Men with progressing mCRPC, detectable soft tissue disease, and tumor DDRm engaged directly or indirectly in homologous recombination repair were included in the TALAPRO-1 study (11-gene panel). Men who were enrolled had advanced on more or around 1 new hormonal therapy and had had 1-2 taxane-based chemotherapy regimens. In accordance with RECIST 1.1, the primary endpoint’s confirmed objective response rate (BICR; blinded independent central review) was 29.8%. Although no data supports it, people with substantial BRCA gene deletions may benefit from poly(ADP-ribose) polymerase inhibitors for longer than is currently believed to be the case. In addition, exploratory post hoc biomarker investigations evaluated the tumor genetics connected to TALAPRO-1’s sustained anticancer effect.

FoundationOne®CDx was used to evaluate tumor changes. Somatic-germline-zygosity was used to predict the zygosity of tumor changes. Radiographic progression-free survival ([rPFS]; RECIST 1.1/PCWG3; BICR) time to an event or censoring was used to measure the benefit duration. Date cutoff: September 4, 2020 (primary completion date).

In the efficacy population of 104 males, 16 had rPFS of ≥12 months. About 15 (94%) of their 16 tumors showed BRCA2 changes, including 10 big structural variations (5 short variants), 9 copy number losses, and 1 rearrangement (SV; 4 homozygous). However, only 6/27 (22%) of the males with rPFS of <2 months had BRCA2 mutations (1 rearrangement, 1 non-defined, and 4 SV with 2 homozygous). Around 36 (59%) of 61 males with rPFS lasting between two and twelve months had BRCA2 mutations (9 copy number loss, 1 rearrangement, 21 SV [11 homozygous], 2 multiple alterations [1 homozygous], and 3 not defined). Contrarily, males with rPFS ≥12 months versus <2 months had a lower prevalence of TP53 changes (2/16 vs. 14/27; P=0.02 Fisher’s exact test, 2-tails), which may indicate a poor prognosis or a subgroup less responsive to PARP inhibition.

The retrospective, exploratory assessments of TALAPRO-1 revealed that males who saw extended benefit generally had homozygous or copy number loss changes to BRCA2, but not TP53 mutations.

Reference: annalsofoncology.org/article/S0923-7534(22)03351-8/fulltext