Talazoparib triplet joins treatment options for HRR-mutated mHSPC

Treatment intensification for metastatic hormone-sensitive prostate cancer (mHSPC) now spans 4 triplet options, with biomarkers, disease burden, and toxicity guiding selection, according to Benjamin Garmezy, MD.¹ Garmezy, associate director of GU Research at Sarah Cannon Research Institute and associate director of Drug Development at SCRI Oncology Partners, presented “Doublets, Triplets, and PARP Therapies: Personalizing APMS/N Prostate Cancer” at the 2026 LUGPA Annual Meeting.¹

Garmezy, a medical oncologist in Nashville, Tennessee, noted the field is moving toward the term metastatic androgen pathway modulation-naive or -sensitive (mAPMN/S) prostate cancer.¹ He outlined a framework for initial metastatic disease.¹ For oligometastatic disease, options include definitive radiation plus stereotactic body radiotherapy as metastasis-directed therapy with androgen deprivation therapy (ADT) and an androgen receptor pathway inhibitor (ARPI), possibly for 2 years.¹

A doublet of ADT plus an ARPI is likely sufficient for most patients with low-risk, low-volume disease, while high-risk, high-volume disease warrants consideration of a triplet.¹ High volume is technically defined by conventional imaging, although many clinicians no longer rely on conventional imaging in this setting, he noted.¹

Choosing the ADT and androgen receptor inhibitor backbone in mHSPC

Garmezy said he views oral relugolix (Orgovyx) and injectable luteinizing hormone-releasing hormone agonists as broadly equivalent, with compliance and preference driving selection.¹ In a randomized comparison, the cumulative incidence of major adverse cardiovascular events at week 48 was 2.8% (95% CI, 1.8-4.5) with relugolix vs 5.6% (95% CI, 3.5-8.9) with leuprolide (HR, 0.46; 95% CI, 0.24-0.88).² He said he prefers relugolix in compliant patients, especially those with cardiac risk.¹

Garmezy places abiraterone acetate (Zytiga) and the AR inhibitors in separate categories because of their different mechanisms of action, while noting cross-resistance between them.¹ In a meta-analysis presented by Fisher et al at the 2025 ASCO Genitourinary Cancers Symposium, abiraterone showed no overall survival (OS) benefit in men aged 75 years or older (HR, 1.01; 95% CI, 0.82-1.26).³ The age interaction was significant (interaction HR, 1.56; P = .001), whereas AR inhibitor trials showed OS benefit in men aged 75 years or older (HR, 0.57; 95% CI, 0.45-0.71).³

Garmezy cautioned these data are not prospective randomized comparisons.¹ Abiraterone carries more cardiovascular adverse effects plus steroid exposure, which may matter for older patients at risk of death from causes other than prostate cancer, he said.¹ In patients younger than 75 years, the agents look more similar than different.¹

To choose among AR inhibitors, Garmezy cited ARACOG (NCT04335682), a phase 2 open-label trial randomly assigning 111 patients with mCRPC, nmCRPC, or mHSPC to darolutamide (Nubeqa) or enzalutamide (Xtandi).⁴ The median change in the maximally changed cognitive domain was −15.8 with darolutamide (n = 48) vs −36.1 with enzalutamide (n = 47; P = .009).⁴ He noted the study’s limitations, including open-label design, darolutamide provided by the study, and enzalutamide billed through standard of care.¹^,⁴

ARACOG does not mean darolutamide for everyone, according to Garmezy, although neurocognitive tolerability may differentiate it as a combination backbone.¹ He said he prefers an AR inhibitor over abiraterone.

“The key is as long as you’re using one of them, you’re doing okay,” he said.¹

Triplet therapy options in high-volume mHSPC: ARASENS and PSMAddition

The phase 3 ARASENS trial (NCT02799602) randomly assigned 1306 patients with mHSPC to darolutamide or placebo plus ADT and 6 cycles of docetaxel.¹ Darolutamide improved OS (HR, 0.68; 95% CI, 0.57-0.80; P < .001) and time to castration resistance (HR, 0.36; 95% CI, 0.30-0.42; P < .001).¹ Garmezy described the ADT-plus-docetaxel comparator as the wrong control arm by modern standards.¹ Adding docetaxel to an ADT-plus-ARPI doublet has never been proven prospectively, although he believes it offers a survival benefit.¹

In the phase 3 PSMAddition trial (NCT04720157), 1144 patients with untreated or minimally treated prostate-specific membrane antigen (PSMA)-positive mHSPC were randomly assigned to ADT plus an ARPI with or without lutetium Lu 177 vipivotide tetraxetan (Pluvicto).⁵ Treatment was 7.4 GBq every 6 weeks for 6 cycles.⁵ Radiographic progression-free survival (rPFS) by blinded independent central review favored the triplet (HR, 0.72; 95% CI, 0.58-0.90; P = .002), with events in 139 of 572 patients (24.3%) vs 172 of 572 (30.1%).⁵

Interim OS showed an HR of 0.84 (95% CI, 0.63-1.13; P = .125), with follow-up ongoing.⁵ Lutetium Lu 177 vipivotide tetraxetan has a survival advantage in later lines, but no data show earlier use is superior, Garmezy noted.¹ Any-grade dry mouth occurred in 262 of 564 patients (46.5%) vs 22 of 565 (3.9%), with no grade 3 or higher events.⁵

Cytopenias occurred in 248 patients (44.0%) vs 115 (20.4%), including grade 3 or higher events in 81 (14.4%) vs 28 (5.0%).⁵ Health-related quality of life was not improved, with HRs of 1.02 (95% CI, 0.87-1.18) for pain intensity and 1.14 (95% CI, 0.98-1.33) for FACT-P total score.⁵

“Don’t set 6 cycles and forget it,” Garmezy advised, noting additional cycles after a strong early response may add toxicity without further benefit.¹

Capivasertib for PTEN-deficient mHSPC: CAPItello-281 efficacy, safety, and FDA approval

CAPItello-281 (NCT04305496) enrolled 1012 patients with newly diagnosed, PTEN-deficient mHSPC, defined as 90% or more of viable malignant cells with no specific cytoplasmic PTEN staining by immunohistochemistry.⁶^,⁷ Of approximately 6200 patients submitting tissue, 97% had a valid result and 25% were PTEN deficient.⁶ Patients were randomly assigned to capivasertib (Truqap) 400 mg twice daily, 4 days on and 3 days off, or placebo, each with abiraterone, prednisone, and ADT.⁶

On June 12, 2026, the FDA approved capivasertib with abiraterone and prednisone for adults with PTEN-deficient mAPMN/S prostate cancer detected by an FDA-authorized test.⁷ The agency also approved the VENTANA PTEN (SP218) RxDx Assay as a companion diagnostic.⁷ The approval was based on investigator-assessed rPFS, with a median of 33.2 months vs 25.7 months (HR, 0.81; 95% CI, 0.66-0.98; 2-sided P = .034).⁷

In an updated analysis, median rPFS was 35.5 months with capivasertib vs 26.0 months with placebo (HR, 0.83; 95% CI, 0.70-0.99; nominal P = .033).⁸ Benefit increased with degree of PTEN loss in the primary analysis.⁶ The rPFS HRs were 0.75 (95% CI, 0.60-0.94) for 95% or greater loss, 0.71 (95% CI, 0.52-0.97) for 99% or greater, and 0.68 (95% CI, 0.48-0.96) for 100%.⁶

Median OS was 57.4 months vs 46.5 months (HR, 0.82; 95% CI, 0.68-0.99; P = .044), although the descriptive analysis did not meet statistical significance.⁸ Garmezy encouraged clinicians to request the exact percentage of PTEN loss from next-generation sequencing vendors and suggested reserving capivasertib for 95% loss or greater.¹ Capivasertib has no later-line indication, so its use is confined to the frontline setting, he noted.¹

Diarrhea occurred in 52.7% of patients receiving capivasertib (6.4% grade 3 or higher), hyperglycemia in 40.4% (11.3%), and rash in 36.4% (12.7%).⁸ The prescribing information includes warnings and precautions for hyperglycemia, diarrhea, cutaneous adverse reactions, and embryo-fetal toxicity.⁷ Garmezy advised checking hemoglobin A1c before starting treatment, monitoring glucose routinely, and setting up a hyperglycemia management plan with advanced practice providers.¹

Talazoparib plus enzalutamide in HRR-mutated mHSPC: TALAPRO-3 and FDA approval

TALAPRO-3 (NCT04821622) randomly assigned 599 patients with homologous recombination repair (HRR) gene-altered mHSPC to talazoparib (Talzenna) 0.5 mg plus enzalutamide 160 mg daily or placebo plus enzalutamide.⁹ In the BRCA-mutated subgroup, the rPFS HR was 0.368 (95% CI, 0.222-0.609; P < .0001), with 36-month rPFS of 77.2% vs 48.8%.⁹ In the non-BRCA-mutated subgroup, the HR was 0.567 (95% CI, 0.392-0.819; P = .0022), with 36-month rPFS of 76.2% vs 60.2%.⁹

Garmezy highlighted benefit in patients without BRCA1/2 mutations as a differentiator for talazoparib, which has greater PARP-trapping activity than other PARP inhibitors.¹ In post hoc gene-level analyses, the rPFS HR was 0.433 (95% CI, 0.238-0.786) for ATM alterations, which he described as the third most common HRR alteration after BRCA mutations.¹^,⁹^,10 ATM showed less activity in mCRPC in TALAPRO-2, where the ATM cluster HR was 0.90 (95% CI, 0.39-2.04).¹1

OS favored talazoparib numerically, with 74 of 300 deaths vs 91 of 299 (HR, 0.77; 95% CI, 0.56-1.04).^9,10 Anemia occurred in 71% of patients receiving talazoparib (51% grade 3 or 4), and myelodysplastic syndrome occurred in 3 patients vs 1, with acute myeloid leukemia in 2 patients vs none.^9,10 Garmezy noted many patients will require transfusions and urged careful planning of blood count monitoring.¹

On October 26, 2026, the FDA approved talazoparib with enzalutamide for mAPMN/S prostate cancer with HRR gene mutations detected by an FDA-authorized test.¹² The approved panel covers ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, and RAD51C, considerably broader than the BRCA2-limited approval for niraparib plus abiraterone, Garmezy noted.^1,12 Given years of potential PARP inhibitor exposure, he urged clinicians to confirm data support the specific mutation before treating.¹

How to select among docetaxel, PARP inhibitor, capivasertib, and PSMA-targeted triplets

Garmezy cited TRITON3 (NCT02975934) to support extrapolating PARP inhibitor use over chemotherapy.¹ In patients with BRCA-mutated mCRPC, rucaparib improved rPFS vs docetaxel (median, 11.2 vs 8.3 months; HR, 0.53; 95% CI, 0.37-0.77).¹³ It also improved rPFS vs a second-generation ARPI (median, 11.2 vs 4.5 months; HR, 0.38; 95% CI, 0.25-0.58).¹³

Among patients with liver metastases, the rPFS benefit was less certain (HR, 0.54; 95% CI, 0.23-1.25; P = .1541).¹⁴ Docetaxel remains a strong option, and 18 weeks of intensification is short relative to the years patients may live with hormone-sensitive disease, Garmezy said.¹ He said he favors docetaxel for patients with liver metastases, aggressive variant molecular signatures such as alterations in 2 or 3 of TP53, RB1, and PTEN, very high disease burden, or Gleason 9 or 10 disease.¹

Garmezy recommends considering a PARP inhibitor triplet for all patients with BRCA1/2 mutations, weighing age, comorbidities, and extent of disease, and considering one for other HRR alterations.¹ Capivasertib is reasonable for PTEN loss, which may also predict docetaxel sensitivity, making the choice between longer oral therapy and chemotherapy a patient conversation.¹ Lutetium Lu 177 vipivotide tetraxetan is reasonable for high PSMA expression, with caution on the number of cycles.¹

No data establish which of the 4 triplet options is most effective for a given patient, according to Garmezy.¹

“It’s going to come down to shared decision making because they’re all reasonable options,” he said.¹ With capivasertib and talazoparib both approved in 2026 for biomarker-selected mAPMN/S disease, next-generation sequencing results, PSMA imaging, and disease volume now directly shape frontline intensification for urologists managing mHSPC.^1,7,12

REFERENCES

1. Garmezy B. Doublets, triplets, and PARP therapies: personalizing APMS/N prostate cancer. Presented at: 2026 LUGPA Annual Meeting; November 5-7, 2026, Chicago, Illinois

2. Shore ND, Saad F, Cookson MS, Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325

4. Morgans A, Bobek O, Kwon DH, et al. Cognitive effects of darolutamide vs enzalutamide: results of ARACOG (AFT-47), a randomized clinical trial from the Alliance for Clinical Trials in Oncology. J Clin Oncol. 2026 (suppl 16; abstr 5005). doi:10.1200/JCO.2026.44.16_suppl.5005

5. Tagawa ST, Sartor O, Piulats JM, et al. Phase III trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Presented at: 2025 European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA6

6. Fizazi K, Clarke NW, De Santis M, et al. Capivasertib plus abiraterone in PTEN-deficient metastatic hormone-sensitive prostate cancer: CAPItello-281 phase III study. Ann Oncol. 2026;37(1):53-68. doi:10.1016/j.annonc.2025.10.004

7. FDA approves capivasertib with abiraterone and prednisone for PTEN-deficient androgen pathway modulation-naïve or -sensitive prostate cancer. US Food and Drug Administration. June 12, 2026. Accessed November 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-capivasertib-abiraterone-and-prednisone-pten-deficient-androgen-pathway-modulation

8. Fizazi K, Clarke NW, De Santis M, et al. Capivasertib (capi) + abiraterone (abi) vs placebo (pbo) + abi in patients (pts) with PTEN-deficient metastatic hormonesensitive prostate cancer (mHSPC): Updated overall survival (OS) from CAPItello-281. Presented at: 2026 European Society for Medical Oncology Congress. October 23-27, 2026. Madrid, Spain. LBA56. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2026_abstracts/LBA56.html.pdf

9. Agarwal N, Matsubara A, Azad A, 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 (suppl 17; abstr LBA5007). doi:10.1200/JCO.2026.44.17_suppl.LBA5007

10. 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(5):427-439. doi:10.1056/NEJMoa2604126

11. Fizazi K, Azad AA, Matsubara N, et al. First-line talazoparib with enzalutamide in HRR-deficient metastatic castration-resistant prostate cancer: the phase 3 TALAPRO-2 trial. Nat Med. 2024;30(1):257-264. doi:10.1038/s41591-023-02704-x

12. FDA approves talazoparib with enzalutamide for metastatic androgen pathway modulation-naïve or -sensitive prostate cancer with HRR gene mutations. US Food and Drug Administration. October 26, 2026. Accessed November 5, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-talazoparib-enzalutamide-metastatic-androgen-pathway-modulation-naive-or-sensitive

13. Fizazi K, Piulats JM, Reaume MN, et al. Rucaparib or physician's choice in metastatic prostate cancer. N Engl J Med. 2023;388(8):719-732. doi:10.1056/NEJMoa2214676

14. Morris D, Bryce AH, Piulats JP, et al. Rucaparib vs docetaxel or second-generation androgen receptor pathway inhibitor therapy for metastatic castration-resistant prostate cancer patients with BRCA mutations with or without liver metastases in TRITON3. J Urol. 2025;213(5S2):e580. doi:10.1097/01.JU.0001109908.15997.76.07