New option for BRCA-mutation associated mCRPC

PARP (poly ADP ribose polymerase) inhibitors, which are well-recognized for efficacy in treating breast and ovarian cancers, are now demonstrating efficacy in prostate cancer — specifically in BRCA mutation-associated metastatic castration-resistant prostate cancer (mCRPC).

For example, the FDA approved rucaparib for treatment of BRCA-linked mCRPC in men who had previously been treated with androgen-receptor directed therapy and a taxane-based chemotherapy. The FDA approval, announced May 15, makes rucaparib the first PARP-inhibitor approved for this indication, but it is the third approved indication for the drug, which was previously approved for maintenance therapy in ovarian cancer as well as treatment of recurrent BRCA-mutated ovarian cancers.

The approval was based on findings from the TRITON2 trial, which is an “ongoing, multi-center, single arm clinical trial in 115 patients… Patients received rucaparib 600 mg orally twice daily and concomitant GnRH analog or had prior bilateral orchiectomy.”

TRITON2 principal investigator Wassim Abida, MD, of Memorial Sloan Kettering Cancer Center, noted that standard treatments for these men was “limited to androgen receptor-targeting therapies, taxane chemotherapy, Radium-223, and sipuleucel-T.”

In TRITON2, the objective response rate, which was assessed in 62 patients, was 44% (95% CI: 31, 57). The median durable response rate was not evaluable but “15 of the 27 (56%) patients with confirmed objective responses had a DOR of ≥6 months,” the FDA said in announcing the approval.

Rucaparib is administered orally, and the recommended dose is 600 mg bid. “Patients receiving rucaparib for mCRPC should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy,” the FDA said.

Just 2 weeks before the FDA action on rucaparib, The New England Journal of Medicine published promising results in prostate cancer for another PARP inhibitor: olaparib.

“Imaging-based progression-free survival was significantly longer in the olaparib group than in the control group among patients with at least one alteration in BRCA1, BRCA2, or ATM,” wrote Johann de Bono, MD, of the Institute of Cancer Research and Royal Marsden Hospital, Surrey, England, and colleagues, “with a 66% lower risk of disease progression or death.”

Of note, the olalparib benefit was seen among men who had disease progression while receiving a new hormonal agent — enzalutamide or abiraterone.

The PROfound trial recruited 4,425 men at 206 sites in 20 countries. After sampling tumor tissue and analyzing biomarkers, the researchers identified 778 men, of whom 387 had alterations in one or more of 15 prespecified genes (BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54I).

Cohort A (n=245) included patients with at least one alteration in BRCA1, BRCA2, or ATM, while cohort B (n=142) patients had alterations in any of the remaining 12 prespecified genes.

In cohort A, 162 men were randomized to olaparib and 83 to a control group (treatment with either enzalutamide or abiraterone). In cohort B, 94 patients were randomized to olaparib and 48 to control.

The study’s primary endpoint was imaging-based progression-free survival in patients with “at least one alteration in BRCA1, BRCA2, or ATM (cohort A),” the study authors wrote. “Imaging-based progression-free survival was defined as the time from randomization until soft-tissue disease progression (by RECIST, version 1.1), bone lesion progression (by Prostate Cancer Clinical Trials Working Group 3 criteria), or death.

Secondary endpoints included objective response rate, time to pain progression, overall survival, a reduction of at least 50% in prostate-specific antigen (PSA) concentration, and the circulating-tumor-cell conversion rate.

“Although baseline characteristics appeared balanced overall between the olaparib group and the control group, the control group had a higher percentage of patients with visceral metastases and a higher median baseline PSA concentration, and the olaparib group had a higher percentage of patients with an ATM alteration,” they wrote.

Among the findings:

  • Median, imaging-based, progression-free survival was 7.4 months for olaparib patients versus 3.4 months for controls (P <0.001).
  • In cohort A, the confirmed objective response rate in evaluable patients olaparib patients was 33% (28 of 84 patients) versus 2% (1 of 43 patients) (P <0.001).
  • Median time to pain progression was significantly longer, “…HR 0.44; 95% CI 0.22-0.91; P =0.02,” favoring olaparib.
  • Overall survival (interim analysis) was 18.5 months in the olaparib group versus 15.1 months for controls, P=0.02.

In the PROfound trial a PSA response was observed in 43% of the olaparib-treated patients versus 8% of controls. In TRITON2, “a 55% confirmed prostate specific antigen (PSA) response rate (95% CI 45, 64) was observed,” investigators said.

When cohorts A and B were evaluated together, “the median imaging-based progression-free survival by independent review was significantly longer in the olaparib group than in the control group (median, 5.8 months versus 3.5 months; hazard ratio, 0.49; 95% CI, 0.38-0.63; P<0.001… the confirmed objective response rate was 22% (30 of 138 patients) in the olaparib group and 4% (3 of 67 patients) in the control group (odds ratio, 5.93; 95% CI, 2.01-25.40).”

  1. Note that rucaparib is the first PARP-inhibitor to be approved for treatment of BRCA-linked mCRPC in men who had previously been treated with androgen-receptor directed therapy and a taxane-based chemotherapy.

  2. Be aware that in the PROfound trial, patients with BRCA1 or BRCA2 alterations appeared to derive the greatest benefit from olaparib therapy.

Peggy Peck, Editor-in-Chief, BreakingMED™

TRITON2 was funded by Clovis Oncology, Inc.

PROfound was funded by AstraZeneca and Merck Sharp & Dohme.

Abida reported consulting for Clovis Oncology, Janssen Pharmaceutical, and More Health, Inc; receiving honoraria from Caret Healthcare; receiving research funding from Clovis Oncology, Zenith Epigenetics, Ltd, and AstraZeneca; and receiving travel funding from Clovis Oncology, Sanofi, and GlaxoSmithKline.

deBono disclosed consultant agreements with Astellas Pharma, Astra Zeneca, Bayer Healthcare, Boehringer Ingelheim, Daiichi Sankyo Company. Genentech, GlaxoSmithKline, Janssen Global Services, Menarini Silion Biosystems, Inc., Merck, Merck, Sharp & Dohme Corporation, Orion Corporation, Pfizer, Qiagen Sciences, LLC, Sanofi-Aventis-U.S., LLC, Sierra Oncology, Taiho Pharmaceutical, and Vertex Pharmaceuticals.

Cat ID: 25

Topic ID: 78,25,730,25,192,73