Author(s): Prof Neeraj Agarwal, MD1;Arun A Azad, MBBS2;Joan Carles, MD3;Prof Andre P Fay, MD4;Prof Nobuaki Matsubara, MD5;Daniel Heinrich, MD6;Prof Cezary Szczylik, MD7,8;Ugo De Giorgi, MD9;Prof Jae Young Joung, MD10;Peter C C Fong, MD11, 12;Eric Voog, MD13;Prof Robert J Jones, MBChB14;Neal D Shore, MD15;Curtis Dunshee, MD16;Stefanie Zschäbitz, MD17;Prof Jan Oldenburg, MD18;Xun Lin, PhD19;Cynthia G Healy, BS20;Nicola Di Santo, MD21;Fabian Zohren, MD22;Prof Karim Fizazi, MD23
BACKGROUND
Co-inhibition of poly(ADP-ribose) polymerase (PARP) and androgen receptor activity might result in antitumour efficacy irrespective of alterations in DNA damage repair genes involved in homologous recombination repair (HRR). We aimed to compare the efficacy and safety of talazoparib (a PARP inhibitor) plus enzalutamide (an androgen receptor blocker) versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC).
METHODS
TALAPRO-2 is a randomised, double-blind, phase 3 trial of talazoparib plus enzalutamide versus placebo plus enzalutamide as first-line therapy in men (age ≥18 years [≥20 years in Japan]) with asymptomatic or mildly symptomatic mCRPC receiving ongoing androgen deprivation therapy. Patients were enrolled from 223 hospitals, cancer centres, and medical centres in 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region. Patients were prospectively assessed for HRR gene alterations in tumour tissue and randomly assigned (1:1) to talazoparib 0·5 mg or placebo, plus enzalutamide 160 mg, administered orally once daily. Randomisation was stratified by HRR gene alteration status (deficient vs non-deficient or unknown) and previous treatment with life-prolonging therapy (docetaxel or abiraterone, or both: yes vs no) in the castration-sensitive setting. The sponsor, patients, and investigators were masked to talazoparib or placebo, while enzalutamide was open-label. The primary endpoint was radiographic progression-free survival (rPFS) by blinded independent central review, evaluated in the intention-to-treat population. Safety was evaluated in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov (NCT03395197) and is ongoing.
FINDINGS
Between Jan 7, 2019, and Sept 17, 2020, 805 patients were enrolled and randomly assigned (402 to the talazoparib group and 403 to the placebo group). Median follow-up for rPFS was 24·9 months (IQR 21·9–30·2) for the talazoparib group and 24·6 months (14·4–30·2) for the placebo group. At the planned primary analysis, median rPFS was not reached (95% CI 27·5 months–not reached) for talazoparib plus enzalutamide and 21·9 months (16·6–25·1) for placebo plus enzalutamide (hazard ratio 0·63; 95% CI 0·51–0·78; p<0·0001). In the talazoparib group, the most common treatment-emergent adverse events were anaemia, neutropenia, and fatigue; the most common grade 3–4 event was anaemia (185 [46%] of 398 patients), which improved after dose reduction, and only 33 (8%) of 398 patients discontinued talazoparib due to anaemia. Treatment-related deaths occurred in no patients in the talazoparib group and two patients (<1%) in the placebo group.
INTERPRETATION
Talazoparib plus enzalutamide resulted in clinically meaningful and statistically significant improvement in rPFS versus standard of care enzalutamide as first-line treatment for patients with mCRPC. Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations.
FUNDING
Pfizer.
Author Affiliations
1Huntsman Cancer Institute (NCI-CCC), University of Utah, Salt Lake City, UT, USA;2Peter MacCallum Cancer Centre, Melbourne, Australia;3Vall d’Hebron University Hospital, Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain;4PUCRS School of Medicine, Porto Alegre, Brazil;5National Cancer Center Hospital East, Chiba, Japan;6Innlandet Hospital Trust, Gjøvik, Norway;7Department of Oncology, European Health Center, Otwock, Poland;8Postgraduate Medical Education Center, Warsaw, Poland;9IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) Dino Amadori, Meldola, Italy;10National Cancer Center, Goyang, South Korea;11Auckland City Hospital, Auckland, New Zealand;12University of Auckland, Auckland, New Zealand;13Clinique Victor Hugo Centre Jean Bernard, Le Mans, France;14School of Cancer Sciences, University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK;15Carolina Urologic Research Center, Myrtle Beach, SC, USA;16Arizona Urology Specialists, Tucson, AZ, USA;17National Center for Tumor Diseases (NCT), Heidelberg University Hospital, Heidelberg, Germany;18Akershus University Hospital (Ahus), Lørenskog, Norway;19Pfizer, La Jolla, CA, USA;20Pfizer, Collegeville, PA, USA;21Pfizer, Durham, NC, USA;22Pfizer, New York, NY, USA;23Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France
