TOPARP-B: A Phase II Randomised Trial of the Poly(ADP)-Ribose Polymerase (PARP) Inhibitor Olaparib for Metastatic Castration Resistant Prostate Cancers (mCRPC) with DNA Damage Repair (DDR) Alterations
Session type: Poster / e-Poster / Silent Theatre session
We previously reported the antitumor activity of olaparib (400mg BID) against molecularly unselected mCRPC (TOPARP-A; Mateo et al NEJM 2015). We now report TOPARP-B, a phase-II trial for patients with mCRPC preselected for putatively pathogenic DDR alterations.
Patients with mCRPC progressing after >1 taxane chemotherapy underwent targeted sequencing of tumour biopsies and were deemed eligible when alterations (germline or somatic; mono- or bi-allelic) in any DDR gene were detected. Patients were randomised 1:1 under a “pick-the-winner” design to 400mg or 300mg of olaparib BID, aiming to exclude <30% response rate (RR) in either arm. The primary endpoint RR was defined as radiological response (RECIST 1.1) and/or PSA50% fall and/or CTC count conversion (Cellsearch; ≥5 to <5), confirmed after 4-weeks. Analyses of RR per gene alteration subgroup was pre-planned. Secondary endpoints included radiographic progression-free survival (rPFS), tolerability.
Overall, 98 patients (mean age 67.6y) were randomised, with 92 patients evaluable for the primary endpoint (70 RECIST-evaluable; 89 PSA50%-evaluable; 55 CTC-evaluable). All had progressed on ADT; all were post-docetaxel; 90% post-abiraterone/enzalutamide, 38% post-cabazitaxel. Overall RR was 54% (95%CI 39-69%, meeting threshold for primary endpoint) in the 400mg cohort and 39% (95%CI 25-55%) in the 300mg cohort. With a median follow-up of 20.5 months (mo), the overall median rPFS (mrPFS) was 5.5 mo. Subgroup analyses per altered gene identified indicated RR for: BRCA1/2 of 83% (25/30; mrPFS 8.3mo); PALB2 57% (4/7; mrPFS 5.3mo); ATM 37% (7/19; mrPFS 5.6mo); CDK12 25% (5/20; mrPFS 2.9mo); others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (4/20; mrPFS 2.8mo). The highest PSA50% response rates were observed in the BRCA1/2 (23/30; 77%) and PALB2 (4/6; 67%) subgroups.
Olaparib has antitumor activity against heavily pre-treated mCRPC with DDR gene defects, with BRCA1/2 aberrant tumours being most sensitive but with confirmed responses in patients with other DDR alterations.
© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved.