Greatest benefit in BRCA1 and BRCA2 alterations

Among men with castration-resistant, metastatic prostate cancer who had specific alterations in DNA repair genes, treatment with the PARP inhibitor olaparib increased median overall survival by more than 3 months, researchers reported.

“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.” The findings were published online April 28 in The New England Journal of Medicine.

Of note, the 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 met had alterations in 1 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, BRCA, or ATM and 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 olaparib group 43% of patients had a PSA response versus 8% of controls.

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 vs 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).”

de Bono and colleagues noted that among “patients in the control group with independent review–confirmed imaging-based disease progression, 81% crossed over to receive olaparib treatment at the investigators’ discretion.”

There were more grade 3 or high adverse events reported among olaparib-treated patients, with the most AEs anemia, nausea, and fatigue. There were, however, 11 cases of pulmonary embolism in the olaparib group versus 1 case among controls.

“Efficacy in cohort A and in the overall population was seen regardless of whether olaparib monotherapy was administered before chemotherapy or after chemotherapy,” the authors concluded. “A benefit was also observed in the overall trial population with an alteration in any of the 15 prespecified genes with a direct or indirect role in homologous re-combination repair.”

  1. Note that in this open-label, prospective, randomized trial, olaparib achieved a significantly better objective response and progression-free survival than did either enzalutamide or abiraterone.

  2. Be aware that patients with BRCA1 or BRCA2 alterations appear to derive the greatest benefit from olaparib therapy.

Peggy Peck, Editor-in-Chief, BreakingMED™

deBono disclosed consultant agreements with Astellas Pharma, Astra Zeneca, Bayer Healthcare, Boehringer Ingleheim, 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: 78,25,730,25,935,192,241,73