Olaparib for the Treatment of Patients With Metastatic Castration-Resistant Prostate Cancer and Alterations in BRCA1 and/or BRCA2 in the PROfound Trial.

Phase III PROfound trial (ClinicalTrials.gov identifier: NCT02987543) met its primary and key secondary objectives, demonstrating significantly longer radiographic progression-free survival (rPFS) and overall survival (OS) with olaparib monotherapy versus abiraterone or enzalutamide (control) in patients with metastatic castration-resistant prostate cancer (mCRPC) with alterations in BRCA1, BRCA2 (BRCA), and/or ATM (cohort A) whose disease had progressed on prior next-generation hormonal agent (NHA). We report exploratory post hoc analysis of the subgroup of patients with mCRPC with BRCA alterations in PROfound.

All patients had an alteration in a homologous recombination repair gene by tumor tissue testing, of which 160 had underlying BRCA alterations. rPFS and OS were estimated using the Kaplan-Meier method. Confirmed objective response rate and safety were also assessed.

Olaparib was associated with longer rPFS (hazard ratio [HR], 0.22 [95% CI, 0.15 to 0.32]) and OS (HR, 0.63 [95% CI, 0.42 to 0.95]) than control. There was an rPFS benefit with olaparib in all zygosity subgroups (biallelic [n = 88]; HR, 0.08 [95% CI, 0.04 to 0.16], heterozygous [n = 15] and unknown [n = 57]; HR, 0.30 [95% CI, 0.16 to 0.60]). Patients with BRCA2 homozygous deletions experienced prolonged responses to olaparib (n = 16; median rPFS, 16.6 months [95% CI, 9.3 to not reached]). Some evaluations are limited by small patient numbers. Germline DNA analysis was performed for 112 (70%) patients; risk of disease progression was similar for patients with germline (n = 61; HR, 0.08 [95% CI, 0.03 to 0.18]) and somatic (n = 51; HR, 0.16 [95% CI, 0.07 to 0.37]) BRCA alterations.

In all subgroups assessed, olaparib improved outcomes versus abiraterone or enzalutamide for patients with mCRPC with BRCA alterations whose disease had progressed on previous NHA.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2023 Nov 14 [Epub ahead of print]

Joaquin Mateo, Johann S de Bono, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N Chi, Neeraj Agarwal, David Olmos, Antoine Thiery-Vuillemin, Mustafa Özgüroğlu, Niven Mehra, Nobuaki Matsubara, Jae Young Joung, Charles Padua, Ernesto Korbenfeld, Jinyu Kang, Helen Marshall, Zhongwu Lai, Alan Barnicle, Christian Poehlein, Natalia Lukashchuk, Maha Hussain

Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron University Hospital Campus, Barcelona, Spain., The Institute of Cancer Research and Royal Marsden, London, United Kingdom., Institut Gustave Roussy, University of Paris Saclay, Villejuif, France., Centre de recherche du Centre Hospitalier de l'Université de Montréal/CRCHUM, Université de Montréal, Montreal, QC, Canada., Carolina Urologic Research Center, Myrtle Beach, SC., Peter MacCallum Cancer Centre, Melbourne, VIC, Australia., BC Cancer Agency, Vancouver, BC, Canada., Huntsman Cancer Institute (NCI-CCC), University of Utah, Salt Lake City, UT., Department of Medical Oncology, Hospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Madrid, Spain., Department of Medical Oncology, Centre Hospitalier Universitaire de Besançon, Besançon, France., Istanbul University-Cerrahpaşa, Cerrahpaşa School of Medicine, Istanbul, Turkey., Radboud University Medical Center, Nijmegen, the Netherlands., National Cancer Center Hospital East, Chiba, Japan., Center for Prostate Cancer, National Cancer Center, Goyang, Republic of South Korea., Cetus Medicina Oncologia, Betim, Brazil., Hospital Británico de Buenos Aires, Buenos Aires, Argentina., Global Medicines Development, Oncology R&D, AstraZeneca, Gaithersburg, MD., AstraZeneca contracted through PHASTAR, Cambridge, United Kingdom., 9Global Medicines Development, Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Global Medicines Development, Oncology R&D, AstraZeneca, Cambridge, United Kingdom., Merck & Co, Inc, Rahway, NJ., 1Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL.