AstaZeneca and Merck Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA
Background
Deleterious germline or somatic HRRm are present in about 20% of mCRPC patients (pts). Preclinically, PARP-inhibition demonstrated synergism with AR-targeted therapy. BRCAAway is a biomarker pre-selected, multicenter, randomized, phase-2 trial which evaluated efficacy of AR-inhibitor (i) vs PARPi vs combination in first-line mCRPC pts with germline and/or somatic mutations in BRCA1/2 or ATM.
Methods
ligibility required front-line mCRPC with no prior exposure to PARPi, ARi, or chemotherapy for mCRPC, and washout of antiandrogen, radiation, and other investigational agents. Eligible pts underwent tumor next-generation sequencing (NGS)/germline testing; pts with inactivating BRCA1/2 and/or ATM alterations were randomized 1:1:1 to Arm I abiraterone (1000 mg qd) + prednisone (5mg bid), Arm II olaparib (300 mg bid), or Arm III olaparib + abiraterone/prednisone. Primary endpoint was progression free survival (PFS) as per RECIST 1.1, PCWG3, clinical assessment, or death. Secondary endpoints included measurable disease response rate (RR), PSA RR, and toxicity. Arm I and II pts could cross over at progression.
Results
165 eligible pts were registered and underwent NGS/germline testing; 61 pts with HRRm were randomized to Arms I-III. Median age: 67 years (range 42-85); 55 White, 6 Black; prior Docetaxel 26% for mHSPC, Darolutamide/Enzalutamide 3.3% for nmCRPC; disease sites: bone n=44, viscera n=12, lymph node n=31, other n=3; median baseline PSA: 14 ng/ml (range 0.15-4,037 ng/ml). HRRm status: BRCA1 n=3, BRCA2 n=46, ATM n=11, multiple n=1 (33 germline, 28 somatic). Median (range) time from randomization to last encounter in pts still alive n=56: 16 (0.8-60), 15 (4.1-36), and 23 (2.9-56) months (m) in Arms I, II and III, respectively. 51 pts had treatment-related AEs; most common Grade 3: fatigue n=3, anemia n=2, and ALT increases n=2. OS is not mature enough with 3 deaths in Arm I and 2 in Arm II. Efficacy results for Arms I-III are presented in the table. At progression 8/19 pts crossed over from abiraterone to olaparib and 8/21 pts vice versa. Median (95% CI) PFS from crossover to: olaparib 8.3 m (5.5, 15), abiraterone 7.2 m (2.8, NR). Median (95% CI) PFS from randomization: olaparib 16 m (7.8-25) and abiraterone 16 m (11-28). RR to crossover treatment: olaparib 38% and abiraterone 25%. PSA RR to crossover treatment: olaparib 50% and abiraterone 63%.
Conclusions
In mCRPC pts with BRCA1/2 or ATM alterations, abiraterone/prednisone + olaparib was well tolerated and resulted in a longer PFS vs either agent alone or sequentially. Clinical trial information: NCT03012321.
| Arm I (n=19) | Arm II (n=21) | Arm III (n=21) | |
| Median PFS from randomization, months (95% CI) | 8.4 (2.9, 25) | 14 (8.4, 20) | 39 (16, NR) |
| Objective RR, % (95% CI) | 21 (6.1, 46) | 9.5 (1.2, 30) | 29 (11, 52) |
| PSA RR, % (95% CI) | 58 (34, 80) | 67 (43, 85) | 95 (76, 100) |