Editing Castrate-Resistant Prostate Cancer (section)

====== 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