FDA Approves Talazoparib Plus Enzalutamide in HRR-Mutated mCSPC

The FDA has approved talazoparib (Talzenna) in combination with enzalutamide (Xtandi) for adults with metastatic androgen pathway modulation-naive or -sensitive (mAPMN/S) prostate cancer, also called metastatic castration-sensitive prostate cancer (mCSPC), with homologous recombination repair (HRR) gene mutations detected by an FDA-authorized test.¹

The October 26, 2026, decision is based on the phase 3 TALAPRO-3 trial (NCT04821622), in which the combination reduced the risk of radiographic progression or death by 52% vs placebo plus enzalutamide (HR, 0.48; 95% CI, 0.36-0.65; P < .0001).¹ Overall survival (OS) data were immature at the time of the analysis, and anemia occurred in 71% of patients who received the combination, making blood count monitoring and transfusion planning central to nursing care.^1,3

The approval moves the PARP inhibitor-androgen receptor pathway inhibitor combination into an earlier disease setting. Talazoparib plus enzalutamide has been approved since June 2023 for HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC), based on the TALAPRO-2 trial.⁶

FoundationOne CDx and FoundationOne Liquid CDx were previously approved as companion diagnostics to identify patients with prostate cancer with HRR gene alterations for treatment with the combination.¹ The review was granted priority review and was conducted under Project Orbis with the Australian Therapeutic Goods Administration and Health Canada.¹

How was TALAPRO-3 designed?

TALAPRO-3 was a randomized, double-blind, placebo-controlled trial that enrolled 599 patients with HRR gene-mutated mAPMN/S prostate cancer. Patients were randomly assigned 1:1 to daily enzalutamide plus either talazoparib or placebo, and all patients continued androgen deprivation therapy (ADT).¹ HRR mutation status in 12 genes (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) was determined prospectively using tumor tissue or circulating tumor DNA (ctDNA)-based next-generation sequencing.¹

Eligible patients had an ECOG performance status of 0 or 1 and could have received up to 3 months of ADT, with or without an androgen receptor pathway inhibitor, for castration-sensitive disease; prior docetaxel was not permitted.³ Randomization was stratified by de novo vs relapsed metastatic disease, high- vs low-volume disease, and BRCA-mutated vs non-BRCA HRR-altered disease.³ Talazoparib was given at 0.5 mg and enzalutamide at 160 mg daily.³

The population was largely high risk: 84% to 85% of patients had de novo metastatic disease, 70% to 71% had high-volume disease, and approximately one-third (35% vs 34%) had BRCA1/2 alterations.³ Median age was 70 years in the talazoparib arm and 69 years in the placebo arm.³

The primary end point was radiographic progression-free survival (rPFS) assessed by investigators according to RECIST version 1.1 and Prostate Cancer Working Group 3 (bone) criteria. OS was an additional efficacy outcome measure.¹ The results were presented at the 2026 ASCO Annual Meeting and simultaneously published in The New England Journal of Medicine.^2,3

How much did talazoparib improve radiographic progression-free survival?

Median rPFS was not reached (95% CI, NR-NR) with talazoparib plus enzalutamide vs 45.8 months (95% CI, 37.7-NR) with placebo plus enzalutamide (HR, 0.48; 95% CI, 0.36-0.65; P < .0001).¹ Median rPFS follow-up was 37.6 months and 37.7 months in the respective arms.³ At approximately 36 months, rPFS rates were 76.6% vs 56.2%.³

The benefit was observed in both genomic strata:

• BRCA1/2 alterations: HR, 0.368 (95% CI, 0.222-0.609; P < .0001)³
• Non-BRCA HRR alterations: HR, 0.567 (95% CI, 0.392-0.819; P = .0022)³

What do the overall survival and secondary end point data show?

OS data were immature at the time of the rPFS analysis.¹ At the interim analysis, there were 74 deaths in the talazoparib arm and 91 in the placebo arm (HR, 0.77; 95% CI, 0.56-1.04), with 36-month OS rates of 78% and 72%, respectively.³ The difference did not reach statistical significance, and follow-up continues.

Talazoparib plus enzalutamide also delayed time to prostate-specific antigen (PSA) progression (HR, 0.513; 95% CI, 0.370-0.712; P < .0001) and time to subsequent systemic anticancer therapy (HR, 0.514; 95% CI, 0.378-0.698; P < .0001).³ PSA response rates of at least 50% were high in both arms and did not differ statistically (90.5% vs 86.5%; P = .1194).³

What adverse events should nurses watch for?

Grade 3 or 4 treatment-emergent adverse events (TEAEs) occurred in 79% of patients in the talazoparib arm vs 41% in the placebo arm.³ The most common TEAEs with the combination were anemia, fatigue, decreased neutrophil count, neutropenia, asthenia, and decreased white blood cell count.³

Anemia was the dominant toxicity:

• Any-grade anemia: 71% vs 22%³
• Grade 3 or 4 anemia: 51% with the combination³
• Grade 1 or 2 anemia already present at baseline: 43% of patients in the combination arm³
• Median time to onset of grade 3 or 4 anemia: 3.2 months³
• Packed red blood cell transfusion: 40% of patients, with a median of 2 transfusions among those transfused³
• Recurrent grade 3 or 4 anemia after talazoparib dose reduction: 14%³

The protocol required a talazoparib dose reduction after grade 3 or 4 anemia. Median duration of talazoparib treatment was similar in patients who did and did not develop grade 3 or 4 anemia (34.2 vs 35.9 months), and 5% of patients permanently discontinued talazoparib because of anemia.³ Permanent discontinuation of talazoparib or placebo for any adverse event occurred in 19% vs 10% of patients.³ Fatigue was reported in 28.4% and decreased neutrophil count in 27.1% of patients receiving the combination.⁵

Myelodysplastic syndrome occurred in 3 patients in the talazoparib arm vs 1 in the placebo arm, and acute myeloid leukemia occurred in 2 patients vs none.³ Venous embolic and thrombotic events occurred in 7 and 5 patients, respectively.³ Patient-reported outcomes were generally similar between arms, apart from greater appetite loss with the combination.³

The prescribing information includes warnings and precautions for myelodysplastic syndrome/acute myeloid leukemia, myelosuppression, and embryo-fetal toxicity.¹

What is the recommended dose?

The recommended talazoparib dose is 0.5 mg orally once daily with enzalutamide until disease progression or unacceptable toxicity; enzalutamide dosing follows its own prescribing information.¹ Patients should also receive a gonadotropin-releasing hormone analog concurrently or should have had a bilateral orchiectomy.¹

How did investigators interpret the results?

"These results support talazoparib plus enzalutamide as a potential treatment option for patients with HRR gene-altered metastatic castration-sensitive prostate cancer, and early molecular testing is critically important now in these patients," said lead investigator Neeraj Agarwal, MD, FASCO, professor and presidential endowed chair of cancer research at Huntsman Cancer Institute, University of Utah, in Salt Lake City, when the data were presented at ASCO.^3,5

How does this approval fit with earlier talazoparib data in prostate cancer?

The FDA has limited talazoparib plus enzalutamide to HRR-mutated disease in both settings. In May 2025, the FDA's Oncologic Drugs Advisory Committee voted 8 to 0 against the risk-benefit profile of the combination in mCRPC without HRR mutations, citing added toxicity and uncertain benefit outside the biomarker-selected population.⁷ TALAPRO-3 enrolled only patients with HRR gene alterations.^1,7

Limitations of the current data include immature OS, an investigator-assessed primary end point, and small patient numbers for some individual HRR genes.^1,3 The trial was sponsored by Pfizer.⁴

What are the key takeaways for oncology nurses?

• Confirm HRR status before treatment. Eligibility depends on an FDA-authorized tissue or ctDNA test, so molecular testing early in metastatic castration-sensitive disease affects who can receive the combination.^1,3
• Plan for anemia from the start. Nearly half of patients had low-grade anemia at baseline, and grade 3 or 4 anemia emerged at a median of 3.2 months; monitor blood counts according to the prescribing information and prepare patients for the possibility of transfusion.^1,3
• Frame dose reductions as expected. Most patients with severe anemia stayed on treatment after a talazoparib dose reduction, so patient education can position dose changes as part of the plan rather than a sign of failure.³
• Watch for fatigue and infection risk. Fatigue and decreased neutrophil counts were among the most common adverse events; teach patients which symptoms to report.^3,5
• Reinforce the long-term safety picture. Counsel patients on the label's warnings and precautions, including myelodysplastic syndrome/acute myeloid leukemia and embryo-fetal toxicity.¹
• Support informed decisions. Grade 3 or 4 adverse events were nearly twice as common with the combination, and OS data are not yet mature; these trade-offs are part of shared decision-making.^1,3
• Keep ADT continuous. Patients need ongoing gonadotropin-releasing hormone analog therapy unless they have had a bilateral orchiectomy.¹

References

1. FDA approves talazoparib with enzalutamide for metastatic androgen pathway modulation-naive or -sensitive prostate cancer with HRR gene mutations. FDA. October 26, 2026. Accessed October 26, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-talazoparib-enzalutamide-metastatic-androgen-pathway-modulation-naive-or-sensitive
2. Agarwal N, Matsubara N, Azad AA, et al. PARP and androgen-signaling inhibition plus ADT in metastatic prostate cancer. N Engl J Med. 2026;395:427-439. doi:10.1056/NEJMoa2604126
3. Agarwal N, Matsubara N, Azad AA, et al. 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. J Clin Oncol. 2026;44(suppl 17):LBA5007. doi:10.1200/JCO.2026.44.17_suppl.LBA5007
4. Study of talazoparib with enzalutamide in men with DDR gene mutated mCSPC (TALAPRO-3). ClinicalTrials.gov identifier: NCT04821622. Updated July 22, 2026. Accessed October 26, 2026. https://clinicaltrials.gov/study/NCT04821622
5. Lutton L. New trial results point toward a more targeted approach to metastatic castration-sensitive prostate cancer | ASCO 2026. Managed Healthcare Executive. May 30, 2026. Accessed October 26, 2026. https://www.managedhealthcareexecutive.com/view/new-trial-results-point-toward-a-more-targeted-approach-to-metastatic-castration-sensitive-prostate-cancer-asco-2026
6. Lovely B. FDA approves talazoparib in combination with enzalutamide for mCRPC. Oncology Nursing News. June 20, 2023. Accessed October 26, 2026. https://www.oncnursingnews.com/view/fda-approves-talazoparib-in-combination-with-enzalutamide-for-mcrpc
7. Wahner A. ODAC votes against talazoparib combo for patients with non-HRR mCRPC. Oncology Nursing News. May 24, 2025. Accessed October 26, 2026. https://www.oncnursingnews.com/view/odac-votes-against-talazoparib-combo-for-patients-with-non-hrr-mcrpc