Editing Castrate-Resistant Prostate Cancer (section)

===== 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.