KEY TAKEAWAYS
- The Phase 2 trial aimed to investigate the efficacy of AR-inhibitor (i) vs PARPi as 1L treatment in mCRPC pts.
- The primary endpoint was to determine PFS, clinical assessment, or death.
- Researchers noticed that in mCRPC pts with BRCA1/2 or ATM alterations, the combination of abiraterone/prednisone + olaparib demonstrated superior tolerability PFS.
Deleterious germline or somatic homologous recombination-repair mutations (HRRm) are observed in approximately 20% of metastatic castration-resistant prostate cancer (mCRPC) patients (pts). Previous preclinical studies have indicated synergistic effects between PARP inhibition and androgen receptor (AR)–targeted therapy. The BRCAAway was designed as a pre-selected biomarker in a multicenter, randomized phase-2 study.
Maha H. A. Hussain and her research team aimed to evaluate the efficacy of AR inhibitor (i) alone, PARP inhibitor (PARPi) alone, or their combination as the first-line treatment for mCRPC pts harboring germline and/or somatic mutations in BRCA1/2 or ATM.
Researchers performed an inclusive analysis to assess eligibility criteria for the BRCAAway trial, focusing on front-line mCRPC pts without prior exposure to poly (ADP-ribose) polymerase inhibitors (PARPi), androgen receptor inhibitors (ARi) or chemotherapy for mCRPC. Additionally, participants underwent a washout period for antiandrogen, radiation, and other investigational agents. Eligible pts underwent tumor next-generation sequencing (NGS) and germline testing, with those exhibiting inactivating BRCA1/2 and/or ATM alterations randomized in a 1:1:1 ratio to receive Arm I (abiraterone 1000 mg qd + prednisone 5mg bid), Arm II (olaparib 300 mg bid), or Arm III (olaparib + abiraterone/prednisone).
The primary endpoint of the study was progression-free survival (PFS), evaluated as per RECIST 1.1, PCWG3 criteria, clinical assessment, or death. Secondary endpoints encompassed measurable disease response rate (RR), prostate-specific antigen response rate (PSA RR), and toxicity assessment. Arm I and II pts could cross over at progression.
About 165 pts were initially registered and underwent NGS and germline testing; subsequently, 61 pts with HRRm were randomized into Arms I-III. The median age of the cohort was 67 years (range 42-85), with 55 individuals identified as White and 6 as Black. Prior treatment history revealed 26% of pts had received Docetaxel for metastatic hormone-sensitive prostate cancer (mHSPC), and 3.3% had received Darolutamide/Enzalutamide for non-metastatic castration-resistant prostate cancer (nmCRPC).
Disease site distribution included bone n=44 pts, viscera n=12, lymph nodes n=31, and n=3 in other locations. The median baseline prostate-specific antigen PSA: 14 ng/ml (range 0.15-4,037 ng/ml). HRRm status distribution comprised BRCA1 n=3, BRCA2 n=46, ATM n=11, multiple n=1 (33 germline, 28 somatic).
The median (range) time from randomization to the last encounter for pts still alive was =56: 16 (0.8-60), 15 (4.1-36), and 23 (2.9-56) months (m) in Arms I, II, and III, respectively. Treatment-related adverse events (AEs) were reported in 51 pts, with the most common Grade 3: fatigue n=3, anemia n=2, and ALT increases n=2.
Overall survival (OS) data were not yet mature, with 3 deaths in Arm I and 2 in Arm II. 8/19 pts in Arm I and 8/21 in Arm II crossed over from abiraterone to olaparib or vice versa at progression. Median (95% CI) PFS from crossover to olaparib 8.3 months (5.5, 15) and to abiraterone was 7.2 months (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%.
The study concluded that in mCRPC pts with BRCA1/2 or ATM alterations, the combination of abiraterone/prednisone + olaparib demonstrated favorable tolerability and significantly extended PFS compared to using either agent alone or sequentially.
The study is sponsored by Northwestern University
Source: https://meetings.asco.org/abstracts-presentations/230557
Clinical Trial: https://clinicaltrials.gov/study/NCT03012321
Hussain M H A, Kocherginsky M, Agarwal N, et al. (2024). “BRCAAway: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) bearing homologous recombination-repair mutations (HRRm).” Presented at ASCO-GU 2024 (Abstract 19).
