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


Year:

Session type:

Theme:

Joaquin Mateo1,Nuria Porta2,Ursula McGovern3,Tony Elliott4,Robert Jones5,Isabel Syndikus6,Christy Ralph7,Suneil Jain8,Mohini Varughese9,Omi Parikh10,Simon Crabb11,Angus Robinson12,Duncan McLaren13,Alison Birtle14,Jacob Tanguay15,Susana Miranda2,George Seed2,Claudia Bertan2,Aude Espinasse2,Peter Chatfield2,Diletta Bianchini16,Emma Hall2,Suzanne Carreira2,Johann De Bono17
1Vall d’Hebron Institute of Oncology, Barcelona, Spain,2The Institute of Cancer Research, London, UK,3University College Hospital, London, UK,4The Christie Hospital, Manchester, UK,5The Beatson West of Scotland Cancer Centre, Glasgow,6The Clatterbridge Cancer Centre, Birkenhead, UK,7St James's University Hospital, Leeds, UK,8Belfast City Hospital, Belfast, UK,9Musgrove Park Hospital, Taunton, UK,10Royal Blackburn Hospital, Blackburn, UK,11Southampton General Hospital, Southampton, UK,12Royal Sussex County Hospital, Brighton, UK,13Western General Hospital, Edinburgh, UK,14Royal Lancaster Infirmary, Lancaster, UK,15Velindre Cancer Centre, Cardiff, UK,16The Royal Marsden NHS Foundation Trust, UK,17The Institute of Cancer Research, London, UK, London & The Royal Marsden NHS Foundation Trust, London, UK

Abstract

Background

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.

Method

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.

Results

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.

Conclusion

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.