Positive results from the phase 3 TALAPRO-2 study of Talazoparib ( Talzenna ), an oral poly ADP-ribose polymerase ( PARP ) inhibitor, in combination with Enzalutamide ( Xtandi ), an androgen receptor pathway inhibitor ( ARPI ), have demonstrated a statistically significant and clinically meaningful improvement in overall survival ( OS ) compared to placebo plus Enzalutamide in patients with metastatic castration-resistant prostate cancer ( mCRPC ), with or without homologous recombination repair ( HRR ) gene mutations.

The TALAPRO-2 study has evaluated two sets of patients, unselected ( cohort 1 ) and selected for HRR gene-mutations ( cohort 2 ). Overall survival was a prespecified, alpha-protected key secondary endpoint. After more than four years of median follow-up ( 52.5 months ), the median overall survival in cohort 1 was 45.8 months with Talazoparib in combination with Enzalutamide, and 37.0 months with Enzalutamide and placebo ( hazard ratio [ HR ] of 0.80; 95% Confidence Interval [CI], 0.66-0.96; p=0.015 ), representing a 20% reduction in the risk of death. This represents a nearly 9-month gain in median overall survival versus standard of care Enzalutamide.

In Cohort 2, a statistically significant and clinically meaningful improvement in overall survival was observed in patients with HRR-mutated metastatic castration resistant prostate cancer. At a median follow-up of 44.2 months, the median overall survival was 45.1 months with Talazoparib in combination with Enzalutamide, and 31.1 months with Enzalutamide and placebo ( HR of 0.62; 95% CI, 0.48-0.81; p=0.0005 ), a 38% reduction in the risk of death. This result represents a 14-month gain in median overall survival versus standard of care Enzalutamide in a patient population with a historically poor prognosis. The overall survival improvement in the HRR-mutated population was observed in patients in both BRCA and non-BRCA gene alterations.

TALAPRO-2 is the first study demonstrating a significant and clinically meaningful survival benefit using a combination of PARP and androgen receptor inhibitors in metastatic castration resistant prostate cancer. Survival rates in metastatic castration-resistant prostate cancer are poor due to the advanced and aggressive stage of the disease.

At the time of the final analysis, updated radiographic progression free survival ( rPFS ) and other secondary efficacy endpoints demonstrated maintained clinical benefit in both cohorts and were consistent with the primary analyses previously reported and published in The Lancet and Nature Medicine.

The safety profile of Talazoparib plus Enzalutamide was generally consistent with the known safety profile of each medicine. The most common all-cause adverse events in the Talazoparib group ( greater than or equal to 30% of patients ) were anemia, neutropenia, and fatigue, and the most common ( greater than or equal to 10% of patients ) grade 3–4 adverse events were anemia (49%) and neutropenia (19.3%). Adverse events were generally manageable with dose modification and supportive care.

TALAPRO-2 trial

The phase 3 TALAPRO-2 trial is a multicenter, randomized, double-blind, placebo-controlled study that enrolled 1,035 unique patients with metastatic castration resistant prostate cancer who had not received new life-prolonging systemic treatments after documentation of metastatic castration resistant prostate cancer at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. The study has included two patient cohorts: unselected (n=805, of whom 169 had HRR mutations and 636 did not) and those with HRR gene mutations (n=399, including 169 patients from Cohort 1 and 230 subsequently enrolled to comprise Cohort 2). Patients with castrate testosterone levels were randomized to receive Talazoparib 0.5 mg/day plus Enzalutamide 160mg/day, or placebo plus Enzalutamide 160mg/day.

The primary endpoint of the trial was radiographic progression-free survival ( rPFS ), defined as the time from the date of randomization to first objective evidence of radiographic progression by blinded independent central review ( BICR ), or death, whichever occurred first, in both Cohort 1 ( unselected ) and Cohort 2 ( those with HRRm ). Secondary endpoints included overall survival, objective response rate ( ORR ), duration of response ( DoR ), prostate-specific antigen ( PSA ) response, time to cytotoxic chemotherapy and PFS2.

Talazoparib

Talazoparib, active substance of Talzenna, is an oral inhibitor of poly ADP-ribose polymerase ( PARP ), which plays a role in DNA damage repair. Preclinical studies have demonstrated that Talazoparib blocks PARP enzyme activity and traps PARP at the site of DNA damage, leading to decreased cancer cell growth and cancer cell death.

Talzenna was initially approved in the U.S., EU, and multiple other regions as a single agent for the treatment of adult patients with deleterious or suspected deleterious gBRCAm HER2-negative locally advanced or metastatic breast cancer.

Talzenna in combination with Xtandi was approved by the U.S. Food and Drug Administration ( FDA ) for the treatment of adult patients with HRR gene-mutated mCRPC in 2023. The combination was also approved by the European Commission in 2024 for the treatment of adult patients with mCRPC in whom chemotherapy is not clinically indicated. Talzenna is the first and only PARP inhibitor licensed in the European Union for use with Xtandi for patients with metastatic castration resistant prostate cancer, with or without gene mutations.

Warnings and precautions

Myelodysplastic syndrome / acute myeloid leukemia ( MDS/AML ), including cases with a fatal outcome, has been reported in patients who received Talazoparib. Overall, MDS/AML has been reported in 0.4% ( 3 out of 788 ) of solid tumor patients treated with as a single agent in clinical studies. In TALAPRO-2, MDS/AML occurred in 2 out of 511 (0.4%) patients treated with Talazoparib and Enzalutamide and in 0 out of 517 (0%) patients treated with placebo and Enzalutamide. The durations of Talazoparib treatment in these five patients prior to developing MDS/AML were 0.3, 1, 2, 3, and 5 years, respectively. Most of these patients had received previous chemotherapy with Platinum agents and/or other DNA damaging agents including radiotherapy.

Myelosuppression consisting of anemia, neutropenia, and/or thrombocytopenia have been reported in patients treated with Talazoparib. In TALAPRO-2, grade greater than or equal to 3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 45%, 18%, and 8% of patients receiving Talazoparib and Enzalutamide. Overall, 39% of patients (199/511) required a red blood cell transfusion, including 22% (111/511) who required multiple transfusions. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 7%, 3%, and 0.4% of patients.

Embryo-Fetal Toxicity: Talazoparib can cause fetal harm when administered to pregnant women. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment with Talazoparib and for 4 months after receiving the last dose.

Adverse reactions

In TALAPRO-2, serious adverse reactions reported in more than 2% of patients included anemia (9%) and fracture (3%). Fatal adverse reactions occurred in 1.5% of patients, including pneumonia, COVID infection, and sepsis (1 patient each).
The most common adverse reactions ( greater than or equal to 10%, all grades ), including laboratory abnormalities, for patients in the TALAPRO-2 study who received Talazoparib in combination with Enzalutamide versus patients receiving placebo with Enzalutamide were hemoglobin decreased (79% vs 34%), neutrophils decreased (60% vs 18%), lymphocytes decreased (58% vs 36%), fatigue (49% vs 40%), platelets decreased (45% vs 8%), calcium decreased (25% vs 11%), nausea (21% vs 17%), decreased appetite (20% vs 14%), sodium decreased (22% vs 20%), phosphate decreased (17% vs 13%), fractures (14% vs 10%), magnesium decreased (14% vs 12%), dizziness (13% vs 9%), bilirubin increased (11% vs 7%), potassium decreased (11% vs 7%), and dysgeusia (10% vs 4.5%).
Clinically relevant adverse reactions in <10% of patients who received Talazoparib with Enzalutamide has included abdominal pain (9%), vomiting (9%), alopecia (7%), dyspepsia (4%), venous thromboembolism (3%) and stomatitis (2%).
Based on animal studies, Talazoparib may impair fertility in males of reproductive potential.

Drug Interactions

Coadministration with P-gp inhibitors: the effect of coadministration of P-gp inhibitors on Talazoparib exposure when Talazoparib is taken in combination with Enzalutamide has not been studied. Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when Talazoparib is coadministered with a P-gp inhibitor.
Coadministration with BCRP inhibitors: monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when Talazoparib is coadministered with a BCRP inhibitor. Coadministration of Talazoparib with BCRP inhibitors may increase Talazoparib exposure, which may increase the risk of adverse reactions.

Use in specific populations

Renal Impairment: the recommended dosage of Talazoparib for patients with moderate renal impairment ( CLcr 30 - 59 mL/min ) is 0.35 mg taken orally once daily in combination with Enzalutamide. The recommended dosage of Talazoparib for patients with severe renal impairment ( CLcr 15 - 29 mL/min ) is 0.25 mg taken orally once daily in combination with Enzalutamide. No dose adjustment is required for patients with mild renal impairment. Talazoparib has not been studied in patients requiring hemodialysis. ( Xagena_2025 )

Source: American Society of Clinical Oncology Genitourinary ( ASCO GU ) Cancers Symposium 2025

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