Talazoparib plus enzalutamide in high-volume metastatic hormone-naive prostate cancer: a randomized phase 2 trial

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.

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Publication Details

Journal
Nature Medicine
Published
2026-10-14
DOI
https://doi.org/10.1038/s41591-026-04671-5
Primary Topic
Prostate Cancer Treatment and Research
Type
article
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0.00

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article

Talazoparib plus enzalutamide in high-volume metastatic hormone-naive prostate cancer: a randomized phase 2 trial

Keyi Zhu, Joan Carles, Mònica Aguilera, Begoña Mellado et al.
Nature Medicine
Prostate Cancer Treatment and Research
article

Talazoparib plus enzalutamide in high-volume metastatic hormone-naive prostate cancer: a randomized phase 2 trial

Keyi Zhu, Joan Carles, Mònica Aguilera, Begoña Mellado, Manuel José Ramos del Río, Nicolás Anselmino, Bernardo Herrera‐Imbroda, Daniel Castellano, Jacques Planas, Patricia Troncoso, Joaquı́n Mateo, Julian Brandariz, Ángel Borque‐Fernando, Daniel Aguilar, Jhudit Pérez‐Escuredo, José A. Guerrero, Sara Simonetti, Amado J. Zurita, Irene Casanova‐Salas, Francesca Zacchi, Ana P. Vivancos, Eduard Porta‐Pardo, Paolo Giovanni Nuciforo, Sara Arce‐Gallego, Paula Gónzález-Alonso, Pablo Cresta Morgado, Alejo Rodríguez‐Vida, Gisela Mir, Heura Domènech, María Isabel Sáez, Albert Font, Victor Esquefa, Anna Oliveira, Miguel Angel Climent, Vanessa Izquierdo, David Lorente, Elena Castro, Kathleen Imbach
article en

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.

Nature Medicine
University of Verona (IT), Hebron University (PS), The University of Texas MD Anderson Cancer Center (US), Research Institute Hospital 12 de Octubre (ES), Josep Carreras Leukaemia Research Institute (ES), Azienda Ospedaliera Universitaria Integrata Verona (IT), Hospital Universitario 12 De Octubre (ES), MedSIR (Spain) (ES), Vall d'Hebron Institut de Recerca (ES), Fundación Instituto Valenciano de Oncología (ES), Hospital Universitario Miguel Servet (ES), Hospital Clínic de Barcelona (ES), Vall d'Hebron Hospital Universitari (ES), Hospital Del Mar (ES), Instituto de Investigación Sanitaria Aragón (ES), Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol (ES), Hospital Clínico Universitario Virgen de la Victoria (ES), Vall d'Hebron Institute of Oncology (ES)
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
Good health and well-being
Openalex Percentile: Top 13%
Prostate Cancer Treatment and Research
DOIOpen Access PDFOpenAlex
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