ASCO GU 2020: PROfound: Efficacy of Olaparib by Prior Taxane Use in Patients with mCRPC and Homologous Recombination Repair Gene Alterations

San Francisco, California (UroToday.com) The Phase III randomized PROfound study is the first positive Phase III study in a molecularly pre-defined group of patients with metastatic castration-resistant prostate cancer (mCRPC) who had an alteration in prespecified genes, with a direct or indirect role in homologous recombination repair (HRR).¹ PROfound met its primary endpoint in that olaparib significantly prolonged radiographic progression-free survival (rPFS) vs physician’s choice of new hormonal agent in patients with mCRPC. Patients in PROfound were only required to have had disease progression prior to new hormonal agents, however, prior taxane chemotherapy was allowed and a stratification factor in the study. Subgroup analyses were prespecified in cohort A and the overall population (cohort A + B) to examine the impact of taxane treatment history on the observed benefit of olaparib, though the study was not powered to examine treatment effect between subgroups. Presenting during the Prostate Cancer Session at the 2020 American Society of Clinical Oncology Genitourinary Cancers Symposium (ASCO GU), Johann de Bono and colleagues reported exploratory subgroup analyses by prior taxane (yes vs no).

Men with mCRPC that had progressed on prior new hormonal agents were randomized to olaparib (300 mg BID) or physician’s choice of new hormonal agent (enzalutamide or abiraterone). Patients had alterations in BRCA1, BRCA2 or ATM (Cohort A) or ≥1 of 12 other prespecified genes with a direct or indirect role in HRR (Cohort B). Stratification factors were prior taxane use and measurable disease. rPFS was assessed by blinded independent central review with RECIST v1.1 + PCWG3.

In this study, there were more older men without prior taxane treatment, and among those with prior taxane treatment, slightly more patients had visceral disease and were more likely to have measurable disease at baseline. As follows is a graph of prior taxane use in Cohort A and the overall population in patients treated with olaparib and physician’s choice of new hormonal agent:

Subgroup analyses of rPFS and overall survival (OS) favored olaparib vs physician’s choice of new hormonal agent irrespective of prior taxane in Cohort A and Cohorts A+B. Below are the Kaplan-Meier curves for OS:

Kaplan Meier curves for OS

In the subgroup analyses of rPFS and OS in patients with BRCA1, BRCA2 or CDK12 also showed favorable effect with olaparib versus physician’s choice of a new hormonal agent with or without prior taxane therapy. In the ATM subgroup, HR point estimates for rPFS and OS were lower in patients that received prior taxane versus patients who had not:

subgroup analysis of patients with gene alterations

Conclusions of this analysis of the PROfound study are as follows:

Patients had received prior new hormonal agent and were chemotherapy-naïve or treated, with two-thirds having previously received taxane therapy.
The benefit of olaparib over physician’s choice of new hormonal agent was generally independent of prior taxane use in mCRPC patients selected for alterations in BRCA1, BRCA2 and/or ATM, and among patients in the overall study population with an alteration in any of 15 prespecified genes with a direct or indirect role in HRR.
These results provide insight into the benefit of olaparib treatment for mCRPC patients with and without taxane treatment

Clinical trial information: NCT02987543

Presented by: Johann De Bono, MD, PhD, Regius Professor of Cancer Research at the Institute for Cancer Research and the Royal Marsden Hospital, London, United Kingdom

Co-Authors: Karim Fizazi, Fred Saad, Neal D. Shore, Guilhem Roubaud, Mustafa Ozguroglu, Nicolas Penel, Nobuaki Matsubara, Niven Mehra, Giuseppe Procopio, Michael Paul Kolinsky, Kazuo Nishimura, Susan Feyerabend, Jae Young Joung, Nicholas J. Vogelzang, Michael Anthony Carducci, Jinyu Kang, Christian Heinrich Poehlein, Wenting Wu, Maha H. A. Hussain; The Institute of Cancer Research and Royal Marsden, London, United Kingdom; Institut Gustave Roussy, University of Paris Sud, Villejuif, France; Centre Hospitalier de l’Université de Montréal/CRCHUM, Montreal, QC, Canada; Carolina Urologic Research Center, Myrtle Beach, SC; Institut Bergonié, Bordeaux, France; Cerrahpaşa School of Medicine, Istanbul University-Cerrahpaşa, Istanbul, Turkey; Department of Medical Oncology, Centre Oscar Lambret, Lille, France; Division of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan; Radboud University Medical Center, Nijmegen, Netherlands; Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy; Department of Medical Oncology, University of Alberta Cross Cancer Institute, Edmonton, AB, Canada; Department of Urology, Osaka International Cancer Institute, Osaka, Japan; Studienpraxis Urologie, Nürtingen, Germany; Center for Prostate Cancer, National Cancer Center, Goyang, South Korea; Comprehensive Cancer Centers of Nevada, Las Vegas, NV; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD; AstraZeneca, Gaithersburg, MD; Merck & Co., Inc., Kenilworth, NJ; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen_md at the 2020 Genitourinary Cancers Symposium, ASCO GU #GU20, February 13-15, 2020, San Francisco, California

Reference:

1. Hussain, M., J. Mateo, K. Fizazi, F. Saad, N. D. Shore, S. Sandhu, K. N. Chi et al. "PROfound: Phase III study of olaparib versus enzalutamide or abiraterone for metastatic castration-resistant prostate cancer (mCRPC) with homologous recombination repair (HRR) gene alterations." Annals of Oncology 30 (2019): v881-v882.

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