Post hoc analysis of rPFS and OS from the TALAPRO-2 (TP-2) study: Genomic subgroups based on likelihood of BRCA or HRR gene alteration status.

Abstract

136 Background: Prior to randomization in TP-2, patients (pts) (N=805; all-comers) were prospectively assessed for HRR gene alterations in tumor tissue and/or ctDNA using FoundationOne CDx and/or FoundationOne Liquid CDx. In the all-comers cohort, talazoparib (TALA) + enzalutamide (ENZA) as first-line treatment for pts with mCRPC significantly improved rPFS vs ENZA (HR 0.63; 95% CI 0.51–0.78). To investigate if ITT results for TP-2 all-comers were driven by unidentified biomarker-positive pts, we assessed the correlation between rPFS/OS outcomes and pt BRCA or HRR alteration status. Methods: Within each analysis by BRCA or HRR alteration status, three exploratory subgroups based on the likelihood of BRCA/HRR alterations were defined using all available FoundationOne records from prospective and retrospective exploratory testing. BRCA1/2 mutated ( BRCAm; 10% ITT) or HRR mutated (HRRm; 33% ITT): pts were identified via a positive test result in either ctDNA and/or tumor tissue testing. Undetermined BRCAm (38% ITT) or undetermined HRRm (28% ITT): pts with one negative BRCAm/HRRm test result not confirmed by the other test, or for whom the results of both tests were indeterminate. Non- BRCAm (51% ITT) or non-HRRm (39% ITT): pts with negative BRCAm or HRRm status confirmed by both ctDNA and tumor tissue testing. Results: A benefit in rPFS was demonstrated in the non- BRCAm and non-HRRm subgroups (Table) with a non- BRCAm median rPFS of 33.1 vs 22.1 months favoring TALA + ENZA (HR 0.71; 95% CI 0.52–0.96). A trend towards improved OS was also observed in the non- BRCAm and non-HRRm subgroups. OS data in the undetermined HRRm (36%) and undetermined BRCAm (39%) groups were least mature. For both rPFS and OS for undetermined BRCAm and undetermined HRRm, HRs were higher than those for BRCAm, non- BRCAm, HRRm, or non-HRRm; the reasons for this are unclear. Conclusions: The statistically significant rPFS improvement in the TP-2 all-comer ITT population did not seem to be attributable to pts with undetected BRCA/HRR alterations. There was evidence of rPFS benefit in the non- BRCAm and non-HRRm subgroups in favor of TALA + ENZA. While the OS data are still maturing, there is a clear benefit for pts with BRCAm and no detrimental impact for pts negative for BRCAm or HRRm by both tumor and ctDNA. Clinical trial information: NCT03395197 . [Table: see text]