Researchers investigating advanced prostate cancer treatments have published findings from the ZZ-FIRST trial, a multicenter phase 2 clinical study evaluating the addition of the PARP inhibitor talazoparib to enzalutamide and androgen deprivation therapy in patients with high-volume mHNPC.
In Plain English: The Clinical Takeaway
- The Regimen: The study evaluated adding talazoparib—a targeted cancer drug that blocks DNA repair—to standard hormone therapies for newly diagnosed advanced prostate cancer.
- The Population: Participants were men with high-volume metastatic prostate adenocarcinoma, meaning the cancer had spread to distant sites like bones or visceral organs before prior systemic treatments.
- The Goal: Investigators tracked how effectively this three-drug combination lowered prostate-specific antigen (PSA) levels and delayed disease progression.
Trial Design and Patient Selection Criteria Across Spanish Centers
Conducted across eight clinical sites in Spain, the investigator-initiated ZZ-FIRST trial operated as an open-label, randomized, two-arm phase 2 study. Medica Scientia Innovation Research (MEDSIR) sponsored the trial, with external funding provided by Pfizer, which supplied study medications alongside Astellas Pharma. Investigators enrolled male participants aged 18 or older with histologically documented prostate adenocarcinoma. High-volume disease was defined as the presence of visceral disease and/or at least four bone metastases on bone scan, with at least one of them beyond spine/pelvis.
ZZFIRST at ASCO 2026: Enzalutamide + Talazoparib + ADT in Metastatic Hormone-Naïve Prostate CancerAt ASCO 2026, Joaquin Mateo, MD, PhD, presented final results from ZZFIRST, a randomized phase 2 trial evaluating enzalutamide + talazoparib + ADT in high-volume metastatic… pic.twitter.com/epXXcxeCxO
Patients initiated enzalutamide at a dose of 160 milligrams once daily alongside standard androgen deprivation therapy upon entry. Following two 28-day cycles, patients underwent a 1:2 randomization to either continue the doublet therapy or add talazoparib at 0.5 milligrams daily. This structural design allowed researchers to collect on-treatment tissue biopsies after roughly one month of initial androgen receptor pathway inhibition, capturing molecular shifts prior to talazoparib exposure.
Stratification via Targeted Next-Generation Sequencing
Randomization was stratified according to homologous recombination repair (HRR) gene mutation status. Prospective central targeted next-generation sequencing was performed using the VHIO-300 hybrid capture-based panel at the Vall d’Hebron Institute of Oncology. Genomic DNA extracted from formalin-fixed paraffin-embedded tissue samples underwent sequencing on an Illumina HiSeq 2500 platform. The prespecified panel assessed pathogenic or likely pathogenic alterations across genes including ATM, ATR, BARD1, BRCA1, BRCA2, BRIP1, CDK12, CHEK1, CHEK2, FANCA, PALB2, RAD50, and RAD51.
Samples where sequencing failed were classified as having unknown HRR status and pooled with the wild-type category for randomization stratification. Efficacy assessments across genomic subgroups were subsequently conducted in patients with evaluable tissue profiles.
Primary Endpoints and Radiographic Surveillance Protocols
The trial’s primary endpoint measured the proportion of patients achieving a prostate-specific antigen value below 0.2 nanograms per milliliter at month 12 of therapy. The statistical design established a null hypothesis assuming a response rate of 20 percent or lower, tested against an alternative hypothesis of 40 percent or higher. Secondary endpoints included radiographic progression-free survival assessed per RECIST version 1.1 criteria for soft tissue and Prostate Cancer Working Group 3 guidelines for bone disease.
Imaging evaluations via computed tomography, magnetic resonance imaging, and bone scintigraphy occurred every eight weeks during the first 24 weeks, shifting to every 12 weeks thereafter. Serial serum prostate-specific antigen levels were monitored every four weeks throughout the initial 12 months. All protocol activities adhered to the Declaration of Helsinki and International Council for Harmonisation Good Clinical Practice guidelines, with ethical approval secured from the ethics committee of Arnau de Vilanova Hospital in Valencia.
Contraindications & When to Consult a Doctor
Patients enrolled in the study were excluded if they presented with prior systemic therapies for metastatic prostate cancer, untreated brain metastases, or clinically relevant cardiovascular disease.
Regulatory Registries and Oversight Framework
Oversight of the ZZ-FIRST trial was maintained by a steering committee comprising the chief investigator, a site principal investigator, two additional expert investigators, and sponsor personnel. The trial is registered on ClinicalTrials.gov under identifier NCT04332744 and listed in the European Union Clinical Trials Register under EU CT 2023-509387-24-00. Data collection, safety monitoring, and adverse event grading followed the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 to establish safety profiles for this treatment combination.
References
- ClinicalTrials.gov. NCT04332744: Talazoparib Plus Enzalutamide in High-Volume Metastatic Hormone-Naive Prostate Cancer (ZZ-FIRST). Available at: https://clinicaltrials.gov/ct2/show/NCT04332744
- European Union Clinical Trials Register. EU CT 2023-509387-24-00.
