2019 ASCO Annual Meeting!
Session: Genitourinary (Prostate) Cancer
Type: Oral Abstract Session
Time: Friday May 31, 2:45 PM to 5:45 PM
Location: Arie Crown Theater
TOPARP-B: A phase II randomized trial of the poly(ADP)-ribose polymerase (PARP) inhibitor olaparib for metastatic castration resistant prostate cancers (mCRPC) with DNA damage repair (DDR) alterations.
Genitourinary (Prostate) Cancer
2019 ASCO Annual Meeting
J Clin Oncol 37, 2019 (suppl; abstr 5005)
Author(s): Joaquin Mateo, Nuria Porta, Ursula Brigid McGovern, Tony Elliott, Robert J Jones, Isabel Syndikus, Christy Ralph, Suneil Jain, Mohini Anna Varughese, Omi Parikh, Simon J. Crabb, Susana Miranda, George Seed, Claudia Bertan, Aude Espinasse, Peter Chatfield, Diletta Bianchini, Emma Hall, Suzanne Carreira, Johann S. De Bono, on behalf of the TOPARP Investigators Group; The Institute of Cancer Research & The Royal Marsden, London, United Kingdom; Clinical Trials and Statistics Unit, The Institute of Cancer Research, London, United Kingdom; University College Hospital, London, United Kingdom; Christie Hospital NHS Foundation Trust, Manchester, United Kingdom; University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom; Clatterbridge Cancer Centre, Wirral, United Kingdom; St. James's Institute of Oncology, University of Leeds, Leeds, United Kingdom; Queen's University, Belfast, United Kingdom; Musgrove Park Hospital, Taunton, United Kingdom; Royal Preston Hospital, Preston, United Kingdom; Southampton Clinical Trials Unit, University of Southampton, Southampton, United Kingdom; The Institute of Cancer Research, London, United Kingdom; Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom
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. Methods: Patients with mCRPC progressing after ≥ 1 taxane chemotherapy underwent targeted sequencing of tumor biopsies and were deemed eligible when alterations (germline or somatic; mono- or bi-allelic) in any DDR gene were detected. Patients were randomized 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 progression-free survival (PFS), tolerability. Results: Overall, 98 patients (median age 67.6y) were randomized, with 92 patients treated and evaluable for the primary endpoint (70 RECIST-evaluable; 89 PSA50%-evaluable; 55 CTC-evaluable). All had progressed on ADT; 99% were post-docetaxel, 90% post-abiraterone/enzalutamide, 38% post-cabazitaxel. The overall RR was 54% (95%CI 39-69%, meeting threshold for primary endpoint) in the 400mg cohort and 37% (95%CI 23-53%) in the 300mg cohort. With a median follow-up of 17.6 months (mo), the overall median PFS (mPFS) was 5.4 mo. Subgroup analyses per altered gene identified indicated response rates for: BRCA1/2 of 80% (24/30; mPFS 8.1mo); PALB2 57% (4/7; mPFS 5.3mo); ATM 37% (7/19; mPFS 6.1mo); CDK12 25% (5/20; mPFS 2.9mo); others [ATRX, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCM, RAD50, WRN] 20% (4/20; mPFS 2.8mo). The highest PSA50% response rates were observed in the BRCA1/2 (22/30; 73%) and PALB2 (4/6; 67%) subgroups. Conclusions: Olaparib has antitumor activity against heavily pre-treated mCRPC with DDR gene defects, with BRCA1/2 aberrant tumors being most sensitive but with confirmed responses in patients with other DDR alterations. Clinical trial information: NCT01682772