Metastatic and Advanced Prostate Cancer

Updated: Sep 07, 2023
  • Author: Martha K Terris, MD, FACS; Chief Editor: Edward David Kim, MD, FACS  more...
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While advanced prostate cancer was historically defined as distant metastatic disease, the current definition includes disease stages that range from recurrence of prostate-specific antigen (PSA) elevation after failure of local treatment to widespread metastasis. [1, 2] Advanced disease can result from any combination of lymphatic, hematogenous, or contiguous local spread.

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.

Although cure of metastatic prostate cancer remains elusive, continuous advances in management have improved the outlook in these patients. Current therapeutic options, often used in combination, include hormonal manipulations, chemotherapy, radiation therapy, surgery, bisphosphonates, and targeted therapy with poly (ADP-ribose) polymerase (PARP) inhibitors. [3, 4] Treatment choices are influenced by life expectancy, comorbidities, patient preferences, and tumor characteristics. [2]

Patient education

In patients considering clinical trial enrollment, the risks and potential benefits of experimental treatment modalities must be clearly outlined. In terminally ill patients with an anticipated poor outcome, family counseling is crucial for guarding against unreasonable expectations.

For patient education information, see Prostate Cancer.

Further information

For more information, see the following:


Epidemiology of Advanced Prostate Cancer

Prostate cancer is the most commonly diagnosed cancer in men in the United States, and the second leading cause of cancer-related deaths. [5] Approximately 12.9% of men will develop prostate cancer in their lifetime, with the likelihood increasing with age; prostate cancer is most often diagnosed in men age 65 to 74 years, and the median age at diagnosis is 67 years. [6] 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. From 2007 to 2014, rates declined sharply, coinciding with less PSA testing because of changes in screening recommendations. Since 2014, however, the overall incidence has increased by 3% per year, and diagnoses of advanced-stage prostate cancer have increased by about 5% per year. [5]

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 by 37% from 2004 to 2007-2013, the annual incidence of metastatic prostate cancer during those years increased by 72%. The increase in metastatic prostate cancer was greatest (92%) in men aged 55–69 years. [7]

At diagnosis, 69% of prostate cancer cases are localized; in 13%, the cancer has spread to regional lymph nodes, and 8% have distant metastasis. The 5-year relative survival rate for localized and regional prostate cancer is 100%, compared with 34.1% for metastatic cases. [6]

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. [5] 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. [8, 9] Death rates are also higher in men who have advanced-stage cancer, and men who are 75 to 84 years of age. [6]  


Presentation of Advanced Prostate Cancer

The most common manifestation of advanced prostate cancer is a rising prostate-specific antigen (PSA) level after failure of initial local therapy. 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. [10] The definition of a rising PSA level is not consistent in the literature, but many agree that 2 consecutive PSA level elevations constitutes 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. A Gleason grade of 7 or less is associated with a better prognosis than a grade of 8 or more, and if the PSA level rise occurs more than 2 years after local treatment, the survival likelihood is greater than if the rise occurs before 2 years.

Signs and symptoms 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 kidney disease
  • Urinary incontinence
  • Symptoms related to bony or soft-tissue metastases

Manifestations of disease must be differentiated from adverse effects of treatment. For example, rectal bleeding, gross hematuria, and urethrorectal fistula are sometimes associated with radiation therapy, while urinary incontinence may occur after prostatectomy.

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 staging system, which classifies prostate cancer into stages A-D (and the stage D subclassification by Crawford and Blumenstein [11] ), is no longer widely used. Prostate cancer does not necessarily progress in a sequential manner.

Currently, the American Joint Committee on Cancer (AJCC) tumor/node/metastasis (TNM) classification and staging system is the accepted approach for prostate cancer. [12] Tumor (T) 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)

Regional lymph node (N) 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 metastasis (M) 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

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 sudden onset of weakness of the legs in an elderly man with a history of prostate cancer should raise the suspicion of spinal cord compression, which necessitates 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); 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 abnormal results on 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

Several commercially available tests (eg, Prolaris, Decipher) use tumor markers for predicting biochemical recurrence of prostate cancer. [13] Currently, however, treatment recommendations for prostate cancer are based on prognosis, estimated through risk stratification, rather than use of predictive biomarkers. [4] In patients with metastatic castration-resistant prostate cancer, germline and somatic genetic testing is, used to identify mutations that may direct targeted therapies. [4, 2]


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 20 ng/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 30 ng/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 PSA level does not always correlate with disease progression, repeat CT or MRI scans can help to determine the treatment response. [14]

PET scanning

American Urological Association/Society of Urologic Oncology (AUA/SUO) guidelines prefer the use of prostate-specific membrane antigen (PSMA) PET imaging, where available, in patients with PSA recurrence after failure of local therapy. PSMA PET imaging has greater sensitivity than conventional imaging, and may also be used when conventional imaging yields negative results. [2] National Comprehensive Cancer Network (NCCN) guidelines suggest considering PET imaging for detection of bone metastasis when initial bone scanning yields equivocal results, or as an alternative to bone scan. [4]

Flotufolastat F 18 (Posluma) is indicated for PET imaging of PSMA-positive lesions in men with prostate cancer with suspected metastasis who are candidates for initial definitive therapy, or those with suspected recurrence based on elevated PSA. Approval was based on the SPOTLIGHT and LIGHTHOUSE studies that detected recurrence and metastatic lesions in newly diagnosed men and those with undetectable metastasis at baseline with conventional imaging. [15, 16]  

Fluciclovine F 18 (Axumin) is indicated 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%. [17] 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. [18]


Treatment Overview

Discerning whether the patient has widely advanced disease versus locally advanced disease (clinical stage T3) assists in selecting treatment options. In patients with newly diagnosed metastatic prostate cancer, further considerations are whether the patient is experiencing symptoms from metastatic disease, and whether the metastatic disease is low volume or high volume. High-volume disease is defined as four or more bone metastases with at least one metastasis outside of the spine/pelvis, and/or the presence of visceral metastases. [2]

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.

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

Diet is one of several aspects of lifestyle that are considered risk factors in the development and progression of prostate cancer. A systematic review found a significant positive association between detrimental dietary patterns such as Western diet and progression of cancer, including prostate cancer, whereas high consumption of fiber such as whole grain cereals and green and cruciferous vegetables seems to be protective against cancer progression and mortality. [19]

A study of saturated fat intake in men with prostate cancer found that the risk of dying from prostate cancer was decreased in men in the lowest tertile of saturated fat intake as compared with those in the highest tertile of saturated fat intake. In addition, since patients undergoing ADT tend to gain fat mass, which increases risk of cardiovascular disease and diabetes, lifestyle interventions such as low-fat diet and increased physical activity and weight control may help prevent those comorbidities in men receiving ADT. [20]

For full discussion of this topic, see Prostate Cancer and Nutrition.)


Biochemical Failure and Recurrence After Local Therapy

The decision algorithm for initiation of treatment for biochemical failure is controversial. 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.

In patients with persistence or recurrence of PSA elevation after radical prostatectomy, the National Comprehensive Cancer Network (NCCN) recommends observation for those whose life expectancy is 5 years or less. For patients with longer life expectancy, the NCCN recommends risk stratification with PSA doubling time, and consideration of bone and soft tissue imaging and prostate bed biopsy (especially if imaging suggests local recurrence). If those studies are negative for distant metastases and pelvic recurrence, the preferred treatment is external beam radiation therapy (EBRT) with or without androgen-deprivation therapy (ADT); if they are positive for pelvic recurrence, the NCCN recommends EBRT plus ADT with or without abiraterone. [4]

As a clinical principle, American Urological Association/Society of Urologic Oncology (AUA/SUO) guidelines recommend following patients with PSA recurrence after exhaustion of local therapy with serial PSA measurements and clinical evaluation. Radiographic assessments may be considered, based on overall PSA and PSA kinetics. Patients who are at higher risk for the development of metastases (eg, PSA doubling time of less than 12 months) should receive periodic staging evaluations consisting of cross-sectional imaging (CT, MRI) and technetium bone scan, and/or preferably prostate-specific membrane antigen (PSMA) PET imaging. [2]

If imaging studies do not show metastatic disease, AUA/SUO guidelines recommend offering the patient observation or clinical trial enrollment. ADT should not be routinely used in this setting; however, if ADT is initiated in the absence of metastatic disease, intermittent ADT may be offered in lieu of continuous ADT. [2]

A balance between disease control with ADT and minimization of the toxicity and intolerance of the treatment is difficult to maintain. Although able to limit disease progression and to reduce urinary outlet obstruction, ADT 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. [21] Studies of epidemiologic databases suggest that long-term ADT may be associated with an increased risk of colorectal cancer. [22]

The risk of osteopenia, osteoporosis, and bone fractures caused by ADT can be mitigated by appropriate bisphosphonate therapy. 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. [23]


Treatment of Hormone-Sensitive Prostate Cancer

Pharmacologic treatment of advanced prostate cancer is with hormonal manipulations: androgen-deprivation therapy (ADT), with chemotherapy and/or androgen receptor–directed therapy. ADT is an option in stage III prostate cancer and is the mainstay of treatment for metastatic prostate cancer. [3] ADT provides strong palliative benefit but is not curative; most men progress to hormone-refractory prostate cancer, also termed androgen-independent or castration-resistant cancer.

Historically, controversies have surrounded early versus delayed initation of ADT. A 2019 Cochrane systematic review concluded that initiating ADT early on in patients with metastatic prostate cancer, when they are still asymptomatic (as opposed to waiting until symptoms develop) probably prolongs survival and may slightly decrease the rate of skeletal events, but may increase fatigue and the risk of heart failure. [24] Current practice supports observation in selected patients with stage IV prostate cancer who are asymptomatic. [3]

Although ADT can be achieved surgically, with bilateral orchiectomy, pharmacologic ADT uses gonadotropin-releasing hormone (GnRH) agonists or antagonists. The following GnRH agonists are approved in the United States:

The following GnRH antagonists are approved in the United States:

Treatment guidelines from the American Society of Clinical Oncology (ASCO), updated in 2023, consider the following regimens as the standard of care for metastatic noncastrate prostate cancer, including in patients who received prior therapies, but whose disease has not yet progressed [25, 26] :

For treatment selection in patients with de novo metastatic noncastrate prostate cancer who are candidates for chemotherapy, ASCO recommendations are as follows [26] :

  • ADT plus adrolutamide plus docetaxel – Darolutamide, 600 mg (two 300 mg tablets orally with food) twice daily (total daily dose 1200 mg); docetaxel, 75 mg/m 2 IV, once every 3 weeks for up to six cycles, beginning within 6 weeks of the first dose of darolutamide
  • In patients with high-volume disease (HVD; defined as four or more bone metastases, one or more of which is outside of the spine or pelvis, and/or the presence of any visceral disease) – ADT plus abiraterone plus prednisone/prednisolone plus docetaxel
  • ADT plus docetaxel – For patients with HVD who are unwilling or unable to receive triplet therapy

For treatment selection in patients with de novo metastatic noncastrate prostate cancer who are not candidates for chemotherapy and are at high risk, ASCO recommends treatment with ADT, abiraterone, and prednisone/prednisolone. [26] In this setting, ASCO follows the definition of high risk for poor prognosis used in the LATITUDE trial of abiraterone plus prednisone, which comprise a positive bone scan or metastatic lesions on CT/MRI at the time of diagnosis, plus at least two of the three following high-risk factors associated with poor prognosis [27] :

  • Gleason score ≥8 (on a scale of 2 to 10, with higher scores indicating more aggressive disease)
  • At least three bone lesions
  • Measurable visceral metastasis

For treatment of metastatic noncastrate prostate cancer that is de novo or occurs after radical prostatectomy, radiation therapy, or ADT, in patients who have received no prior chemotherapy, ASCO recommends one of the following [26] :

  • ADT plus enzalutamide
  • ADT plus apalutamide

American Urological Association/Society of Urologic Oncology (AUA/SUO) guidelines for treatment of hormone-sensitive metastatic prostate cancer largely match ASCO guidelines. In addition, AUA/SUO guidelines include the following recommendations for these patients [2] :

  • In selected patients with low-volume metastatic disease, ADT combined with primary radiotherapy to the prostate may be considered.
  • Obtain a baseline PSA and serial PSAs at three- to six-month intervals after initiation of ADT, and consider periodic conventional imaging.
  • Do not offer first-generation antiandrogens (bicalutamide, flutamide, nilutamide) in combination with LHRH agonists, except to block testosterone flare.
  • Do not offer oral androgen pathway–directed therapy (eg, abiraterone acetate plus prednisone, apalutamide, bicalutamide, darolutomide, enzalutamide, flutamide, nilutamide) without ADT.

Bone protection

AUA/SUO guidelines include the following recommendations regarding bone protection in patients with advanced prostate cancer [2] :

  • Have a discussion with patients about the risk of osteoporosis associated with ADT and assess their risk of fragility fracture.
  • In patients receiving ADT, recommend preventive treatment for fractures and skeletal-related events (SREs), including supplemental calcium, vitamin D, smoking cessation, and weight-bearing exercise.

A Cancer Care Ontario guideline, endorsed by ASCO, includes the following recommendations regarding bone health and bone-targeted therapies for prostate cancer [28] :

  • For men with nonmetastatic prostate cancer who are receiving ADT and are at high risk of fracture, consider prescribing denosumab at the osteoporosis-indicated dosage, to reduce the risk of fracture. If denosumab is contraindicated or not available, a bisphosphonate is a reasonable option.

  • Fracture risk can be estimated based on risk prediction tools such as the World Health Organization Fracture Risk Assessment Tool or the Canadian Association of Radiologists and Osteoporosis Canada tool.

  • Baseline bone mineral density (BMD) testing with conventional dual x-ray absorptiometry is encouraged for men before starting ADT, to help determine fracture risk and to identify patients who would probably benefit from pharmacologic intervention. If BMD test has been done in the past 1-2 years, a repeat test may not be needed before starting ADT unless the patient was started on denosumab or a bisphosphonate.

  • The optimum duration of therapy is unknown. Current studies provide results up to 36 months of therapy.

  • Denosumab was shown to reduce fractures in this population. Other agents only improved BMD. However, there is substantial indirect evidence of fracture reduction in other populations with the use of bisphosphonates.

  • Men with castration-sensitive prostate cancer and bone metastasis may derive benefit for fracture prevention from starting or continuing denosumab at the osteoporosis-indicated dosage or a bisphosphonate. However, few trials included such men and analyses stratified by the presence or absence of bone metastases were not carried out. Therefore, the evidence of benefit is less compelling in this scenario. The ASCO Expert Panel’s opinion is that oral and intravenous bisphosphonates are also reasonable options for risk modification in this setting even though they have not been studied for fracture prevention.


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, combining EBRT with androgen-deprivation therapy (ADT) may improve progression-free survival (PFS). [4]

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 (> 78 Gy) 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 20 ng/mL indicated a risk of PSA failure that was 6.8 times higher. [29]

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.

In patients with oligometastatic recurrent prostate cancer, the phase II Observation Versus Stereotactic Ablative Radiation for Oligometastatic Prostate Cancer (ORIOLE) study demonstrated a survival benefit from stereotactic ablative radiation (SABR) treatment. ORIOLE randomly assigned 54 men who had one to three metastatic lesions measuring ≤5 cm to either SABR or observation for 6 months. Median PFS was not reached for men treated with SABR but was 5.8 months for men who underwent observation (hazard ratio, 0.30; P = 0.002). [30]


Hormone-Refractory Prostate Cancer

In patients who have castrate levels of serum testosterone, 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 with other evidence of disease progression, the PSA level does not rise at diagnosis or throughout the entire course of the disease.

Eventually, 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.

American Urological Association/Society of Urologic Oncology (AUA/SUO) guidelines include the following recommendations for determining prognosis in patients with metastatic castration-resistant prostate cancer (mCRPC) [2] :

  • Obtain baseline laboratory studies (eg, PSA, testosterone, lactate dehydrogenase [LDH], hemoglobin, alkaline phosphatase level) and review location of metastatic disease (lymph node, bone, visceral), disease-related symptoms, and performance status to inform discussions of prognosis and treatment decision-making.
  • In mCRPC patients without PSA progression or new symptoms, perform imaging at least annually.
  • In mCRPC patients with disease progression (PSA or radiographic progression or new disease-related symptoms) who previously received docetaxel and androgen pathway inhibitor, and are considering 177Lu-PSMA-617, order PSMA PET imaging.
  • Offer germline testing (if not already performed) and somatic genetic testing to identify DNA repair deficiency, microsatellite instability (MSI) status, tumor mutational burden, and other potential mutations that may inform prognosis and familial cancer risk, as well as direct potential targeted therapies.

AUA/SUO guidelines include the following recommendations for treatment of mCRPC [2] :

  • In patients with newly diagnosed mCRPC who have not received prior androgen receptor pathway inhibitors, offer continued ADT with abiraterone acetate plus prednisone, docetaxel, or enzalutamide.
  • In mCRPC patients who are asymptomatic or minimally symptomatic, consider offering sipuleucel-T.
  • In patients with symptoms from bony metastases from mCRPC and without known visceral disease or lymphadenopathy > 3 cm, offer radium-223.
  • In patients with progressive mCRPC who previously received docetaxel and an androgen pathway inhibitor and have a positive PSMA PET imaging study, offer 177Lu-PSMA-617.
  • In mCRPC patients who received prior docetaxel chemotherapy, with or without abiraterone acetate/prednisone or enzalutamide, consider offering cabazitaxel.
  • In mCRPC patients who received prior docetaxel chemotherapy and abiraterone acetate plus prednisone or enzalutamide, recommend cabazitaxel rather than an alternative androgen pathway–directed therapy.
  • Offer a PARP inhibitor to patients with deleterious or suspected deleterious germline or somatic homologous recombination repair gene-mutated mCRPC following prior treatment with enzalutamide or abiraterone acetate, and/or a taxane-based chemotherapy. Platinum-based chemotherapy may be offered as an alternative for patients who cannot use or obtain a PARP inhibitor.
  • In patients with mismatch repair deficient or microsatellite instability-high (MSI-H) mCRPC, offer pembrolizumab.

ASCO/Cancer Care Ontario recommendations for treatment of mCRPC include the following recommendations [31] :

  • Maintain continuous androgen deprivation (pharmaceutical or surgical) indefinitely regardless of additional therapies.

  • Therapies in addition to ADT that have demonstrated survival and quality-of-life benefits that should be offered: Abiraterone acetate and prednisone; enzalutamide; radium-223, in men with bone metastases; docetaxel plus prednisone

  • Therapies with demonstrated survival benefit and unclear quality-of-life benefit that may be offered: Sipuleucel-T, to men who are asymptomatic or minimally symptomatic; cabazitaxel and prednisone, to men who experience progression with docetaxel

  • Therapies with quality-of-life benefit but without demonstrated survival benefit that may be offered: Mitoxantrone plus prednisone

  • Therapies with biologic activity and unknown survival or quality-of-life benefit that may be offered: Antiandrogens (eg, bicalutamide, flutamide, nilutamide), low-dose corticosteroid monotherapy

  • Therapies without demonstrated survival or quality-of-life benefit that should not be offered: Bevacizumab, estramustine, sunitinib

  • Offer palliative care to all patients, particularly to those exhibiting symptoms or quality-of-life decrements, regardless of treatment type.

In a 2023 update, ASCO recommends using 177Lu-PSMA-617 IV once every 6 weeks for 4-6 cycles as a treatment option in patients with PSMA PET/CT–positive mCRPC that has progressed on one prior line of androgen receptor pathway inhibitor therapy and at least one line of prior chemotherapy. [32]

Individual agents

Agents used in treatment of mCRPC include the following:

  • Radium-223 dichloride
  • Cabazitaxel
  • Sipleucel-T
  • Abiraterone
  • Enzalutamide
  • Apalutamide
  • PARP inhibitors – rucaparib and olaparib
  • Lutetium Lu 177 vipivotide tetraxetan
  • Niraparib/abiraterone 

Radium-223 dichloride

Radium-223 dichloride (Xofigo), formerly alpharadin, is an alpha-particle–emitting radioactive therapeutic agent that was approved by the US Food and Drug Adminstration (FDA) in 2013. It is indicated 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. [33] 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 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. [34]

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 those in the placebo group (median 15.6 months vs 9.8 months) and were less likely to require external beam radiation therapy for bone pain and spinal cord compression. [35]


Cabazitaxel (Jevtana), a microtubular inhibitor, is a second-generation taxane approved by the FDA for second-line chemotherapy. This agent is indicated in combination with prednisone for mCRPC previously treated with a docetaxel-containing regimen. In TROPIC, an open-label randomised phase III trial in men with mCRPC who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen, median survival was 15.1 months in patients treated with cabazitaxel group, versus 12.7 months in patients treated with mitoxantrone. Median PFS was 2.8 months in the cabazitaxel group versus 1.4 months in the mitoxantrone group (P < 0.0001). [36]

Although cabazitaxel is approved for use with concomitant low-dose prednisone, a review by Buonerba et al found that omitting corticosteroids in cabazitaxel-treated patients had no negative impact on either survival or safety. An ongoing prospective phase II trial is addressing this issue. [37]


Sipuleucel-T (Provenge) is an autologous cellular immunotherapy that is approved for asymptomatic or minimally symptomatic prostate cancer with metastases resistant to standard hormone treatment. Sipuleucel-T is prepared from the patient's peripheral blood mononuclear cells, including antigen-presenting cells (APCs). These cells are activated ex vivo with recombinant human protein consisting of prostatic acid phosphatase, an antigen expressed in prostate cancer tissue. [38]


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 mCRPC as well as metastatic high-risk castration-sensitive prostate cancer (mCSPC). Trials in both mCRPC and mCSPC were halted after interim analysis showed significantly better survival with abiraterone than with placebo. [39] [40, 41]  


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

Approval was based on the phase 3 MAGNITUDE trial, a randomized, placebo-controlled trial with 423 patients, 225 (53%) of whom had BRCA gene mutations. In the subgroup with a BRCA mutation, radiographic progression-free survival was a median of 19.5 months vs 10.9 months (P = 0.0007). The subgroup with non-BRCA homologous recombination repair mutations did not demonstrate a significant improvement in radiographic progression-free survival. [42]   


Enzalutamide (Xtandi) is an oral androgen receptor inhibitor that was approved in the United States and Europe in 2014 as first-line therapy for mCRPC. [43, 44]  In 2018, the FDA expanded the approval of enzalutamide to include nonmetastatic CRPC. In 2019, enzalutamide gained FDA approval for mCSPC.

Approval for mCRPC 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. [45]

Enzalutamide proved superior to bicalutamide in the TERRAIN clinical trial, a double-blind, randomized phase 2 study in 375 asymptomatic or minimally symptomatic men with prostate cancer progression on ADT. Median progression-free survival was significantly longer with enzalutamide than bicalutamide (15.7 versus 5.8 months; 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. [46]

The ARCHES clinical trial (n = 1150) supported the approval of enzalutamide for mCSPC. Patients were randomly assigned 1:1 to enzalutamide (160 mg/day) or placebo, plus ADT, stratified by disease volume and prior docetaxel chemotherapy. The risk of radiographic progression or death was significantly reduced with enzalutamide plus ADT compared with placebo plus ADT (HR, 0.39; 95% confidence interval [CI], 0.30 to 0.50; P <  0.001; median not reached vs 19.0 months). [47]


Another androgen receptor–targeting therapy, apalutamide (Erleada), was approved in 2018 for use in nonmetastatic CRPC. The FDA based its new approval on safety and efficacy data from the phase 3 SPARTAN (Selective Prostate Androgen Receptor Targeting With ARN-509) trial. Median metastasis-free survival, which was the primary trial endpoint, was 40.5 months in the apalutamide group (n=806) as compared with 16.2 months in the placebo group (n=401). That translated into a 72% reduction in the relative risk for metastasis or death with apalutamide (HR, 0.28; 95% CI 0.23 - 0.35; P < 0.001). All participants also received hormone therapy, either gonadotropin-releasing hormone analogue therapy or surgical castration. [48]

Apalutamide was also approved for mCSPC in 2019. Approval was based on the phase 3 TITAN trial (n = 1052)j, in which apalutamide plus ADT significantly extended overall survival compared with placebo plus ADT (HR=0.67; 95% CI, 0.51-0.89; P = 0.0053). Progression-free survival was also significantly improved in the apalutamide group (HR=0.48; 95% CI, 0.39-0.60; P< 0.0001). [49]

PARP inhibitors

The PARP inhibitor rucaparib was approved by the FDA in 2020 for deleterious BRCA mutation (germline and/or somatic)–associated mCRPC 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% in the multicenter, single-arm TRITON2 clinical trial. The confirmatory TRITON3 trial is ongoing. [50]   

Another PARP inhibitor, olaparib, was approved in 2020 for deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene–mutated mCRPC in patients who had progressed following treatment with enzalutamide or abiraterone. Approval was supported by the PROfound phase III clinical trial, in which olaparib reduced risk of disease progression or death by 66% (HR 0.34, P < 0.0001) compared with abiraterone or enzalutamide. [51]  

Radioligand therapy

Lutetium Lu 177 vipivotide tetraxetan (Pluvicto) is indicated for the treatment of men with prostate-specific membrane antigen (PSMA)-positive, mCRPC who have been treated with androgen receptor pathway inhibition and taxane-based chemotherapy. It is a radioligand therapeutic agent. The active moiety is the radionuclide lutetium-177, which is linked to a moiety that binds to PSMA, a transmembrane protein expressed in prostate cancer, including mCRPC. Upon binding to PSMA-expressing cells, the lutetium-177 delivers beta-minus radiation to the cells, as well as to surrounding cells, inducing DNA damage that can lead to cell death. [52]  

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

Bone protection

AUA/SUO guidelines recommend that patients with mCRPC who are at high fracture risk due to bone loss receive preventive treatment with bisphosphonates or denosumab and referral to physicians who have familiarity with the management of osteoporosis when appropriate. [2]

Similarly, National Comprehensive Cancer Network (NCCN) guidelines recommend treatment with one of the following, in patients with prostate cancer whose absolute fracture risk warrants drug therapy [4] :

In the United Kingdom, National Institute for Health and Care Excellence (NICE) guidelines include the following recommendations [53] :

  • In patients with hormone-relapsed metastatic prostate cancer, consider zoledronic acid to prevent or reduce SREs
  • Consider oral or intravenous bisphosphonates for pain relief for patients with hormone-relapsed metastatic prostate cancer when other treatments, including analgesics and palliative radiotherapy, have not provided satisfactory pain relief.

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, 10.3 y) 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. [54]

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. [55] 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. [4]



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.

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. [56]

If given enough time, all cases of 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). [57]

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. [57]


Questions & Answers


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