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Talazoparib plus enzalutamide significantly delays progression in HRR gene–altered mCRPC

Article

The benefit in radiographic progression-free survival extended across all subgroups of patients with HRR-deficient metastatic castration-resistant prostate cancer.

First-line treatment with the combination of talazoparib (Talzenna) and enzalutamide (Xtandi) significantly reduced the risk of disease progression or death in patients with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations, according to a subgroup analysis of the phase 3 TALAPRO-2 trial (NCT03395197).1,2

“Based on these data, I believe that talazoparib plus enzalutamide, if approved, should become a standard of care for patients with mCRPC and HRR alterations,” said Karim Fizazi, MD.

“Based on these data, I believe that talazoparib plus enzalutamide, if approved, should become a standard of care for patients with mCRPC and HRR alterations,” said Karim Fizazi, MD.

In the HRR gene–altered subgroup of the TALAPRO-2 trial, the median radiographic progression-free survival (rPFS) was not yet reached (95% CI, 21.9-NR) in patients receiving talazoparib plus enzalutamide (n = 200) vs 13.8 months (95% CI, 11.0-16.7) in patients receiving enzalutamide plus placebo arm (n = 199), translating to a 55% reduction in the risk of disease progression or death (HR, 0.45; 95% CI, 0.33-0.61; P <.0001).

According to Karim Fizazi, MD, who presented these data at the 2023 ASCO meeting, the rPFS benefit extended to all subgroups of HRR deficient patients, including those with BRCA1/2 mutations. In the BRCA mutation–positive group, the talazoparib combination led to an 80% reduction in the risk of disease progression or death versus the control arm (HR, 0.20; 95% CI, 0.11-0.36, P <.0001). Among patients without BRCA1/2 mutations, there was a much smaller rPFS benefit observed in the talazoparib arm (HR, 0.72; 95% CI, 0.49-1.07; P = 0.10).

The overall phase 3 TALAPRO-2 study compared the combination of the PARP inhibitor talazoparib and androgen receptor enzalutamide compared with placebo and enzalutamide in an all-comer population of 805 patients receiving first-line treatment for mCRPC.

At baseline, those with a BRCA2 alteration in their disease made up 31% of patients in the talazoparib arm compared with 36.7% in the placebo arm, whereas patients with a BRCA1 alteration made up 5.5% and 6%, respectively. HRR deficient patients with only a BRCA2 alteration (n = 55) in the combination arm had a significant rPFS compared to the BRCA2 patients (n = 60) on the placebo arm (HR, 0.19; 95% CI, 0.10-0.38, P < 0.0001). Similar results were seen with patients who had only a BRCA1 alteration (HR, 0.17; 95% CI, 0.02-1.51, P = 0.074) and significant rPFS benefit was seen in patients with a BRCA cluster in their disease (HR, 0.20; 95% CI, 0.11-0.36, P < 0.0001).

“I think it’s [also] important to mention that men who had prior abiraterone, or docetaxel for castration sensitive disease, tend to benefit quite the same as compared to those who did not receive these agents, with a hazard ratio of approximately 0.45,” added Fizazi, a medical oncologist at Gustave Roussy and professor of oncology at the University of Paris-Saclay.

Patients given prior abiraterone or docetaxel made up 37.5% of patients in the combination arm compared with a similar rate in the placebo arm at 37.2%. More patients in the combination arm and placebo arm had just docetaxel vs abiraterone at 8% vs 30.2% and 8% vs 28.5%, respectively. Overall, most patients disease was in the bone in both arms at 87.5% in the talazoparib arm and 79.4% in the placebo arm, with a similar median range of prostate specific antigen (PSA) at 19.6 ng/mL (range, 0.2-3412.0) in the talazoparib arm compared with 18.0 ng/mL (range, 0.0-1055.0) in the placebo and enzalutamide arm.

The combination of talazoparib with first-line enzalutamide also prolonged the time to PSA progression for these mCRPC patients, which according to Fizazi, was a dramatic improvement of approximately 40% reduction of risk between both arms. A median of 28.6 months (95% CI, 26.7-NR) time to PSA progression in the treatment arm was seen compared with 11.1 months (95% CI, 9.3-13.9) in the placebo and enzalutamide arm (HR, 0.41; 95% CI, 0.30-0.57, P < 0.0001). These results extended to improving the time to cytotoxic chemotherapy at 38 events in the combination arm vs 65 in the placebo arm (HR, 0.46; 95% CI, 0.31-0.79, P = 0.0001) and a median PFS2 of 36.4 months (95 CI, 364.4-NR) and 28.1 months (95% CI, 24.5-NR), respectively (HR, 0.57; 95% CI, 0.39-0.85, P = 0.0045).

An objective response rate (ORR) of 67.1% was seen in the combination arm with 38.4% of those responses being complete responses and a stable disease rate of 26% was observed, while 5.6% of remaining patients on the combination arm had progressive disease. In comparison, the ORR was 40% in the placebo arm with 18.5% of those responses being complete, 32.3% had stable disease and 20% had progressive disease.

Ultimately, no new safety signals were identified with the combination regimen, but grade 3-4 treatment emergent adverse effects (TEAEs) made were seen in 66.2% of patients on the combination therapy vs 37.2% of those on the placebo and enzalutamide treatment. Dose interruption of talazoparib due to an AE was seen in 67.2% of patients compared with 19.6% of those on the placebo arm and just over half of patients (55.6%) in the combination arm had to dose reduce their talazoparib.

Still, discontinuation rates were low in the combination arm at 10.1% compared with 7% in the placebo arm, and AEs of interest with talazoparib remained low with no reported cases of myelodysplastic syndrome or acute myeloid leukemia. Fizazi also highlighted that the use of talazoparib and enzalutamide prolonged the time to a clinically meaningful deterioration of quality of life at a median of 27.1 months (95% CI, 21.2-NR) compared with 19.3 months (95% CI, 16.6-23) in the placebo arm (HR, 0.69; 95% CI, 0.49-0.97, P = 0.032).

“Based on these data, I believe that talazoparib plus enzalutamide, if approved, should become a standard of care for patients with mCRPC HRR alterations, [and] mostly those with BRCA alterations,” Fizazi concluded.

References

1. Fizazi K, Azad A, Matsubara N, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2023;5004(suppl 16). doi: 10.1200/JCO.2023.41.16_suppl.5004

2. Agarwal N, Azad A, Carles J, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023. doi: 10.1016/S0140-6736(23)01055-3

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