Results from the phase 3 TALAPRO-3 trial show that the combination of enzalutamide and talazoparib reduces the risk of progression or death by 52% in patients with metastatic prostate cancer with alterations in DNA repair genes.
Meanwhile, the academic ZZFIRST trial evaluated the same drug combination in a broader patient population and provides new evidence on how tumours adapt to hormonal therapy. This knowledge will be key to designing new, more personalised and effective treatments.
These two studies are being presented today in two oral presentations at the Congress of the American Society of Clinical Oncology (ASCO), being held in Chicago from 29 May to 2 June. The TALAPRO-3 trial results are being published today simultaneously with their presentation in The New England Journal of Medicine.
The Prostate Cancer Group at the Vall d’Hebron Institute of Oncology (VHIO) has participated in two of the studies being presented today at the Congress of the American Society of Clinical Oncology (ASCO). These provide new advances in precision medicine for patients with metastatic prostate cancer and reinforce the importance of molecular tumour characterisation in personalising treatment.
The results of the TALAPRO-3 and ZZFIRST studies show that the combination of the androgen inhibitor enzalutamide and the PARP inhibitor talazoparib can improve anti-tumour response in certain subgroups of patients with advanced prostate cancer.
The annual incidence of prostate cancer in 2022 was 1.47 million new cases worldwide, according to GLOBOCAN data, and projections indicate that this figure will double to reach approximately 2.9 million cases by 2040. Although most cases are detected as localised tumours, 10% already present with distant metastases at the time of diagnosis, and these cases account for more than 50% of mortality from this disease. “Although patients with metastatic disease initially respond to hormonal treatment, the tumour ultimately adapts and begins to grow again. It is therefore essential to investigate the biological mechanisms that allow the tumour to develop resistance to hormonal treatment and to identify new therapeutic strategies capable of delaying or preventing this process,” explains Dr Joaquin Mateo, medical oncologist at Vall d’Hebron University Hospital and Head of the Prostate Cancer Research Group at VHIO.
Academic clinical trial investigating tumour evolution over time
Dr Joaquin Mateo presented today the results of the phase 2 academic clinical trial ZZFIRST, which evaluate the efficacy of the combination of enzalutamide and talazoparib in hormone-sensitive metastatic prostate cancer. The trial also included the study of tumour adaptations that enable resistance to hormonal therapy, known as castration resistance.
The clinical trial included 54 patients, 37 of whom were treated with enzalutamide and talazoparib and 17 with enzalutamide alone. Patients treated with the experimental combination achieved radiographic progression-free survival, this being the time from the start of treatment until tumour progression is detected through medical imaging, of 45.3 months compared with 31.1 months in patients treated with enzalutamide monotherapy. In addition, the time until PSA progression, a blood biomarker for prostate cancer, and until the development of castration resistance was also longer in patients treated with the new combination.
In this academic trial, the research team analysed adaptive tumour changes through tumour biopsies obtained at the start of the study and during treatment. “By observing changes in tumour cells during the first weeks of treatment, we can anticipate how the tumour will attempt to become resistant to the drug and design more precise treatment strategies,” explains Dr Joaquin Mateo. “Specifically, the combination with PARP inhibitors is indicated for patients with certain mutation profiles in DNA repair genes.”
The ZZFIRST trial, led by Dr Joaquin Mateo and sponsored by MedSir, received external funding from Pfizer, the Spanish Association Against Cancer (AECC) and the United States Department of Defense (DoD).
New treatment option in patients with metastatic prostate cancer with alterations in DNA repair genes
Dr Joaquin Mateo from VHIO has participated in the phase 3 TALAPRO-3 clinical trial, the results of which are being presented today at ASCO by Dr Neeraj Agarwal of the Huntsman Cancer Institute (HCI) at the University of Utah (USA), and are being published simultaneously in The New England Journal of Medicine (NEJM).
The TALAPRO-3 clinical trial evaluates the efficacy of the same drug combination, enzalutamide and talazoparib, in patients with hormone-sensitive metastatic prostate cancer who present alterations in homologous recombination repair (HRR) genes. These alterations occur in between 20% and 25% of metastatic prostate cancers and are associated with a more aggressive disease and a poorer prognosis.
The function of these genes is to repair DNA damage in cells. When they do not function correctly, tumour cells lose this repair capacity and become destabilised. This vulnerability can be exploited therapeutically with drugs such as PARP inhibitors, which block other repair pathways, inducing tumour cell death. This is known as synthetic lethality.
The trial included 599 patients; half received enzalutamide and talazoparib and the other half enzalutamide plus placebo. In patients treated with the experimental combination, the risk of disease progression or death was reduced by 52%. The median radiographic progression-free survival was not reached in the experimental arm compared with 45.8 months in the control arm. An improvement in overall survival was also observed, although it is not yet statistically significant. The adverse effects of the experimental combination were manageable.
“In conclusion,” explains Dr Joaquín Mateo, “these results support the use of talazoparib plus enzalutamide as a potential therapeutic option for patients with hormone-sensitive metastatic prostate cancer with alterations in HRR genes. In addition, they highlight the importance of identifying patients whose tumours present this type of mutation. Therefore, it is very important to equip our healthcare systems with access to genomic testing for all patients with metastatic prostate cancer.”
New therapeutic opportunities thanks to the development of personalised medicine
The evolution of clinical research with PARP inhibitors has transformed the management of metastatic prostate cancer and consolidated precision medicine as a therapeutic strategy for these patients. “Pioneering trials such as TOPARP first demonstrated in 2015 that tumours with alterations in DNA repair genes could respond effectively to this type of targeted treatment. Subsequently, studies such as PROfound or TALAPRO have confirmed the clinical benefit of incorporating PARP inhibitors into hormonal therapy at different stages of the disease, thus expanding therapeutic options and opening the door to increasingly personalised treatments based on the molecular characteristics of each tumour. Many of these advances have been made possible thanks to the role of academic trials driven by researchers, which allow the exploration of new biological mechanisms and the development of innovative strategies focused on yet unmet clinical needs,” concludes Dr Mateo.
References
ASCO 2026
Session details
Oral Abstract Session – Genitourinary Cancer—Prostate, Testicular, and Penile
Date: 30/05/2026
Time 22:00 CEST
5006 – Final results from ZZFIRST: A randomized phase 2 trial of enzalutamide (EZ) and talazoparib (TALA) in metastatic hormone-naïve prostate cancer (mHNPC).
Joaquin Mateo, Elena Castro, Francesca Zacchi, Maria Isabel S. Medina, Kathleen Imbach, Alejo Rodriguez-Vida, Gisela Mir Arnau, Begoña Mellado, Sara Simonetti, Daniel Castellano Gauna, Miguel A. Climent Duran, Angel Borque-Fernando, Albert Font Pous, Jose A. Guerrero-Martinez, Vanesa Izquierdo, Jhudit Perez-Escuredo, Paula Gonzalez-Alonso, Eduard Porta, Amado J. Zurita, Joan Carles
Speaker: Joaquin Mateo
LBA 5007 – TALAPRO-3: Talazoparib (TALA) + enzalutamide (ENZA) compared with placebo (PBO) + ENZA for the treatment of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations.
Neeraj Agarwal, Nobuaki Matsubara, Arun Azad, Fred Saad, Joaquin Mateo, Shusuan Jiang, Dingwei Ye, Eric Voog, Neal D. Shore, Timucin Cil, Christof Vulsteke, Hsiao-Jen Chung, Stefanie Zschaebitz, Douglas Laird, Xiaoxi Zhang, Prachi Nandoskar, Sarah Fenech Chetcuti, Fong Wang, Karim O. Fizazi
Speaker: Neeraj Agarwal
