BRCAAWAY: A randomized phase 2 trial of abiraterone, olaparib, or abiraterone + olaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) with DNA repair defects.

Abstract

5018 Background: The PARP-inhibitor olaparib is approved for mCRPC patients (pts) with deleterious germline or somatic homologous recombination repair gene mutations (HRRm). PARP1 interacts with androgen signaling, and castration-resistant tumor cells exhibit increased PARP1 activity. Preclinically PARP1-inhibition synergizes with androgen receptor (AR) targeted therapy. BRCAAway is a biomarker selected, randomized, open-label, multicenter phase 2 trial evaluating efficacy of targeting AR vs PARP vs combination in first line mCRPC patients with germline and/or somatic HRRm in BRCA1, BRCA2, or ATM. Methods: Eligible mCRPC pts underwent tumor next generation sequencing and germline testing. Pts with inactivating BRCA1, BRCA2 and/or ATM alterations were randomized 1:1:1 to Arm 1 abiraterone (1000 mg daily) + prednisone (5mg bid) (Abi/pred), Arm 2 olaparib (300 mg bid) or Arm 3 olaparib + Abi/pred. The primary end point is progression-free survival (PFS) analyzed using Kaplan-Meier estimates and Cox regression. Secondary endpoints include measurable disease response rate (RR) by RECIST, PSA-RR, undetectable PSA (≤ 0.2 ng/ml) and toxicity. Arms 1 and 2 pts were allowed to cross over at progression. Pts with other HRRm were treated with olaparib; Arm 4 (ongoing). Results: 161 pts were registered and had NGS testing; 60 pts were randomized to Arms 1-3; to date 59 are evaluable for toxicity and 53 are evaluable for PFS. Baseline median age 67 (range 42-85) years; 54 pts were White, 6 were Black; sites of disease: bone only (n=31), soft tissue only (n=18), bone and soft tissue (n=10); median PSA 14.61 ng/ml (range 0.15-4036.8). Mutational status: BRCA1 only n = 2, BRCA2 only n = 39, ATM only n = 8, and > 1 HRRm n = 11. 34 pts had germline and 26 had somatic mutations. Median (range) follow-up time: 8.3 (0.8, 33.3), 12.2 (2.7, 21.8) and 16.8 (2.9, 41.7) months in Arms 1, 2 and 3. 43 pts had treatment-related adverse events; most common were fatigue (23 pts; 1 Grade (G) 3, 22 G1/2), nausea (17 pts, G1/2), and anemia (9 pts, 2 G3, 7 G1/2). ≥50% PSA decline was 79%, 67%, and 85% of pts in Arms 1, 2, and 3, respectively. Median PSA nadir (ng/mL) (95% CI) Arms 1-3: 2.17 (0.44, 49.27), 3.10 (0.83, 12.01), and 0.50 (0.10, 2.13), respectively. Undetectable PSA, median PFS, and 12-month PFS by Arm are listed in the table. Conclusions: In mCRPC pts with inactivating BRCA1, BRCA2 and/or ATM alterations Abi/pred + olaparib was well tolerated and resulted in longer PFS and better PSA response vs either agent alone. Clinical trial information: NCT03012321. [Table: see text]

PROMISE Registry: A prostate cancer registry of outcomes and germline mutations for improved survival and treatment effectiveness

“…The PROpel have paved the way to support these developments. [24][25][26][40][41][42] Recent biomarker driven studies in the neoadjuvant space (NCT05498272, NCT05806515) and in the BCR space (NCT04019964), could directly benefit from referrals. As such, data from the PROMISE Registry will be integral in defining patient determinants of success and barriers to enrollment in future biomarker studies.…”

“…Of direct interest, three new combination FDA approvals with an emphasis on targeted therapies are moving to the forefront of the prostate cancer treatment landscape. The findings of PROfound and TRITON3, as well as MAGNITUDE, TALAPRO‐2, BRCAAway, and PROpel have paved the way to support these developments 24–26,40–42 . Recent biomarker driven studies in the neoadjuvant space (NCT05498272, NCT05806515) and in the BCR space (NCT04019964), could directly benefit from referrals.…”

Double trouble for prostate cancer: synergistic action of AR blockade and PARPi in non-HRR mutated patients

“…Crossover at progression was considered in the first two arms. While final results have not yet been published, an interim analysis presented at ASCO 2022, showed a strong benefit of the combination therapy over either agent alone (54). With the great results of using PARP-inhibition in mCRPC setting, multiple new trials testing these in a mHSPC population are starting.…”

Poly(ADP-ribose) Polymerase Inhibitor Combinations in First-Line Metastatic Castration-Resistant Prostate Cancer: Increasing Toxicity With Unclear Benefits

“…16 A few trials are currently underway and may add further clarity to the issue of combining or sequencing PARP inhibition in prostate cancer. 25,26 Finally, while therapeutic advances are vital for patients with cancer, so is the responsibility to navigate the pitfalls in data and deliver the best treatment for each patient. Some patients with HRRm will likely benefit from an early use of PARP inhibitors with ARPI, but practitioners cannot ignore the possibility that many patients will be exposed to higher levels of toxicity years before they need to be, without clear evidence to date that doing so will improve overall survival.…”

“…16 A few trials are currently underway and may add further clarity to the issue of combining or sequencing PARP inhibition in prostate cancer. 25,26…”