medwireNews: Adding talazoparib to enzalutamide significantly improves the outcomes of untreated patients with metastatic castration-resistant prostate cancer (mCRPC), regardless of homologous recombination repair (HRR) mutation status, shows the TALAPRO-2 trial.
“Statistically significant and clinically meaningful improvements in rPFS [radiographic progression-free survival] were seen for the all-comers population (the primary endpoint), HRR-deficient subgroup, and HRR-non-deficient or unknown subgroup,” highlight the study authors.
“In addition, key secondary endpoints, including time to PSA [prostate-specific antigen] progression, time to cytotoxic chemotherapy, and time to progression or death on first subsequent antineoplastic therapy, all favoured the talazoparib group,” they add.
The researchers continue: “[R]esults from the primary analysis of the all-comers population of the TALAPRO-2 trial support the consideration of talazoparib plus enzalutamide as a first-line treatment option in patients with mCRPC.
“Final overall survival data and additional long-term safety follow-up will further clarify the clinical benefit of the treatment combination in patients with and without tumour HRR gene alterations.”
As reported in The Lancet, the double-blind, phase 3 study enrolled 805 adult men with asymptomatic or mildly symptomatic mCRPC who were receiving androgen deprivation therapy but had not received prior systemic therapy for CRPC or mCRPC.
After a median follow-up of around 25 months, median PFS was unreached for the 402 patients who were randomly assigned to receive talazoparib 0.5 mg/day alongside enzalutamide 160.0 mg/day and was 21.9 months for their 403 counterparts who instead received placebo plus enzalutamide.
The between-group difference was significant and equated to a significant hazard ratio (HR) for progression or death of 0.63 in favor of talazoparib, report Neeraj Agarwal (Huntsman Cancer Institute, Salt Lake City, Utah, USA) and co-researchers.
Analysis by HRR gene alteration status showed that the PFS benefit offered by adding the PARP inhibitor remained significant in the HRR-deficient and nondeficient or unknown subgroups, with respective HRs of 0.46 and 0.70.
The significant PFS advantage was also maintained when just considering patients with a nondeficient status by prospective tumor tissue testing, at an HR of 0.66.
The talazoparib plus enzalutamide combination was also associated with significantly longer median time to PSA progression (26.7 vs 17.5 months; HR=0.72), time to initiation of cytotoxic therapy (unreached vs unreached; HR=0.49), and time to progression or death on the first subsequent anticancer therapy (36.4 vs 35.3 months; HR=0.77) than placebo plus enzalutamide.
As for the safety of the combination, the profile was “consistent” with that of the individual medicines, say Agarwal and colleagues, but they point out that “the grades and frequencies of haematological adverse events were higher than with talazoparib monotherapy.”
Anemia was the most frequent adverse event (AE) of at least grade 3 in the talazoparib arm, occurring in 46% of patients versus 4% of those in the placebo, followed by neutropenia, in 18% versus 1%.
The rates of AE-related dose interruptions, reductions, and discontinuations were higher for talazoparib than placebo, at 75% versus 23%, 56% versus 7%, and 19% versus 12%, respectively. But there were no deaths attributable to AEs in the talazoparib group and two in the placebo group.
Writing in a linked commentary, Wassim Abida (Memorial Sloan Kettering Cancer Center, New York, USA) and Gerhardt Attard (University College London, UK) say that “TALAPRO-2 provides the most convincing evidence of benefit to date for patients without a detectable HRR alteration.”
But “[w]hether any androgen receptor [blocker] plus PARP inhibitor combination should become standard practice for patients with mCRPC remains unclear.”
The commentators note that “for patients with BRCA mutations, the rPFS benefit of combining [a next-generation hormonal agent] and a PARP inhibitor is now clear based on three phase 3 studies, but an overall survival benefit will be needed to confirm that earlier combination is favoured over the current practice of sequential use of these two active agents.”
And for those with nondeficient HRR status, the “benefit is less than for BRCA-mutated mCRPC, and it is not yet established whether the benefit is due to synergy in HRR-proficient disease, or due to the inclusion of HRR-deficient tumours in the non-HRR-mutated cohort due to limitations in biomarker assays,” they conclude.
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