Preclinical evidence has suggested an interplay between the androgen receptor, which largely drives the growth of prostate cancer cells, and poly(ADP-ribose) polymerase. This association provides a rationale for their co-inhibition for the treatment of metastatic castration-resistant prostate cancer (mCRPC), an area of unmet medical need. The phase 3 TALAPRO-2 study investigated combining the poly(ADP-ribose) polymerase inhibitor talazoparib with enzalutamide versus enzalutamide alone as first-line treatment of mCRPC. Patients were prospectively assessed for tumor alterations in DNA damage response genes involved in homologous recombination repair (HRR). Two cohorts were enrolled sequentially: an all-comers cohort that was enrolled first (cohort 1; N = 805 (169 were HRR-deficient)), followed by an HRR-deficient-only cohort (cohort 2; N = 230). We present results from the alpha-controlled primary analysis for the combined HRR-deficient population (N = 399). Patients were randomized in a 1:1 ratio to talazoparib or placebo, plus enzalutamide. The primary endpoint, radiographic progression-free survival, was met (median not reached at the time of the analysis for the talazoparib group versus 13.8 months for the placebo group; hazard ratio, 0.45; 95% confidence interval, 0.33 to 0.61; P < 0.0001). Data for overall survival, a key secondary endpoint, are immature but favor talazoparib (hazard ratio, 0.69; 95% confidence interval, 0.46 to 1.03; P = 0.07). Common adverse events in the talazoparib group were anemia, fatigue and neutropenia. Combining talazoparib with enzalutamide significantly improved radiographic progression-free survival in patients with mCRPC harboring HRR gene alterations, supporting talazoparib plus enzalutamide as a potential first-line treatment for these patients. ClinicalTrials.gov Identifier: NCT03395197 .
Nature medicine. 2023 Dec 04 [Epub ahead of print]
Karim Fizazi, Arun A Azad, Nobuaki Matsubara, Joan Carles, Andre P Fay, Ugo De Giorgi, Jae Young Joung, Peter C C Fong, Eric Voog, Robert J Jones, Neal D Shore, Curtis Dunshee, Stefanie Zschäbitz, Jan Oldenburg, Dingwei Ye, Xun Lin, Cynthia G Healy, Nicola Di Santo, A Douglas Laird, Fabian Zohren, Neeraj Agarwal
Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France. ., Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., National Cancer Center Hospital East, Chiba, Japan., Vall d'Hebron University Hospital, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain., PUCRS School of Medicine, Porto Alegre, Brazil., IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy., National Cancer Center, Goyang, Republic of Korea., Auckland City Hospital, Auckland, New Zealand., Clinique Victor Hugo Centre Jean Bernard, Le Mans, France., School of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK., Carolina Urologic Research Center, Myrtle Beach, SC, USA., Arizona Urology Specialists, Tucson, AZ, USA., National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany., Akershus University Hospital (Ahus), Lørenskog, Norway., Fudan University Shanghai Cancer Center, Shanghai, China., Pfizer Inc., La Jolla, CA, USA., Pfizer Inc., Collegeville, PA, USA., Pfizer Inc., Durham, NC, USA., Pfizer Inc., New York, NY, USA., Huntsman Cancer Institute (NCI-CCC), University of Utah, Salt Lake City, UT, USA. .