ASCO 2017: PROfound: A randomized Phase III trial evaluating olaparib in patients with metastatic castration-resistant prostate cancer and a deleterious homologous recombination DNA repair aberration

Chicago, IL (UroToday.com) The genetic landscape for men with metastatic castration resistant prostate cancer (mCRPC) is rapidly evolving. At the 2017 ASCO prostate cancer poster session, Dr. Johann De Bono and colleagues presented their phase III trial design for PROfound, an evaluation of olaparib in patients with mCRPC and a deleterious homologous recombination DNA repair aberration. There are available agents that may be offered with limited therapeutic benefit for these patients, however no molecularly stratified treatment has been approved for this heterogeneous disease.

A number of patients with mCRPC have loss of function aberrations in genes involved in homologous recombination repair (HRR), such as BRCA1/2 and ATM. Importantly, these aberrations can confer sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition. Previously, a phase II study determined that PARP inhibitor olaparib had antitumor effect in 33% of mCPRC patients.1 Furthermore, patients treated with olaparib had a higher composite response rate in patients with deleterious HRR gene aberration (HRRa) (88%) compared to without HRRa (6%). The objective of this study is to evaluate olaparib efficacy and safety versus physician’s choice of either abiraterone acetate or enzalutamide, in patients with mCRPC and a HRRa.

mCRPC patients eligible for this multinational, open-label, Phase III study must have progressed on prior hormonal treatment and have a tumor HRRa in one of 15 genes, as confirmed by an HRR Assay. Patients in Cohort A (n = ~240) will have mutations in BRCA1BRCA2 or ATM, while patients with a mutation in 12 other HRR genes will be assigned to Cohort B (n = ~100). Patients will be randomized (2:1) to olaparib (300 mg PO BID) or physician’s choice of either enzalutamide (160 mg PO daily) or abiraterone acetate (1000 mg PO daily with 5 mg BID prednisone) and treatment continued until radiographic progression (as assessed by blinded independent central review) or lack of treatment tolerability. The primary endpoint of radiographic progression-free survival (rPFS) will be assessed in Cohort A using RECIST 1.1 (for soft tissue lesions) and PCWG3 (for bone) criteria. The primary endpoint is radiographic progression-free survival (rPFS) and will be assessed in Cohort A using RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria. Key secondary efficacy endpoints include confirmed objective response rate, time to pain progression, overall survival (Cohort A) and rPFS (both cohorts combined). 

This study is currently accruing patients across a number of centers worldwide, with the first patient randomized in April 2017.
Clinical trial: NCT02987543

Presented By: Johann S. De Bono, The Institute of Cancer Research and The Royal Marsden Hospital, London, UK

Co-Authors: Maha Hussain, Antoine Thiery-Vuillemin, Joaquin Mateo, A. Oliver Sartor, Kim N. Chi, Karim Fizazi, Przemyslaw Twardowski, Neeraj Agarwal, Shahneen Kaur Sandhu, David Olmos, Neal D. Shore, Fred Saad, Sherry Liu, Carsten Dietrich Goessl, Joe Burgents

Written By: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @zklaassen_md

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 - Chicago, Illinois, USA

REFERENCES:
1. Mateo J, Carreira S, Sandhu S, et al. DNA-Repair Defects and Olaparib in Metasatic Prostate Cancer. N Engl J Med 2015 Oct 29;373(18):1697-1708.
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