BRCAAway: Abiraterone, Olaparib Combinations in Patients With mCRPC Bearing HRR Mutations

In the Oral Abstract Session focusing on prostate cancer at this year’s ASCO Genitourinary Cancer Symposium held Thursday January 25, 2024 in San Francisco, Dr. Maha Hussain presented results of the BRCAAway trial, assessing combinations of abiraterone, olaparib, or a combination of the two in patients with metastatic castration resistant prostate cancer (mCRPC) who have homologous recombination-repair mutations (HRRm).

It has been well recognized that HRRm is associated with an adverse prognosis in patients with mCRPC. Its incidence varies according to disease state in prostate cancer, representing approximately 20% of those with mCRPC. While there are currently a large number of treatment options in mCRPC, androgen-receptor (AR) targeting agents are the current clinical backbone. In pre-clinical data, inhibition of PARP has demonstrated synergistic effects with AR-targeted therapies.

BRCAAway (NCT03012321) was designed as a biomarker pre-selected, multicenter, randomized, phase-2 trial with the goal to evaluate the efficacy of AR-inhibition (ARi) compared with PARP inhibition and the combination of these two approaches. The authors enrolled patients in the first-line mCRPC who had evidence of germline and/or somatic mutations in BRCA1/2 or ATM. In keeping with their first-line mCRPC status, these patients had no prior exposure to PARPi, ARi, or chemotherapy for mCRPC. However, they could have received intensified therapy in the mCSPC space. Further, patients had to have washout of antiandrogen, radiation, and other investigational agents prior to study initiation.

All potentially eligible patients underwent tumor next-generation sequencing (NGS) for somatic testing or germline testing. Patients who had evidence of inactivating BRCA1/2 and/or ATM alterations were randomized in a 1:1:1 fashion to receive abiraterone (1000 mg qd) + prednisone (5mg bid) (Arm I), olaparib (300 mg bid) (Arm II), or the combination of olaparib + abiraterone/prednisone (Arm III). The authors followed these patients to assess the primary endpoint of progression free survival (PFS) as per RECIST 1.1, PCWG3, clinical assessment, or death. In addition, they assessed a number of secondary endpoints including measurable disease response rate (RR), PSA RR, and toxicity. Notably, patients in the monotherapy arms (Arm I and II) could cross over at progression.

The authors registered 165 eligible patients who underwent NGS/germline testing. Of these 165 patients, 61 were found to have HRRm and were subsequently randomized to Arms I-III. Notably, germline mutations were found in over 50% of patients with BRCA2 being the most commonly identified alteration. Importantly, 26% had received prior Docetaxel 26% for mHSPC and 3.3% had received either Darolutamide or Enzalutamide nmCRPC.

Overall, Dr. Hussain emphasized that treatment was overall well tolerated, while 51 patients had treatment-related AEs, most were relatively low grade. The most common Grade 3 events were fatigue (n=3), anemia (n=2), and ALT increases (n=2). While OS is not mature (3 deaths in Arm I and 2 in Arm II), Dr. Hussain demonstrated promising results for the combination arm: median PFS was 39 months (16-NR) in Arm III compared with 8.4 (2.9-25) in Arm I and 14 (8.4-20) in Arm II. Similarly, objective response rates were higher in the combination Arm III (29%, 11-52%) compared with Arm I (21%, 6.1-46%) or Arm II (9.5%, 1.2-30%) as were PSA response rates (95% vs 58 or 67%).

Importantly, at the time of progression 8 of 19 patients crossed over from abiraterone to olaparib and 8 or 21 patients had the opposite cross-over. The response rate to the cross-over manoeuvre was 38% for olaparib and 25% for abiraterone and the corresponding PSA RR was 50% and 63%, respectively.

Thus, Dr. Hussain concluded that, in patients with mCRPC who have BRCA1/2 or ATM alterations, the combination of abiraterone/prednisone with olaparib was well tolerated and resulted in a longer PFS vs either agent alone or sequentially.