Editing Castrate-Resistant Prostate Cancer

'''See 2021 CUA CRPC Guideline Notes'''

'''See 2020 AUA Advanced Prostate Cancer Guideline Notes'''

'''Includes 2021 CUA CRPC Guidelines'''

== Background ==

* '''Treatment with androgen-deprivation therapy (ADT) almost always leads to resistance to ADT''' (i.e., cancer progression despite castrate levels of serum testosterone i.e. castrate-resistent prostate cancer)
** '''Follow-up in patients treated with ADT'''
**# '''PSA'''
**# '''Imaging (bone scan and CT scan)'''
**# '''Serum testosterone'''
*** PSA, bone scans, and CT scans provide information on disease progression.
**** '''Rising PSA is usually the first manifestation of disease progression on ADT'''
***** In patients with metastatic disease, a rise in serum PSA level precedes evidence of advancing disease on the bone scan, and during this time patients may remain relatively asymptomatic.
*** '''Serum testosterone levels may provide important information when there might be reasons to suspect treatment non-compliance''' or if the choice of previous treatment involved regimens known not to result in a sustained suppression of serum testosterone to castrate levels (e.g., monotherapy with non-steroidal androgen-receptor antagonist)
* '''Definition of castration-resistant prostate cancer (CRPC): disease progression despite castrate levels of testosterone and may present as either (3):'''§
*# '''Continuous rise in serum prostate-specific antigen (PSA) levels'''
*# '''Progression of pre-existing disease'''
*# '''and/or the appearance of new metastases'''
* '''Most important urologic sequelae of advanced prostate cancer: obstructive uropathy'''
* '''Paraneoplastic effects of CRPC (5)'''
*# '''Anemia'''
*# '''Weight loss'''
*# '''Fatigue'''
*# '''Hypercoagulability'''
*# '''Increased susceptibility to infection'''

== Prognosis ==

* '''Prognostic factors (8):'''§
*# '''PSA'''
*# '''PSA doubling time'''
*# '''Performance status'''
*# '''Presence of visceral metastases'''
*# '''Presence of bone pain'''
*# '''Extent of disease on bone scan'''
*# '''Serum lactate dehydrogenase'''
*# '''Serum alkaline phosphatase'''
* '''PSA doubling time'''
** '''Associated with risk of progression to clinical metastases or death in patients with nmCRPC'''
** '''Predicts the rapidity of bone scan progression and survival''' [in patients with CRPC]
*** '''PSADT < 3 months associated with a rapid clinical course and should possibly be considered for more aggressive management approaches'''

== '''Management''' ==

=== '''UrologySchool.com Summary''' ===

* Based on 2021 CUA CRPC Guidelines)

* '''General principles'''
** '''Whenever possible, clinical trials should remain the first choice in patients with CRPC.'''
** '''ADT should be continued'''
* '''Non-metastatic CRPC'''
** '''PSADT <10 months and life expectancy > 5 years: apalutamide, enzalutamide, or darolutamide'''
* '''Metastatic CRPC'''
** '''Asymptomatic or minimially symptomatic:'''
*** '''First-line: abiraterone or enzalutamide'''
*** '''Second-line: docetaxel'''
*** Minimally symptomatic defined as pain that is relieved by acetaminophen or a non-steroidal anti-inflammatory
** '''Moderate or severe symptoms:'''
*** '''First-line: docetaxel or radium-223'''
**** '''Radium-223 if pain due to bone metastases AND no visceral metastases, AND ≤3cm lymph node metastases'''
*** '''Abiraterone or enzalutamide in patients that cannot tolerate docetaxel'''
** '''Progression after docetaxel:'''
*** '''Cabazitaxel'''
*** '''Radium-223'''
*** '''If not received prior to docetaxel:'''
**** '''Abiraterone acetate'''
**** '''Enzalutamide'''
** '''Olaparib in mCRPC patients with homologous recombination repair (HRR) mutation who have progressed on a previous androgen receptor-axis-targeted therapy (ARAT) i.e., abiraterone, enzalutamide, apalutamide, darolutamide, without or without previous docetaxel'''
** '''Bone metastasis'''
*** '''Daily calcium and vitamin D supplementation'''
*** '''Denosumab (120 mg subcutaneous) or zoledronic acid (4 mg intravenous) every four weeks'''

=== '''General principles''' ===

* '''Because any treatment for advanced disease remains non-curative, patients with advanced prostate cancer should be encouraged to participate in clinical trials.§'''
** '''Whenever possible, clinical trials should remain the first choice in patients with CRPC.'''
* '''Androgen-deprivation therapy (ADT)'''
** '''Should be continued for the remainder of a patient’s life, even during the course of subsequent therapies including chemotherapy'''
*** '''Because the androgen receptor remains active in most patients who have developed castration-resistant disease, it is recommended that ADT should be continued for the remainder of a patient’s life'''
*** '''Almost all clinical trials that test novel therapies for men with CRPC mandate continued suppression of serum testosterone levels, either with chronic ADT or with surgical castration'''
** '''In patients who develop CRPC, the addition or change of first-generation androgen receptor antagonists (flutamide, bicalutamide, or nilutamide) may be considered.§'''
*** '''Changing the anti-androgen or using corticosteroids with or without ketoconazole have been noted to cause transient PSA reductions in ≈30% of patients but have not been shown to improve any of the clinically meaningful outcome measures'''
*** '''In patients treated with luteinizing hormone-releasing hormone (LHRH) analogue monotherapy or those who have had an orchidectomy, the addition of androgen receptor antagonists, such as bicalutamide, can offer modest PSA responses that are short-lived in 30–35% of patients.'''
** '''For patients who have undergone total androgen blockade (TAB), the androgen receptor antagonist should be discontinued to test for an anti-androgen withdrawal response.§'''
*** '''Anti-androgen withdrawal phenomenon'''
**** '''Patients treated with a combination of an AR-antagonist and an LHRH agonist can experience a decline in PSA and even in objective responses with the withdrawal of the anti-androgen from the combination.'''
***** '''Based on this response, it appears that the AR-antagonist is actually exerting agonistic activity on prostate cancer cells'''
***** '''15-30% of patients may have PSA declines of > 50% after antiandrogen withdrawal, and the declines have a median duration of 3.5 to 5 months.'''
***** '''Objective, measurable tumor responses are observed less commonly'''
***** '''Overall survival is not improved in those patients demonstrating the antiandrogen withdrawal phenomenon compared to those who have not.'''
** '''Patients who do not respond to first-line ADT or who progress clinically or radiologically without significant PSA elevations may have neuroendocrine differentiation.'''
*** '''Biopsy of accessible lesions should be considered to identify these patients; these patients should then be treated with combination chemotherapy, such as cisplatin/etoposide or carboplatin/etoposide''' 

=== '''Non-metastatic CRPC§''' ===

* '''First-generation androgen receptor antagonists should be discontinued in patients already receiving these agents'''
* '''If PSADT'''
** '''≥ 10 months: observation or secondary hormonal treatments'''
** '''< 10 months (high-risk nmCRPC) AND estimated life expectancy > 5 years'''
*** '''First-line options (2):'''
***# '''Apalutamide'''
***# '''Enzalutamide'''
***# '''Darolutamide'''
**** '''All options should be with continuous ADT'''
**** '''Until 2018, there was no standard of care and no approved regimen for the nmCRPC state.'''
*** '''Second-line options in high-risk nmCRPC who are felt to be unsuitable or refuse approved therapies:'''
***# '''Observation'''
***# '''Use of first-generation androgen receptor antagonists may be attempted [if patient not previously on first-generation androgen receptor antagonist]'''
** '''PSADT < 10 months has been associated with worse outcomes and has been used in recent clinical trials as the definition for high-risk nmCRPC.'''
* '''Randomized trials in non-metastatic CRPC'''
** '''All 3 trials:'''
**# '''Included patients with PSA doubling time ≤10 months'''
**# '''Primary outcome was metastasis-free survival'''
**#* '''Given the time required for maturation of OS data in such trials, MFS is now a commonly used surrogate endpoint defined as time from randomization to date of first evidence of recorded distant metastases or death, whichever occurred first.§'''
**# '''Found significantly improved overall (≈12 months) and metastasis-free survival (≈22 months)'''
** '''Apalutamide'''
*** '''See Hormonal Therapy Chapter Notes'''
*** '''SPARTAN'''
**** '''Population: 1207 men with non-metastatic CRPC and PSA doubling time ≤10 months'''
**** '''Randomized to apalutamide (240mg daily) or placebo'''
**** '''Primary outcome: metastasis-free survival'''
**** '''Results:'''
***** '''Median follow-up: 52 months (2021 update)'''
***** '''Metastasis-free survival significantly improved by 24 months in the apalutamide arm (40 months apalutamide vs. 16 months placebo (HR for metastasis or death, 0.28)'''
***** '''Overall survival significantly improved by 14 months in the apalutamide arm (74 apalutamide vs. 60 months placebo, HR=0.78; 95% CI, 0.64 to 0.96; p=0.00002).'''
***** '''Additionally, secondary endpoints including time to symptomatic progression (HR= 0.45, p<0.001) and time to metastasis (HR=0.27, p<0.001) were significantly longer in the apalutamide arm compared to placebo. Median progression-free survival was 40.5 months in the apalutamide group versus 14.7 months in the placebo group (HR=0.29; p<0.001).'''
***** '''Overall, 10.6% of patients receiving apalutamide discontinued treatment due to adverse events compared to 7.0% of patients receiving placebo.'''
**** '''Smith, Matthew R., et al."Apalutamide treatment and metastasis-free survival in prostate cancer." New England Journal of Medicine 378.15 (2018): 1408-1418.'''
**** '''Smith, Matthew R., et al."Apalutamide and overall survival in prostate cancer." ''European urology'' 79.1 (2021): 150-158.'''
*** '''Particular attention should be paid to monitoring thyroid stimulating hormone (TSH) in individuals with known hypothyroidism given observed changes in thyroid function with apalutamide treatment'''
** '''Enzalutamide'''
*** '''See Hormonal Therapy Chapter Notes'''
*** '''PROSPER''' 
**** '''1401 men with non-metastatic CRPC, PSA doubling time ≤10 months and PSA ≥2ng/mL'''
**** '''Randomized to enzalutamide or placebo'''
**** '''Primary outcome: metastasis-free survival'''
**** '''Results:'''
***** '''Median follow-up: 48 months (2020 update)'''
***** '''Metastasis-free survival significantly improved by 22 months in the enzalutamide arm (37 enzalutamide vs. 15 months placebo (HR for metastasis or death, 0.28))'''
***** '''Overall survival'''
****** '''Original 2018 publication: median OS was not reached in either group; however, there was a 20% reduction in the relative risk of death with enzalutamide compared to placebo.'''
****** '''Updated 2020 publication: significantly improved by 11 months (67 enzalutamide vs. 56 placebo, HR 0.73)'''
***** '''Additionally, median time to PSA progression was approximately 33 months longer in patients receiving enzalutamide compared to those receiving placebo with a 93% reduction in the relative risk of PSA progression (37.2 months in the enzalutamide group compared to 3.9 months in the placebo group; HR= 0.07; P<0.001).'''
***** '''Adverse events as the primary reason for treatment discontinuation occurred in 87 patients (9%) receiving enzalutamide compared to 28 (6%) receiving placebo. Deaths due to adverse events on trial irrespective of attribution occurred in 32 patients (3%) receiving enzalutamide and 3 patients (1%) receiving placebo. Adverse events noted to occur more frequently with enzalutamide included convulsion, hypertension, neutropenia, memory impairment disorders, and major cardiovascular events'''
**** '''Hussain, Maha, et al."Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 378.26 (2018): 2465-2474.'''
**** '''Sternberg, Cora N., et al. "Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer." ''New England Journal of Medicine'' (2020).'''
** '''Darolutamide'''
*** '''See Hormonal Therapy Chapter Notes'''
*** '''ARAMIS'''
**** '''Population: 1509 men with nonmetastatic, CRPC and a PSA doubling time ≤10 months'''
**** '''Randomized to darolutamide (600 mg [two 300-mg tablets] twice daily) vs. placebo'''
**** '''Primary outcome: metastasis free survival'''
**** '''Results:'''
***** '''Metastasis-free survival improved by 22 months in the darolutamide arm (40 darolutamide vs. 18 months placebo)'''
***** '''Overall survival significantly improved by 6% at 3 years in the darolutamide arm (83% darolutamide vs. 77% placebo)'''
***** '''Darolutamide was also associated with benefits with regard to all secondary end points, including overall survival, time to pain progression, time to cytotoxic chemotherapy, and time to a symptomatic skeletal event.'''
**** '''Fizazi, Karim, et al."Darolutamide in nonmetastatic, castration-resistant prostate cancer." New England Journal of Medicine 380.13 (2019): 1235-1246.'''
**** '''Fizazi, Karim, et al."Nonmetastatic, castration-resistant prostate cancer and survival with darolutamide." ''New England Journal of Medicine'' 383.11 (2020): 1040-1049.'''
* '''Detection of metastases and imaging in untreated patients§'''
** '''Recommended screening for patients who progress on ADT without evidence of distant metastases:'''
*** '''Modalities:'''
**** '''Bone scans for bone metastases'''
**** '''Imaging of the chest/abdomen/pelvis to monitor for lymph node and visceral metastases/progression'''
***** '''Imaging techniques most commonly used include abdominal/pelvic CT and chest X-ray.'''
***** '''The role of positron-emission tomography (PET) such as PSMA-PET are still unclear and the benefits unknown'''
*** '''Frequency of imaging'''
**** '''PSADT <10 months or PSA >20: every 3–6 months'''
***** '''At high risk for developing metastases earlier'''
**** '''PSADT > 10 months: every 6–12 months'''
*** '''If metastases are detected, patients should be treated based on metastatic CRPC recommendations.'''

=== '''Metastatic CRPC''' ===

* '''mCRPC is heterogeneous, both in terms of distribution of metastatic sites and in terms of PSA kinetics (e.g., PSADT).'''
* '''Sites of metastases'''
** '''Bone'''
*** '''90% of males with CRPC will develop bone metastases'''
*** '''Morbidity of bone metastases'''
***# '''Pain'''
***# '''Pathological fractures'''
***# '''Spinal cord compression'''
***# '''Bone marrow failure'''
***#* '''Extensive bone marrow replacement may cause impairment in hematologic function (most often manifested as anemia and thrombocytopenia)'''
*** '''Spinal cord compression from malignancy is an emergency'''
**** '''See Radiation Chapter Notes'''
** '''Visceral'''
*** '''Clinical involvement of visceral sites (excluding lymph nodes) is less common, even in patients with widespread castration resistant disease.'''
*** '''Even more rare is the occurrence of visceral disease in the absence of any bone involvement.'''
* '''CRPC Clinical Trial Endpoints'''
** '''The evaluation of “response rate” as the primary end point in clinical trials of mCRPC is discouraged because the majority of tumor burden in metastatic prostate cancer is found in bone'''
*** '''Responses to treatment (e.g., tumor shrinkage) in soft-tissue sites alone (e.g., nodal or visceral sites) might not reflect a major treatment benefit because it represents only a small proportion of the overall disease burden.'''
** '''“Progression-free survival” (PFS) (that takes into account radiographic progression of bone and/or soft-tissue disease) is a much more acceptable trial end point'''

==== '''Management''' ====

* '''Older agents such as diethylstilbestrol (DES), aminoglutethimide, ketoconazole, and corticosteroids have been reported to produce some benefit. These have largely been replaced by newer therapies.'''
* '''Current approved options (8):'''
** '''Chemotherapy (2):'''
**# '''Docetaxel'''
**# '''Cabazitaxel (after docetaxel)'''
** '''Androgen receptor-antagonists (1):'''
**# '''Enzalutamide (before and after docetaxel):'''
** '''Androgen synthesis-inhibitor (1)'''
**# '''Abiraterone (before and after docetaxel):'''
** '''Radiopharmaceuticals'''
*** '''Radium-223 (before and after docetaxel in patients with pain due to bone metastases AND no visceral metastasis AND lymph node metastases ≤3cm)'''
** '''Immunotherapy (1):'''
*** '''Sipuleucel-T (before and after docetaxel in asymptomatic or minimally asymptomatic)'''
** '''PARP inhibitor (2):'''
*** '''Olaparib (before and after docetaxel in patients with homologous recombination repair (HRR) mutation who have progressed on a previous androgen receptor-axis-targeted therapy (ARAT) i.e., abiraterone, enzalutamide, apalutamide, darolutamide)'''
*** '''Rucaparib in patients with BRCA 1/2 associated with mCRPC who have progressed on a previous ARAT and a taxane-based chemotherapy'''

===== '''Chemotherapy: mitoxantrone, docetaxel, cabazitaxel''' =====

* '''Mitoxantrone'''
** '''First step forward in the chemotherapeutic management of CRPC; prednisone used prior'''
** '''2 RCTs found that addition of mitoxantrone to either prednisone (Tannock et al, 1996) or hydrocortisone (Kantoff et al, 1999) resulted in significant improvements of various QOL parameters, including pain, but no difference in survival'''
** '''In 1997, FDA approved mitoxantrone with prednisone for patients with symptomatic CRPC'''
** '''Although it does not prolong survival, mitoxantrone has been approved to palliate symptoms associated with metastatic disease, and was often used in patients who have previously received docetaxel and/or cabazitaxel, or in those who would not tolerate these agents.[historical?]'''
* '''Docetaxel'''
** '''The next significant advance in the use of chemotherapy for CRPC'''
** '''MOA: inhibits microtubule assembly and disassembly; member of the taxane family'''
** '''Standard first-line chemotherapy for mCRPC'''
*** '''Prolongs progression-free and overall survival'''
*** '''Reduces pain and improves quality of life'''
*** '''TAX 327'''
**** '''Population: 1006 mCRPC patients with no previous chemotherapy treatment and stable pain scores'''
**** '''Randomized to (all with concomitant prednisone 5 mg twice daily) mitoxantrone vs. docetaxel 75 mg/m2 IV every 3 weeks vs. docetaxel 30 mg/m2 IV weekly. All patients remained on ADT'''
**** '''Results:'''
***** '''Median follow-up: 20.7 months'''
***** '''OS significantly improved in the every-3-week docetaxel group, not in the weekly docetaxel group (18.9 months every 3 weeks, 17.3 months in the weekly docetaxel group, and 16.4 months in the mitoxantrone group)'''
** '''Adverse events (6):'''
**# '''Myelosuppression (neutropenia)'''
**# '''Fatigue'''
**# '''Fever'''
**# '''Diarrhea, abdominal pain, constipation'''
**# '''Peripheral edema'''
**# '''Neurotoxicity'''
**# '''Hyperlacrimation'''
**# '''Nail dystrophy'''
* '''Cabazitaxel'''
** '''MOA: inhibits microtubule assembly and disassembly; member of the taxane family'''
** '''Indications'''
*** '''mCRPC, post-docetaxel'''
** '''TROPIC trial'''
*** '''Population: 755 patients with mCRPC who had progressed after docetaxel-based chemotherapy'''
*** '''Randomized to mitoxantrone + prednisone vs. cabazitaxel + prednisone, each administered every 3 weeks'''
*** '''Results:'''
**** '''Median follow-up: 12.8 months,'''
**** '''Cabazitaxel significantly improved OS by 2 months (median OS 15.1 months in the cabazitaxel arm compared to 12.7 months in men receiving mitoxantrone)'''
**** '''Cabazitaxel also improved PFS by 1.4 months (2.8 months cabazitaxel vs. 1.4 months mitoxantrone)'''
**** '''Cabazitaxel resulted in more-clinically-significant diarrhea, but its primary toxicity is hematologic with 82% of patients developing grade 3 or 4 neutropenia, 8% developing febrile neutropenia and 5% resulting in death. The FDA label indication for this drug recommends prophylactic neutrophil growth factor support in those patients most susceptible to neutropenia, including older individuals and those with significant prior radiotherapy.'''
*** '''De Bono, Johann Sebastian, et al. "Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial." The Lancet 376.9747 (2010): 1147-1154.'''
** '''FDA-approved in 2010 for the second-line treatment of docetaxel-refractory mCRPC'''
** '''Adverse events'''
**# '''Neutropenia (including febrile neutropenia)'''
**# '''Diarrhea'''
*** '''Use of growth factor support should be strongly considered when administering cabazitaxel'''
* '''Given the activity of cabazitaxel in docetaxel-pretreated patients, FIRSTANA assessed whether cabazitaxel 20 mg/m2 (C20) or 25 mg/m2 (C25) is superior to docetaxel 75 mg/m2 (D75) in terms of OS in patients with chemotherapy-naïve mCRPC. C20 and C25 did not demonstrate superiority for OS versus D75 in patients with chemotherapy-naïve mCRPC'''

===== '''Androgen receptor-antagonists: enzalutamide''' =====

* '''Enzalutamide'''
** '''See Hormonal Therapy Chapter Notes'''
** '''Indications'''
*** '''mCRPC, pre- or post-docetaxel'''
** '''AFFIRM (2012)'''
*** Population: 1,199 men with mCRPC who had failed docetaxel, ketoconazole naïve
*** Randomized to enzalutamide (160mg/day) vs. placebo
*** Primary outcome: OS
*** Results:
**** Significantly improved OS by 5 months with enzalutamide (18.4 enzalutamide vs. 13.6 months placebo)
**** All secondary endpoints were also significantly improved with enzalutamide: percentage of patients with 50% PSA reduction, soft-tissue response rate, QOL response rate, time to PSA progression, radiographic PFS (5.3 months) and time to first SRE.
*** Scher, Howard I., et al."Increased survival with enzalutamide in prostate cancer after chemotherapy." ''New England Journal of Medicine'' 367.13 (2012): 1187-1197.
*** FDA-approved in 2012 for treatment of mCRPC in patients who have previously received docetaxel-containing chemotherapy
** To evaluate the efficacy of enzalutamide in the prechemotherapy setting, the PREVAIL study was designed.
** '''PREVAIL (2014)'''
*** Population: 1,717 chemotherapy-naïve patients with asymptomatic or minimally symptomatic mCRPC
*** Randomized to oral enzalutamide (160mg/day) or placebo. Patients also had not received previous ketoconazole or abiraterone.
*** Results:
**** Significantly improved OS (HR 0.71) and radiographic PFS (HR 0.19) with enzalutamide
*** Beer, Tomasz M., et al."Enzalutamide in metastatic prostate cancer before chemotherapy." New England Journal of Medicine 371.5 (2014): 424-433.
*** FDA-approved in 2015 for treatment of mCRPC in docetaxel-naive patients

===== '''Androgen synthesis-inhibitor: abiraterone''' =====

* '''Standard hormonal therapies such as LHRH analogues inhibit gonadal androgenesis but do not affect androgen synthesis from adrenal or other extragonadal sources that may account for up to 10% of total androgen production'''. It has also been suggested that CRPC itself may produce intratumoral androgens autonomously
* '''Abiraterone acetate'''
** '''See Hormonal Therapy Chapter Notes'''
** '''Indications'''
*** '''mCRPC, pre- or post-docetaxel'''
** '''Dosing: abiraterone 1000 mg daily'''
** '''COU-AA-301'''
*** Population: 1,195 men with docetaxel-pretreated ketoconazole-naive mCRPC
*** Randomized to abiraterone 1000 mg daily plus prednisone 10 mg daily or placebo plus prednisone
*** Results:
**** OS significantly improved by 4 months with abiraterone (median OS 14.8 abiraterone vs. 10.9 months placebo (HR 0.65)).
**** Abiraterone also improved radiographic PFS (5.6 vs. 3.6 months), improved time to PSA progression (10.2 vs. 6.6 months), and produced more PSA responses (38% vs. 10%.
**** Abiraterone also had significant benefits compared with placebo in terms of pain relief, patient reported fatigue, delaying pain progression, and prevention of skeletal-related events
*** In 2010, the FDA has approved abiraterone plus prednisone for the treatment of patients with mCRPC who have received previous docetaxel chemotherapy based on the results of the COU-AA-301 study.
*** De Bono, Johann S., et al."Abiraterone and increased survival in metastatic prostate cancer." ''New England Journal of Medicine'' 364.21 (2011): 1995-2005.
** Because of the success of abiraterone in the post-docetaxel setting, a second randomized phase III trial (COU-AA-302) targeting men with docetaxel- and ketoconazole-naive CRPC was undertaken.
** '''COU-AA-302''' [Ryan et al. NEJM 2013, updated results Ryan et al. Lancet Oncol 2015]
*** Population: 1,088 asymptomatic or mildly symptomatic chemotherapy-naive patients with mCRPC
*** Randomized to abiraterone (1000mg/day) and prednisone (5mg/BID) or placebo and prednisone.
*** The coprimary end points of this trial were radiographic PFS and overall survival
*** Results:
**** PFS significantly improved by 8 months with abiraterone (16 abiraterone vs. 8 months placebo)
**** OS significantly improved by 4 months with abiraterone
*** Ryan, Charles J., et al."Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study." ''The Lancet Oncology'' 16.2 (2015): 152-160.
*** In 2015, the FDA expanded the label for abiraterone to encompass all patients with mCRPC (i.e., including those who have not received docetaxel chemotherapy) based on the results of the COU-AA-302 trial
* Additional CYP17-targeting agents (e.g., orteronel) and AR-targeting agents (e.g., ARN-509) are in clinical development

===== '''Radiopharmaceuticals''' =====

* '''Radium-223'''
** '''MOA: Alpha-emitting radiopharmaceutical'''
** '''Indications'''
*** '''mCRPC, pain from bone metastasis AND no evidence of visceral metastasis AND bulky (>3cm) lymph-node metastases, pre- or post-docetaxel'''
** '''Adverse events'''
*** '''Lymphocytopenia'''
** '''A bone-supportive agent (denosumab or zoledronic acid) should always be used in mCRPC (see below), but especially when using radium-223'''
** '''PSA measurements while receiving radium-223 cannot provide evidence of whether patients are benefitting or not.'''§
*** '''Given the mechanism of action of the drug, alkaline phosphatase appears to be better marker of activity.'''
** '''ALSYMPCA'''
*** '''Population''': 921 '''men with symptomatic and progressive mCRPC with or without prior docetaxel and no evidence of visceral metastasis or bulky (>3cm) lymph-node metastases'''
*** '''Randomized to radium-223 vs. placebo'''
*** Primary outcome: OS
*** Results:
**** '''OS improved by 4 months''' (14.9 months radium-223 vs. 11.3 months placebo, HR 0.70) in Radium-223 arm
**** Time to first SRE improved from 9.8 month with placebo to 15.6 months with radium-223 (HR=0.66). Significant improvements in QOL measurements were reported in the patients treated with radium-223.
**** Rates of grade 3 or 4 neutropenia and thrombocytopenia were low at 2.2% and 6.3%, respectively. Diarrhea was the most common side effect in 223Ra-treated patients
*** Parker, Christopher, et al."Alpha emitter radium-223 and survival in metastatic prostate cancer." ''New England Journal of Medicine'' 369.3 (2013): 213-223.
** '''Should not be combined with abiraterone'''
*** ERA 223 was a RCT that compared the combination of radium-223 with abiraterone/prednisone vs. abiraterone/prednisone alone and in the first-line mCRPC setting demonstrated no advantage and an increased risk of fractures§
* '''Lutetium-177–PSMA-617'''
** MOA: radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment
** '''VISION trial'''
*** Population: 831 patients with metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor–pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)–labeled PSMA-11 positron-emission tomographic–computed tomographic scans
*** Randomized to 177Lu-PSMA-617 vs. standard of care
*** Alternate primary end points: imaging-based progression-free survival and overall survival
*** Results
**** Median follow-up 20.9 months
**** 177Lu-PSMA-617 significantly improved progression-free survival and overall survival
*** Sartor, Oliver, et al."Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer." ''New England Journal of Medicine'' (2021).
** '''TheraP trial'''
*** Phase 2 trial of 200 males with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment
*** Randomized to 177Lu-PSMA-617 vs cabazitaxel
*** Primary outcome: PSA response defined by a reduction of at least 50% from baseline.
*** Results
**** Significantly improved PSA response with 177Lu-PSMA-617
*** Hofman, Michael S., et al."[177Lu] Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial." ''The Lancet'' 397.10276 (2021): 797-804.

===== '''Immunotherapy''' =====

* '''Sipuleucel-T (Provenge)'''
** '''MOA: personalized vaccine that is derived from autologous CD54+ dendritic cells'''
** '''Indications'''
*** '''mCRPC, asymptomatic or minimally symptomatic, pre- or post-docetaxel'''
**** Minimally symptomatic defined as pain that is relieved by acetaminophen or a non-steroidal anti-inflammatory
** '''IMPACT'''
*** '''Population''': 512 '''men with asymptomatic or minimally symptomatic, pre- or post-docetaxel, mCRPC'''
**** Notably, this study did not enroll men with visceral metastases or those taking narcotics for cancer pain, and most patients (85%) were chemotherapy naïve
*** Randomized to sipuleucel-T or placebo
*** Results:
**** OS was improved by 4 months in the sipuleucel-T group (median OS 26 months in the sipuleucel-T arm vs. 22 months in the placebo group (HR 0.78, P = .03)), despite 64% of patients on placebo crossing over to receive salvage sipuleucel-T at the time of disease progression.
**** In the subset of patients with previous chemotherapy exposure, overall survival trended in favor of sipuleucel-T, but this effect was not statistically significant. Therefore, '''although this immunotherapy is approved for all patients with asymptomatic or minimally symptomatic CRPC, it will likely provide its largest impact in the pre-chemotherapy setting.'''
**** Similar to previous studies with sipuleucel-T, the IMPACT study detected no difference in PFS or PSA/radiographic response rates between the two treatment arms.
*** Kantoff, Philip W., et al."Sipuleucel-T immunotherapy for castration-resistant prostate cancer." ''New England Journal of Medicine'' 363.5 (2010): 411-422.
** '''Indications'''
**# '''mCRPC, asymptomatic or minimally symptomatic AND without visceral metastases or cancer-related pain requiring narcotics.'''
**#* '''Should not be used in patients with visceral disease, or in those requiring narcotic analgesics for cancer-related pain.'''
**#* '''In 2010, the FDA approved Sipuleucel-T as the first therapeutic vaccine to be approved for the treatment of any cancer'''
* ProstVac-VF
** Poxviral-based PSA-directed prostate cancer vaccine
** Administered by subcutaneous injection
** In phase III testing for men with asymptomatic or minimally symptomatic mCRPC.
* '''Pembrolizumab'''
** '''KEYNOTE-199'''
*** Phase II trial
*** '''Population: mCRPC treated with docetaxel and one or more targeted endocrine therapies'''
**** 3 cohorts: Cohorts 1 and 2 enrolled patients with RECIST-measurable PD-L1-positive and PD-L1-negative disease, respectively. Cohort 3 enrolled patients with bone-predominant disease, regardless of PD-L1 expression.
*** All patients received pembrolizumab 200 mg every 3 weeks for up to 35 cycles.
*** Primary outcome: objective response rate per RECIST
*** Results:
**** Objective response rate was 5% (95% CI, 2% to 11%) in cohort 1 and 3% (95% CI, < 1% to 11%) in cohort 2. 
*** Antonarakis, Emmanuel S., et al."Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study." ''Journal of Clinical Oncology'' 38.5 (2020): 395.
* '''Ipilumab'''
** MOA: blockade of the immune checkpoint molecule CTLA-4 (cytotoxic T lymphocyte-associated antigen-4)
** '''CA184-043'''
*** Population: 799 patients with mCRPC with progression after docetaxel
*** Randomized to ipilimumab vs. placebo
*** Resuls:
**** OS not improved in the ipilimumab arm (median OS 11.2 months with ipilimumab vs. 10.0 months with placebo
*** Kwon, Eugene D., et al."Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial." The lancet oncology 15.7 (2014): 700-712.
** Other trial
*** Randomized to ipilimumab vs. placebo
*** Results:
**** OS not improved in the ipilimumab arm (median OS 28.7 months in the ipilimumab arm vs. 29.7 months in the placebo arm (HR 1.11, P = .3667)).
**** Median progression-free survival was significantly improved - 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (HR 0.67; 95.87% CI, 0.55 to 0.81).
*** Beer, Tomasz M., et al."Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer." J Clin Oncol 35.1 (2017): 40-47.

===== '''PARP inhibitors''' =====

* '''Olaparib'''
** Homologous recombination repair (HRR) gene mutations occur in approximately 20–30% of prostate cancers from patients with metastatic disease, with the most common altered gene being BRCA2.
*** Defective HRR renders a cancer susceptible to poly (ADP-ribose) polymerase (PARP) inhibition in a form of synthetic lethality.
** '''MOA: poly(adenosine diphosphate–ribose) polymerase (PARP) inhibitor'''
** '''Indications'''
*** '''2021 CUA CPRC Guidelines'''
**** '''mCPRC and homologous recombination repair (HRR) mutation who have progressed on a previous androgen receptor-axis-targeted therapy (ARAT) i.e., abiraterone, enzalutamide, apalutamide, darolutamide'''
*** Health Canada approval for patients with deleterious or suspected deleterious germline or somatic BRCA1/2 or ATM mutations who have progressed following prior treatment with an NHT (i.e., abiraterone, enzalutamide, apalutamide, darolutamide).
*** U.S. Food and Drug Administration approved prostate cancers harboring a broader spectrum of 11 additional genes that are directly or indirectly involved in HRR (BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, RAD51B, RAD51C, RAD51D, and RAD54L), which comprised an additional cohort in the PROfound study.
*** European regulatory authority approved only for BRCA1/2 alterations.
** '''PROfound'''
*** Population: 387 patients with metastatic castration-resistant prostate cancer who had disease progression while receiving a new hormonal agent (e.g., enzalutamide or abiraterone). 
**** All the men had a qualifying alteration in prespecified genes with a direct or indirect role in homologous recombination repair. 
***** Cohort A (245 patients) had at least one alteration in ''BRCA1'', ''BRCA2'', or ''ATM''
***** Cohort B (142 patients) had alterations in any of 12 other prespecified genes, prospectively and centrally determined from tumor tissue.
*** Randomized to in a 2:1 ratio to receive olaparib or the physician’s choice of enzalutamide or abiraterone (control)
*** Primary outcome: imaging-based progression-free survival in cohort A 
*** Results:
**** Imaging-based progression-free survival in cohort A: significantly improved in the olaparib group (7.4 months olaparib vs. vs. 3.6 months control; hazard ratio for progression or death, 0.34)
**** Overall survival improved with olaparib by 4.4 months in cohort A (19.1 months olaparib vs. 15.7 months control) and by 2.6 months in cohort B
**** Adverse events: anemia, fatigue or asthenia, nausea, diarrhea
*** de Bono, Johann, et al."Olaparib for metastatic castration-resistant prostate cancer." ''New England Journal of Medicine'' 382.22 (2020): 2091-2102.
*** Hussain, Maha, et al. "Survival with olaparib in metastatic castration-resistant prostate cancer." ''New England Journal of Medicine'' 383.24 (2020): 2345-2357.
* '''Rucaparib'''
** '''Indications'''
*** '''FDA-approved for patients with BRCA 1/2 associated with mCRPC who have been treated with an ARAT and a taxane-based chemotherapy'''
** '''TRITON-2'''
*** Phase II trial
*** Population: 115 patients with a ''BRCA'' alteration, who progressed after one to two lines of next-generation androgen receptor-directed therapy and one taxane-based chemotherapy for mCRPC, with or without measurable disease
*** Abida, Wassim, et al."Rucaparib in men with metastatic castration-resistant prostate cancer harboring a BRCA1 or BRCA2 gene alteration." ''Journal of Clinical Oncology'' 38.32 (2020): 3763.

===== '''Targeted treatments''' =====

* Despite negative studies with bevacizumab and aflibercept, angiogenesis remains a valid therapeutic target in prostate cancer, as exemplified by the novel agent tasquinimod.
* Because of the reciprocal interactions between the PI3K/Akt/mTOR pathway and the AR signaling pathway, dual inhibition of both pathways concurrently will likely represent the most fruitful therapeutic strategy
* Cabozantinib
** Inhibitor of c-Met and VEGFR2
** Studied in two phase III trials in men with mCRPC with progressive disease following treatment with docetaxel and a novel AR-directed agent (abiraterone or enzalutamide)
*** COMET-1 evaluated the efficacy of single-agent cabozantinib versus placebo, with a primary end point of overall survival.
*** COMET-2 investigated the effect of cabozantinib versus mitoxantrone on quality-of-life measures and pain control; the primary end point of that study was the frequency of durable pain responses lasting at least 12 weeks (whereas overall survival was a secondary end point).
*** These trials were considered the registrational studies for cabozantinib in advanced CRPC. Both studies failed to meet their primary end points. However, '''cabozantinib appeared particularly active in treating bone metastases''', with 12% of patients showing complete resolution of disease on technetium-99 bone scan. Reductions in pain scores and narcotic use were also observed in a significant proportion of patients. Importantly, PSA changes did not correlate with the favorable results seen on imaging studies or other signs of clinical benefit; some patients exhibited rising PSA levels despite reductions in the size of soft-tissue lesions or bone metastases.
* Custirsen is an antisense oligonucleotide against clustering mRNA, which may play a role in reversing resistance to taxane chemotherapies

==== '''Approach to mCRPC management''' ====

* '''Chemotherapy naïve mCRPC'''
** '''Asymptomatic or minimally symptomatic'''

**** '''First-line (2):'''
****# '''Abiraterone acetate 1000 mg/day plus prednisone 5 mg PO BID OR'''
****# '''Enzalutamide 160 mg/day'''
****#* '''Patients who have had little or no response to hormonal agents OR who progress with minimal change in PSA OR with significant visceral metastases should be considered for early chemotherapeutic options'''
***** Minimally symptomatic defined as pain that is relieved by acetaminophen or a non-steroidal anti-inflammatory
**** '''Second-line: Docetaxel (75 mg/m2 every 3 weeks plus prednisone 5 mg PO BID)'''
***** The timing of docetaxel therapy in men with evidence of metastases but without symptoms should be individualized based on patients’ clinical status and preferences
***** '''Rising PSA only during docetaxel chemotherapy should not be used as the sole criteria for progression; assessment of response should incorporate clinical and radiographic criteria'''
*** '''Moderate or severe symptoms'''
**** '''Docetaxel''' (75 mg/m2 every 3 weeks plus prednisone 5 mg PO BID) '''is recommended'''
**** '''Radium-223 every 4 weeks for six cycles is recommended in patients with pain due to bone metastases and who do not have visceral metastases'''
***** '''Radium-223 significantly improved overall survival and reduced symptomatic skeletal related events in patients with symptomatic mCRPC who had previously received docetaxel chemotherapy or were deemed unfit for docetaxel'''
**** '''Abiraterone''' (1000 mg/day plus prednisone 5 mg twice daily) '''or enzalutamide''' (160mg/day) '''may be considered as first-line therapy in patients who cannot receive or refuse docetaxel'''
***** NOTE: The studies in the chemo-naive setting did not include patients with moderate or severe symptoms; however, abiraterone and enzalutamide may be potential therapeutic options in patients who are deemed chemotherapy-ineligible or refuse chemotherapy
**** '''Alternative therapies that have not demonstrated improvement in OS but can provide disease control, palliation, and improve quality of life include:'''
***** '''Weekly docetaxel plus prednisone'''
***** '''Mitoxantrone plus prednisone'''
** '''mCRPC who progress after docetaxel-based chemotherapy'''
*** '''Options with survival benefit (5):'''
**** '''Cabazitaxel''' (25 mg/m2) plus prednisone (5 mg/day) '''TROPIC trial'''
**** '''Radium-223 every four weeks for six cycles ALSYMPCA trial'''
**** '''If not received prior to docetaxel:'''
***** '''Abiraterone acetate''' (1000 mg per day) '''plus prednisone''' (5 mg twice daily) '''COU-AA-301 trial'''
***** '''Enzalutamide''' (160 mg/day) '''AFFIRM trial'''
*** '''Options with unknown survival benefit'''
**** '''Docetaxel plus prednisone re-exposure in patients who have had a previous favourable response to docetaxel may be reasonable'''
**** '''Mitoxantrone may be considered a therapeutic option in symptomatic patients with mCRPC in the first- or second-line setting. Mitoxantrone has not shown any survival advantage but may provide symptomatic relief'''
** '''Other supportive agents'''
*** '''Systemic corticosteroid therapy with low-dose prednisone or dexamethasone may also offer improvements in PSA values and/or palliative outcomes in up to 30% of patients in both symptomatic and asymptomatic men.'''
**** '''Steroids may also exert an anti-neoplastic effect on prostate cancer'''
** '''mCRPC with bone metastasis'''
*** '''Denosumab (120 mg subcutaneous) or zoledronic acid (4 mg intravenous) every 4 weeks, along with daily calcium and vitamin D supplementation, is recommended to prevent disease-related skeletal related events'''§
**** '''Skeletal related events include (4):'''
****# '''Pathological fractures'''
****# '''Spinal cord compression'''
****# '''Surgery'''
****# '''Radiation therapy to bone'''
**** '''Bisphosphonates''' '''-dronate''' (pami'''dronate''', alen'''dronate''', rise'''dronate''', and zole'''dronate''')
***** '''MOA: reduce bone resorption by inhibiting osteoclastic activity and proliferation'''
***** Bisphosphonates other than zoledronic acid are not known to be effective to prevent disease-related SREs.§
***** '''Zoledronate'''
****** '''A potent intravenous bisphosphonate'''
****** '''Indications:'''
******* '''Progressive mCRPC with evidence of bone metastasis.'''
******** '''In a prospective randomized trial of 422 patients with progressive CRPC and bone metastases, zoledronate was shown to reduce the incidence of skeletal-related events (e.g., pain, fractures) compared with placebo (Saad et al, 2004).'''
******* In non-metastatic prostate cancer patients receiving long-term ADT, zoledronate and pamidronate have been shown to '''increase bone mineral density'''
******* '''In hormone-sensitive prostate cancer, STAMPEDE showed that the addition of zoledronic acid did not significantly reduce time to first skeletal-related event compared to ADT alone.''' STAMPEDE showed that docetaxel + ADT had reduced time to first skeletal-related events compared to ADT alone
****** '''Contraindications (1)'''
******# '''Renal impairment'''
******#* '''Should not be used with baseline creatinine clearance <30 mL/min'''
******#* '''Can be dose adjusted for decreased renal function'''
****** '''Adverse events:'''
******* '''Osteonecrosis of the jaw'''
******* '''Hypocalcemia'''
******** '''Concomitant administration of oral calcium supplements (1000 mg/day) and vitamin D (800 units/day) is often recommended.'''
******* '''Fatigue'''
******* '''Myalgias'''
******* '''Fever'''
******* '''Anemia'''
******* '''Mild elevation of serum creatinine'''
**** '''Denosumab'''
***** '''MOA: human monoclonal antibody against RANK ligand,''' which mediates osteoclast differentiation and activation
***** '''Improve BMD and decrease risk of vertebral fractures in men with non-metastatic PCa receiving ADT at high risk of fracture§'''
***** '''Denosumab vs. zoledronate in mCRPC'''
****** Population: 1904 patients with bisphosphonate-naive mCRPC
****** Randomized to denosumab vs. zoledronate
****** Primary outcome: skeletal related events
****** Results:
******* Denosumab showed an improved time-to-first skeletal-related event (20.7 vs. 17.1 months, P = .008) and a longer time to first-and-subsequent skeletal-related events (HR 0.82, P = .004) (Fizazi et al, 2011).
******* No difference in overall survival or PFS between study arms
***** '''Adverse effects:'''
****** '''Osteonecrosis of the jaw'''
******* '''Occurs in about 2-4% of patients'''
****** '''Hypocalcemia'''
******* '''Concomitant administration of oral calcium supplements (1000 mg/day) and vitamin D (800 units/day) is often recommended.'''
****** '''Fatigue'''
****** '''Nausea'''
****** '''Hypophosphatemia'''
***** '''Advantage of denosumab is that it does not require dose adjustment or monitoring for renal impairment'''
**** '''Optimal duration of zoledronic acid and denosumab in CRPC and bone metastases is undefined.§'''
***** '''The risk of osteonecrosis of the jaw appears to be related to time on bone-targeted therapy, caution should be taken in using these agents > 2 years'''
***** Methods to reduce risk of osteonecrosis of the jaw (ONJ) for patients treated with bone-targeted therapies (3):
****** Encourage good oral hygiene
****** Baseline dental evaluation for high-risk individuals
****** Avoidance of invasive dental surgery during therapy
**** Denosumab and zoledronic acid are not approved and not indicated for SRE prevention in the treatment of metastatic castration-sensitive prostate cancer or for bone metastases prevention
**** Zoledronic acid and denosumab have been used in combination with all the agents presently in use for the treatment of mCRPC. To date, there have been no additional safety issues of concern that have been reported.§
*** '''Palliative radiation'''
**** '''Focal bone pain in patients with CRPC can be well controlled using external-beam localized radiation therapy.'''
**** '''In general, it is also recommended that painful areas that are shown to be abnormal on bone scintigraphy should be evaluated with plain radiographs or CT imaging to exclude the presence of osteolytic lesions or pathologic fractures.'''
**** '''Malignant spinal cord compression is an oncological emergency that requires immediate diagnosis, if suspected, with an MRI. Options for treatment are radiation with (3):'''§
****# '''Steroids'''
****# '''Debulking surgery'''
****# '''Vertebrectomy with stabilization'''
** '''Sequential treatments in mCRPC'''
*** '''The optimal sequence of available options remains unknown. In general, it is felt that changing therapeutic mechanism of action with each line of therapy is likely to lead to better and longer lasting response'''

== Questions ==

# What is the mechanism of action of docetaxel? What toxicities are associated with its use?
#* MOA: inhibits microtubule assembly/disassembly
#* Toxicities: myelosuppression, neurotoxicity, fatigue, peripheral edema, hyperlacrimation, and nail dystrophy

== Answers ==

# What is the mechanism of action of docetaxel? What toxicities are associated with its use?
#* MOA: inhibits microtubule assembly/disassembly
#* Toxicities: myelosuppression, neurotoxicity, fatigue, peripheral edema, hyperlacrimation, and nail dystrophy

== References ==

* Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 121
* Saad, Fred, et al."2021 Canadian Urological Association (CUA)-Canadian Uro Oncology Group (CUOG) guideline: Management of castration-resistant prostate cancer (CRPC)." ''Canadian Urological Association Journal'' 15.2 (2021): E81.