted cancer-specific survival with a c-index of 0.84 among 19,265 men in a Japanese registry. [29]

Cardiovascular and colorectal cancer risk

Studies of epidemiologic databases indicate that long-term ADT may be associated with an increased risk of cardiovascular disease and colorectal cancer. [30]


Early Versus Delayed Treatment

In the years following the introduction by Huggins and Hodges of hormone therapy for prostate cancer, [31] early institution of such treatment was recommended based on comparison with historical controls. [32]

Later, the Veterans Administration Cooperative Urology Research Group (VACURG) studies reversed the recommendation of early hormone therapy; instead, hormone therapy was deferred until symptomatic progression. In addition, prolongation of survival was believed to be secondary to the alteration of the nature of metastatic lesions, thereby creating earlier androgen resistance, rather than a result of early hormone manipulation.

In more recent years, the old controversy of appropriate androgen-deprivation therapy (ADT) timing has gained new and stronger popularity because of the advent of less-toxic and well-tolerated pharmaceutical agents, such as luteinizing hormone-releasing hormone (LHRH) agonists and antiandrogens. Laboratory studies have demonstrated that early hormone therapy does not confer early resistance. An update of the VACURG study by Byar and Corle determined that disease progression from stage C to stage D was decreased from 50% to 10% with diethylstilbestrol (DES) therapy. [33] Crawford and associates also showed a benefit of early hormone therapy in patients with distant metastases. [34]

The Medical Research Council study found that overall survival was significantly prolonged in patients who were treated early. [35] This was a randomized study of 938 patients with locally advanced or asymptomatic metastatic prostate cancer in which individuals received treatment with orchiectomy or an LHRH agonist, either immediately or after symptoms occurred. Development of extraskeletal metastases, pathologic bone fractures, spinal cord compression, and ureteral obstruction was twice as common in the deferred-treatment group. [35]

In a study by the Eastern Cooperative Oncology Group (ECOG), immediate therapy significantly improved survival and reduced the risk of progression. [36] In this trial, 98 patients who underwent radical prostatectomy and were found to have lymph node metastases were randomly assigned to either immediate castration (ie, LHRH agonist/orchiectomy) or therapy instituted at disease progression.


Hormone-Refractory Prostate Cancer

In patients with serum testosterone castrate levels, hormone-refractory prostate cancer is defined as 2-3 consecutive rises in prostate-specific antigen (PSA) levels obtained at intervals of greater than 2 weeks and/or documented disease progression based on findings from CT scan and/or bone scan, bone pain, or obstructive voiding symptoms. In a subgroup of patients, the PSA level does not rise at diagnosis or throughout the entire course of the disease.

If given enough time, all patients with metastatic disease become resistant to androgen ablation. The median time to symptomatic progression after a rise in PSA level of more than 4 ng/mL is approximately 6-8 months, with a median time to death of 12-18 months. Once the patient exhibits symptoms, the median survival is less than 1 year. No method predicts whether these patients may benefit from androgen withdrawal versus continued hormone therapy.

Therapeutic options for patients with hormone-refractory prostate cancer are limited, with lack of evidence for long-term survival. The best outcome for these patients is to maintain or to improve their quality of life.

In a large-scale, placebo-controlled trial, denosumab (Xgeva) significantly increased bone metastasis–free survival by a median of 4.2 months compared with the placebo group. Denosumab also notably delayed time to first bone metastasis. Between the groups, overall survival did not differ. Osteonecrosis of the jaw and hypocalcemia were observed in 5% and 2% of patients, respectively. [37] The FDA has approved denosumab for prevention of skeletal-related events (eg, bone fractures and pain) in patients with bone metastases from prostate cancer and other solid tumors.

Short-term palliative response and improved quality of life in these patients is achieved presently by single or multimodal therapies, which may include the following:

  • Second-line hormonal manipulations
  • Addition of antiandrogens
  • Corticosteroids
  • Radiation therapy
  • Chemotherapeutic agents
  • Mitoxantrone
  • Taxanes<
  • Bisphosphonates
  • Chemohormonal therapy
  • Other investigational approaches

Bisphosphonate therapy

Bisphosphonates, which are stable analogues of calcium pyrophosphate, inhibit osteoclastic activity in bone, relieving bone pain. These agents may also limit progression of prostate cancer and are also being studied for the treatment of osteoporosis induced by androgen-deprivation therapy (ADT). [38] More recently, zoledronic acid (Zometa) has shown further promising results.

Bisphosphonates used in conjunction with antiangiogenic factors may increase the risk of osteonecrosis of the jaw over bisphosphonates alone. This may warrant pretreatment evaluation of dentition.

Radium-223 dichloride

Radium-223 dichloride (Xofigo), formerly alpharadin, is an alpha-particle–emitting radioactive therapeutic agent that was approved by the FDA in May 2013. 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. [39] 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).

In prespecified subgroup analysis from the ALSYMPCA trial, radium-223 dichloride was found to be equally effective whether or not the patient has previously received chemotherapy with docetaxel. Median overall survival with radium-223 was 14.4 months for patients who received previous docetaxel and 16.1 months for patients who did not. Correspondingly, median time to first symptomatic skeletal event was 13.5 months and 17.0 months, respectively, for the two groups. Compared with placebo, hazard ratios for the two groups of patients were 0.70 and 0.69, respectively, and both were statistically significant. [40]

In a separate analysis, time to first symptomatic skeletal event was assessed. Patients in the radium-223 treatment group went longer before the first symptomatic skeletal event than with placebo (median 15.6 months vs 9.8 months). The risks of external beam radiation therapy for bone pain and spinal cord compression were reduced with radium-233 compared with placebo. [41]

Chemotherapy/chemohormonal therapy

The rationale behind chemohormonal regimens for hormone-naive advanced disease is based on earlier exposure of prostate cancer to cytotoxic chemotherapy, before clonal expansion of androgen-independent cells or constitutive expression of cell survival genes becomes established and before patients develop hormone-refractory prostate cancer. In the past, chemotherapy for prostate cancer was found to be ineffectual. However, developments with antimicrotubule agents and inhibition of tyrosine kinase show promise.

Docetaxel is the drug of choice over mitoxantrone in patients with advanced prostate cancer that has become hormone refractory. In a phase 3 trial, Tannock et al demonstrated that docetaxel plus prednisone every 3 weeks improved patient survival by 3 months over mitoxantrone plus prednisone. [42] As secondary endpoints, the investigators found that patients also had an improved PSA response, decreased pain, and better quality of life.


Suramin acts via growth factor inhibition and remains active in patients with hormone-refractory cancer. This drug may be used in combination with other agents. Adverse effects include the following:

  • Edem
  • Leukopenia
  • Infection
  • Hyperglycemia
  • Anemia
  • Anorexia
  • Dyspnea
  • Platelet abnormalities
  • Elevated creatinine levels
  • Malaise
  • Arrhythmias
  • Coagulopathy


In June 2010, cabazitaxel (Jevtana), a microtubular inhibitor, was approved by the FDA for second-line treatment. This agent is indicated in combination with prednisone for hormone-refractory metastatic prostate cancer previously treated with a docetaxel-containing regimen.


In April 2010, sipuleucel-T (Provenge) was approved for asymptomatic or minimally symptomatic prostate cancer with metastases resistant to standard hormone treatment. Sipuleucel-T is an autologous cellular immunotherapy prepared from peripheral blood mononuclear cells, including antigen presenting cells (APCs). These cells are activated during a defined culture period with recombinant human protein consisting of prostatic acid phosphatase, an antigen expressed in prostate cancer tissue.


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. It is indicated in combination with prednisone for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) and metastatic high-risk castration-sensitive prostate cancer (CSPC). [19] [17, 43]


Enzalutamide (Xtandi) is an oral androgen receptor inhibitor that was approved by the FDA as first-line therapy for metastatic castration-resistant prostate cancer (mCRPC) in September 2014. [44] The Committee for Medicinal Products for Human Use (CHMP) in Europe made a similar recommendation in October 2014. [45]

Approval was based on results from the phase III PREVAIL study, in which enzalutamide treatment significantly reduced the risk for death and radiographic progression as compared with placebo treatment. The trial was halted early after a planned interim analysis found a survival benefit in favor of enzalutamide.

In PREVAIL, enzalutamide reduced the risk for death by 29% (hazard ratio [HR], 0.71; P < 0.0001) and the risk for radiographic progression or death by 83% (HR, 0.17; P < 0.0001). Treatment with enzalutamide also delayed time to initiation of chemotherapy and time to a skeletal-related event. [46]

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. [47]

In July 2018, the FDA expanded the approval of enzalutamide to include nonmetastatic CRPC. Another androgen receptor–targeting therapy, apalutamide (Erleada) was approved in February 2018 for use in nonmetastatic CRPC.  [53]

American Urological Association guidelines

American Urological Association guidelines for the management of CRPC describe six index-patient scenarios for which recommendations could be formulated. [48]

Index patient no. 1: Asymptomatic non-metastatic CRPC

Recommendations are as follows:

  • Observation with continued ADT

  • First-generation antiandrogens (flutamide, bicalutamide, and nilutamide) or first-generation androgen-synthesis inhibitors (ketoconazole plus steroid) to patients unwilling to accept observation.

  • Systemic chemotherapy or immunotherapy should not be offered to patients with non-metastatic CRPC outside the context of a clinical trial

Index patient no. 2: Asymptomatic or minimally-symptomatic, metastatic CRPC with good performance status and without prior docetaxel chemotherapy

Recommendations are as follows:

  • Abiraterone plus prednisone, enzalutamide, docetaxel, or sipuleucel-T

  • First-generation antiandrogen therapy or ketoconazole plus steroid or observation to patients who do not want or cannot have one of the standard therapies

Index patient no. 3: Symptomatic, metastatic CRPC with good performance status and no prior docetaxel chemotherapy

Recommendations are as follows:

  • Docetaxel

  • Abiraterone plus prednisone, enzalutamide, or docetaxel

  • Ketoconazole plus steroid, mitoxantrone, or radionuclide therapy for patients who do not want or cannot have one of the standard therapies

  • Radium-223 to patients with symptoms from bony metastases and without known visceral disease

  • Treatment with either estramustine or sipuleucel-T should not be offered

Index patient no. 4: Symptomatic, metastatic CRPC with poor performance status and no prior docetaxel chemotherapy

Recommendations are as follows:

  • Abiraterone plus prednisone or enzalutamide

  • Ketoconazole plus steroid or radionuclide therapy to patients who are unable or unwilling to receive abiraterone plus prednisone

  • Docetaxel or mitoxantrone chemotherapy in select cases, specifically when performance status is directly related to the cancer

  • Radium-223 to patients with symptoms from bony metastases and without known visceral disease in select cases, specifically when the performance status is directly related to symptoms related to bone metastases.

  • Treatment with sipuleucel-T should not be offered

Index patient no. 5: Symptomatic, metastatic CRPC with good performance status and prior docetaxel chemotherapy

Recommendations are as follows:

  • Abiraterone plus prednisone, cabazitaxel, or enzalutamide

  • If the patient received abiraterone plus prednisone prior to docetaxel chemotherapy, offer cabazitaxel or enzalutamide

  • Ketoconazole plus steroid if abiraterone plus prednisone, cabazitaxel, or enzalutamide is unavailable

  • Re-treatment with docetaxel for patients who were benefiting from but discontinued treatment with docetaxel because of reversible adverse effects

  • Radium-223 to patients with symptoms from bony metastases and without known visceral disease

Index patient no. 6: Symptomatic, metastatic CRPC with poor performance status and prior docetaxel chemotherapy

Recommendations are as follows:

  • Palliative care

  • For selected patients, offer treatment with abiraterone plus prednisone, enzalutamide, ketoconazole plus steroid, or radionuclide therapy

  • Systemic chemotherapy or immunotherapy should not be offered

Bone health recommendations

Because the skeletal system is the most common site for prostate cancer metastasis, the guideline also makes recommendations regarding bone health not specific to any index patient group:

  • Offer preventive treatment (eg, supplemental calcium, vitamin D) for fractures

  • Choose either denosumab or zoledronic acid as preventive treatment for skeletal-related events



Surgery and Advanced Prostate Cancer

An indication for immediate bilateral orchiectomy is spinal cord compression. Surgical intervention is mandatory for pathologic fractures involving weight-bearing bones.

In patients with clinical stage T3 prostate cancer at initial presentation, radical prostatectomy (RP) has not historically been considered beneficial, because of the increased probability of incomplete resection of the cancer, likelihood of micrometastatic disease, and increased morbidity.

However, a retrospective review of approximately 840 men with stage cT3 prostate cancer who underwent RP at the Mayo Clinic (median follow-up, 10.3y) reported outcomes similar to those with organ-confined disease (stage T2c) during the same period at this institution. Pathologic stage, Gleason grade, positive surgical margin, and nondiploid chromatin were found to be independently associated with increased progression of disease. [49]

In another Mayo Clinic study, in which the long-term survival of patients with high-risk prostate cancer was compared after RP and after external beam radiation therapy (EBRT), RP alone and EBRT plus ADT provided similar long-term cancer control. [50] However, the risk of all-cause mortality was greater after EBRT plus ADT than after RP.

In the study, RP was used in 1238 men, EBRT plus ADT was used in 344 men, and 265 received EBRT alone. The 10-year cancer-specific survival rates in the study were 92% in patients treated with RP or EBRT plus ADT, and 88% in those receiving EBRT alone, with a median follow-up of 6-10 years.

Current National Comprehensive Cancer Network (NCCN) guidelines recommend RP plus pelvic lymph node dissection as an option for initial therapy in patients with T3a disease. The NCCN considers salvage RP an option for highly selected patients who have local recurrence without metastasis after EBRT, brachytherapy, or cryotherapy. However, salvage RP is associated with high rates of morbidity (ie, incontinence, loss of erection, anastomotic stricture), so the NCCN advises that the operation be performed by surgeons experienced in salvage RP. [20]



Despite the steady decline in the incidence of newly diagnosed metastatic prostate cancer and microscopic lymph node metastasis, the risk of extraprostatic disease in patients with clinically localized disease remains high (30-60%). Depending on the prostate-specific antigen (PSA) value, pathologic stage, and histologic grade of the tumor, approximately 50% of patients with clinically localized prostate cancer are estimated to progress despite initial treatment with intent to cure. The Partin tables are the best nomogram for predicting prostate cancer spread and prognosis.

Although a Gleason grade of 7 or less is associated with a better prognosis than a grade of 8 or more, if the PSA level rise occurs after 2 years following local treatment, the associated survival likelihood is greater than if the rise occurs before 2 years.

In a study on higher serum concentrations of C-reactive protein, Prins et al found that inflammation may have a crucial role in the natural history of advanced prostate cancer. C-reactive protein is a readily measurable biomarker with the potential to enhance prognostic models and should be validated in a prospective clinical trial. [51]

If given enough time, all patients with metastatic disease become resistant to androgen ablation. The median time to symptomatic progression after a rise in the PSA level of more than 4 ng/mL is approximately 6-8 months, with a median time to death of 12-18 months. Once the patient exhibits symptoms, the median survival is less than 1 year.

Elevated serum levels of markers of bone turnover may be prognostic for poor survival in castration-resistant prostate cancer. Lara and colleagues demonstrated the prognostic and predictive value of markers for bone resorption (N-telopeptide and pyridinoline) and formation (C-terminal collagen propeptide and bone alkaline phosphatase) in castration-resistant prostate cancer patients treated in a placebo-controlled phase III trial of docetaxel with or without the bone targeted endothelin-A receptor antagonist atrasentan (SWOG S0421). [52]

Elevated baseline levels of each of the markers were associated with worse survival (P < 0.001), and increasing marker levels by week 9 of therapy were also associated with subsequent poor survival (P < 0.001). Patients with the highest marker levels (upper 25th percentile) not only had a poor prognosis (hazard ratio, 4.3) but also had a survival benefit from atrasentan. [52]