Editing Castrate-Resistant Prostate Cancer (section)

==== Options ====

* 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 These have largely been replaced by newer therapies.
* '''<span style="color:#ff0000">Current approved options (8):'''
** '''<span style="color:#ff0000">Chemotherapy (2):'''
**# '''<span style="color:#ff0000">Docetaxel'''
**# '''<span style="color:#ff0000">Cabazitaxel (after docetaxel)'''
** '''<span style="color:#ff0000">Androgen receptor-antagonists (1):'''
**# '''<span style="color:#ff0000">Enzalutamide (before and after docetaxel):'''
** '''<span style="color:#ff0000">Androgen synthesis-inhibitor (1)'''
**# '''<span style="color:#ff0000">Abiraterone (before and after docetaxel):'''
** '''<span style="color:#ff0000">Radiopharmaceuticals'''
*** '''<span style="color:#ff0000">Radium-223 (before and after docetaxel in patients with pain due to bone metastases AND no visceral metastasis AND lymph node metastases ≤3cm)'''
** '''<span style="color:#ff0000">Immunotherapy (1):'''
*** '''<span style="color:#ff0000">Sipuleucel-T (before and after docetaxel in asymptomatic or minimally asymptomatic)'''
** '''<span style="color:#ff0000">PARP inhibitor (2):'''
*** '''<span style="color:#ff0000">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)'''
*** '''<span style="color:#ff0000">Rucaparib in patients with BRCA 1/2 associated with mCRPC who have progressed on a previous ARAT and a taxane-based chemotherapy'''

===== Chemotherapy =====

===== Options (3): =====

# Mitoxantrone (historical)
# Docetaxel
# Cabazitaxel

====== Mitoxantrone ======
* Historical
*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 ======
* '''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 no 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