Antitumour Activity of the Parp Inhibitor Olaparib in Unselected Sporadic Castration-Resistant Prostate Cancer (Crpc) in the Toparp Trial

Abstract

Aim: Next generation sequencing studies have identified defects in DNA repair machinery in 20-40% of sporadic castration resistant prostate cancer (CRPC) patients (pt). We hypothesized that single agent PARP inhibition would have antitumour activity based on synthetic lethality in CRPC.Methods: An investigator initiated adaptive multi-part Phase II trial (TOPARP; CR-UK/11/029) was pursued to assess olaparib antitumour activity and identify predictive biomarkers for response in CRPC. Part A is a 2-stage open labeled multi-centre study [po = 0.05; p1= 0.20; α = 0.02; β = 0.10; 30/45 pt]. Olaparib dosing was with 400mg tablets BID continuously. The primary endpoint was response, defined as a confirmed radiological response (RECIST 1.1), confirmed PSA decline ≥50% and/or confirmed circulating tumour cells (CTC) count fall from ≥5 to <5/7.5ml blood. Paired tumour biopsies at screening and day 8-28 of treatment were mandated for biomarker studies, including exome, transcriptome and functional DNA repair studies.Results: Preliminary results are available for the first stage after 30 pt have been evaluated for the primary endpoint. Prior lines of treatment include docetaxel (n = 30, 100%), cabazitaxel (17, 57%), abiraterone (29, 97%) and enzalutamide (5, 17%). CRPC biopsies for biomarker studies were acquired from bone marrow (17), nodal/soft tissue disease (10) or visceral metastasis (3). The most common grade > 3 adverse events (AE) were anaemia (6, 20%) and fatigue (3, 10%). Olaparib was well tolerated; 6 (20%) pt required a dose reduction, with no permanent discontinuations due to drug-related AEs. Response rate was 33% (10/30 pt, Table 1). Median time on treatment for responding pt was 6.9 months (range 2.8m-14.4m). Somatic cell exome and transcriptome analyses have identified loss of function of genes involved in DNA repair including BRCA2 and ATM among the responding patients. Response assessment (PSA, CTC count and radiological response) for the patients who achieved a response per protocol definition (10 out of 30, response rate 33%)Conclusions: Olaparib has antitumour activity in sporadic mCRPC with DNA repair defects; multiple durable responses have led to continuation to the next stage of this trial, which is nearing completion.Disclosure: A.G. Omlin: has served as advisor for Astra-Zeneca; J.S. de Bono: has served as paid advisor for Astra-Zeneca. All other authors have declared no conflicts of interest.