Talazoparib plus enzalutamide in high-volume metastatic hormone-naive prostate cancer: a randomized phase 2 trial
Year: 2026
Type: article
Study design: Clinical Trial
Abstract: Combining inhibition of poly(ADP-ribose) polymerase and androgen receptor (AR) pathway has demonstrated clinical activity in men with metastatic prostate cancer, although the extent of benefit in tumors lacking homologous recombination repair (HRR) gene alterations remains uncertain. We conducted a randomized phase 2 trial evaluating talazoparib plus enzalutamide versus enzalutamide alone in men with high-volume metastatic hormone-naive prostate cancer (mHNPC). Fifty-four patients starting androgen deprivation therapy received two cycles of enzalutamide lead-in before 1:2 randomization to enzalutamide (n = 17) or enzalutamide plus talazoparib (n = 37). The primary endpoint was met, with a 73% prostate-specific antigen (PSA) <0.2 ng ml−1 response rate at 12 months in the combination arm (95% confidence interval (CI) = 56–86%), exceeding the prespecified efficacy threshold (P < 0.001); the PSA <0.2 rate in the control arm was 64.7% (95% CI = 38–86%, P = 0.54 for exploratory comparison between arms). Grade ≥3 adverse events occurred in 68% patients receiving the combination versus 35% with enzalutamide alone, predominantly anemia (41%). Two fatal therapy-emergent myeloid neoplasms occurred in the enzalutamide plus talazoparib arm in patients with underlying genomic susceptibility. Analyses of paired tumor biopsies acquired at baseline and during enzalutamide lead-in phase demonstrated marked tumor transcriptional reprogramming after AR inhibition, including suppression of proliferation-associated and HRR-related gene expression programs, but without functional impairment of homologous recombination activity. Overall, talazoparib plus enzalutamide demonstrated clinical activity in patients with high-volume mHNPC but did not establish clear additional clinical benefit over enzalutamide alone in this biomarker-unselected population, while being associated with increased toxicity. ClinicalTrials.gov identifier: NCT04332744 . In the randomized multicenter phase 2 ZZ-FIRST trial, patients with high-volume metastatic hormone-sensitive prostate cancer treated with poly(ADP-ribose) polymerase inhibitor talazoparib combined with androgen receptor inhibitor enzalutamide had an improved prostate-specific antigen response compared with enzalutamide alone, and spatial transcriptomic analyses of paired biopsies linked AR inhibition-induced suppression of HRR-related programs to proliferation arrest rather than functional HRR deficiency.
Source: Nature Medicine
Authors: Francesca Zacchi, Elena Castro, Kathleen Imbach, Alejo Rodriguez-Vida, Sara Simonetti, Begoña Mellado, Gisela Mir Arnau, Daniel Aguilar, Daniel Castellano, Miguel Angel Climent, Manuel J. Ramos, Angel Borque-Fernando, Jose Antonio Guerrero, Paula Gonzalez-Alonso, Jhudit Perez-Escuredo, Vanessa Izquierdo, Maria Isabel Saez, Heura Domenech, Sara Arce-Gallego, Bernardo Herrera-Imbroda, Jacques Planas, David Lorente, Albert Font, Anna Oliveira, Pablo Cresta Morgado, Victor Esquefa, Julian Brandariz, Nicolas Anselmino, Keyi Zhu, Patricia Troncoso, Monica Aguilera, Ana Vivancos, Paolo Nuciforo, Irene Casanova-Salas, Eduard Porta, Joan Carles, Amado J. Zurita, Joaquin Mateo
Institutions: University of Verona, Azienda Ospedaliera Universitaria Integrata Verona, Vall d'Hebron Institute of Oncology, Research Institute Hospital 12 de Octubre, Hospital Universitario 12 De Octubre, Josep Carreras Leukaemia Research Institute, Hospital Del Mar, Hospital Clínic de Barcelona, Fundación Instituto Valenciano de Oncología, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria Aragón, MedSIR (Spain), Hospital Clínico Universitario Virgen de la Victoria, Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol, The University of Texas MD Anderson Cancer Center, Vall d'Hebron Hospital Universitari, Hebron University, Vall d'Hebron Institut de Recerca
Language: English
Subfield: Pulmonary and Respiratory Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: U.S. Department of Defense, Prostate Cancer Foundation, Pfizer, Fundación Cellex, “la Caixa” Foundation, Centres de Recerca de Catalunya, European Commission, Generalitat de Catalunya, Astellas Pharma, Associazione Italiana per la Ricerca sul Cancro, CRIS Cancer Foundation, Instituto de Salud Carlos III, Agencia Estatal de Investigación
OpenAlex ID: W7221824367