Background: Multiple lines of evidence suggest a crosstalk between androgen receptor (AR) signaling and DNA damage repair (DDR) in prostate cancer. Co-targeting both pathways in mHNPC can result in a clinically relevant synergistic effect. ZZFIRST trial is evaluating the combination of TALA –a poly(ADP-ribose) polymerase inhibitor– and EZ –an AR signaling inhibitor– in mHNPC patients. Methods: This is a multicenter, open-label, randomized, investigator-initiated phase 2 clinical trial. Men aged ≥18 years with histologically confirmed mHNPC, an ECOG performance status of 0-1, and a prostate-specific antigen (PSA) ≥4 ng/mL at enrolment are eligible. Patients must have not received previous systemic treatment for locally advanced or mHNPC. A total of 54 patients will start treatment with EZ 160 mg/day for 2 28-day cycles in addition to standard androgen-deprivation therapy (ADT). Patients are then randomized and stratified based on homologous recombination gene alterations on a 1:2 ratio to either continue EZ 160 mg/day, or to receive EZ 160 mg/day plus TALA 0.5 mg/day. In both arms, patients will continue ADT throughout the trial. Treatment will continue until progressive disease (PD) or unacceptable toxicity. PSA will be determined every 4 weeks and radiological tumor extend will be assessed at screening and every 8 weeks for the 6 initial months of treatment and every 12 weeks thereafter until PD. Primary endpoint is PSA-complete response defined as the percentage of patients with PSA < 0.2 ng/mL at 12 months of therapy. Secondary endpoints include PSA-complete response at any time point and at month 7, PSA response ( < 4 ng/ml) at 7 and 12 months, PSA-progression-free survival (PSA-PFS), radiologic PFS, time to castration resistance based on PSA-PFS and rPFS, and overall survival. Safety will be assessed as per NCI-CTCAE 5.0. Exploratory endpoints include analysis of transcriptional changes in AR and DDR pathways and assessment of genomic signatures on tumor and liquid biopsies collected at baseline, 4 weeks, and PD. An imaging sub-study of whole-body diffusion weighted MRI will help to further study antitumor activity and drug resistance mechanisms. This trial was opened to accrual in July 2020. Currently 44 patients have been enrolled (with 37 randomized by cycle 3 day 1) out of 54 expected. Analysis will be assessed with the exact binomial test. At least 11 patients must maintain PSA < 0.2 ng/mL by 12 months of therapy among 32 evaluable patients in the combination arm to justify further investigation of this strategy. A drop-out rate of 10% has been considered. Clinical trial information: NCT04332744.