Treatment Intensification Slows Metastatic Hormone-Sensitive Prostate Cancer

CHICAGO — Men with metastatic castration-sensitive prostate cancer (mCSPC) and DNA repair alterations had significantly longer progression-free survival (PFS) with a targeted drug plus an androgen receptor pathway inhibitor (ARPI), results from an international randomized trial showed.

Radiographic (r)PFS at 3 years improved from 50% with enzalutamide (Xtandi) and placebo to 77% with enzalutamide plus the PARP inhibitor talazoparib (Talzenna). A preliminary analysis of 3-year overall survival (OS), a secondary endpoint, showed no difference between the two groups but a trend in favor of the talazoparib arm (78% vs 72%). Exploratory analyses suggested the talazoparib combination improved rPFS in patients with homologous recombination repair (HRR) alterations other than BRCA.

Serious adverse events (SAEs) occurred more often in the talazoparib group, and half the patients randomized to the PARP inhibitor had grade ≥3 anemia, reported Neeraj Agarwal, MD, of the University of Utah Huntsman Cancer Institute in Salt Lake City, at the American Society of Clinical Oncology (ASCO) annual meeting. The results were published simultaneously in the New England Journal of Medicine.

“Talazoparib-enzalutamide leads to a clinically meaningful and statistically significant prolongation of rPFS versus active enzalutamide control,” said Agarwal. “The rPFS benefit was consistent across clinical subgroups, including BRCA mutations and non-BRCA mutation subgroups. The time to PSA progression and subsequent anti-neoplastic therapy were aligned with the primary rPFS results.”

“Treatment-emergent adverse events [TEAEs] were manageable through dose modification and supportive measures,” he stated. “The median duration of treatment was comparable between patients who developed grade 3/4 anemia versus those who did not, and 5% of patients had to discontinue because of anemia. The addition of talazoparib to enzalutamide generally did not result in clinically meaningful differences in patient-reported outcomes.”

The results support talazoparib-enzalutamide as a treatment option for patients with HRR-altered mCSPC and emphasize the “critical importance” of early molecular testing to identify specific HRR alterations, he added.

The TALAPRO-3 trial reinforces an ARPI/PARP inhibitor combination as standard of care for mCSPC and BRCA mutations, as previously established in the AMPLITUDE trial, said invited discussant David Olmos, MD, PhD, of Hospital Universitario 12 de Octubre in Madrid. The study also showed that selected patients with non-BRCA alterations might also benefit from the combination. Previous research showed that patients with metastatic castration-resistant prostate cancer (mCRPC) and BRCA1/2 progress earlier on first-line standard-of-care therapy.

However, neither TALAPRO-3 nor AMPLITUDE showed an OS benefit, questioning whether PARP inhibitors should be used in mCSPC or reserved for mCRPC, Olmos continued. In an effort to address the issue, he performed his own analysis of data from the two trials. Acknowledging differences between the two trials — AMPLITUDE enrolled more patients with BRCA mutations and included patients with prior docetaxel exposure, which TALAPRO-3 did not — the analysis showed a statistically significant OS benefit in the combined data, a 22% reduction in the survival hazard (95% CI 0.63-0.96).

“When we pull together TALAPRO-3 and AMPLITUDE, using meta-analysis methodology, there is a clear significant advantage in overall survival in the strategy of adding ARPIs plus PARP in metastatic castration-sensitive prostate cancer,” Olmos said.

The potential for differential response between BRCA and non-BRCA alterations is not resolved but the rPFS data show a “clear benefit in the BRCA population, but also a robust signal for non-BRCA HRR patients.”

Agarwal noted that the TALAPRO-2 trial showed that talazoparib plus enzalutamide significantly improved rPFS and OS in mCRPC and that patients with HRR-altered disease benefited the most. In mCSPC associated with HRR alterations, outcomes remain suboptimal with treatment intensification with androgen deprivation therapy (ADT) and ARPIs. The TALAPRO-3 trial tested the hypothesis that talazoparib plus enzalutamide would improve efficacy versus enzalutamide alone in men with HRR-altered mCSPC receiving ADT.

The study involved 599 men with HRR-altered mCSPC receiving ADT and no exposure to docetaxel. They were randomized to receive enzalutamide plus talazoparib or placebo, and the primary endpoint was investigator-assessed rPFS.

The study population had a median age of about 70, a third had BRCA1/2 mutations, 85% had de novo disease, and 70% had high-volume disease.

After a median follow-up of about 38 months, the trial met the primary endpoint of rPFS, showing a 52% reduction in the hazard ratio (95% CI 0.357-0.647, P<0.0001). The 3-year rPFS was 76.6% in the talazoparib arm and 56.2% in the control group. Median rPFS had yet to be reached in the talazoparib arm versus 45.8 months in the control group. Patients with and without BRCA mutations derived significant rPFS benefit at 3 years from the addition of talazoparib (77.2% vs 48.8% and 76.2% vs 62%, respectively). Analysis by specific HRR alterations showed a consistent benefit.

Time to PSA progression, time to subsequent systemic antineoplastic therapy, and response in patients with measureable disease all favored the talazoparib arm.

Grade 3/4 TEAEs occurred almost twice as often in the talazoparib arm (79% vs 41%). AEs leading to discontinuation occurred more often with talazoparib (30% vs 19% including 19% vs 10% for talazoparib vs placebo). Median duration of treatment was longer in the talazoparib arm (about 35 vs 33 months).

Addressing the 51% incidence of grade 3/4 anemia, Agarwal noted that median duration of talazoparib treatment was similar between patients with (34 months) and without (36 months) grade 3/4 anemia.