Background: Pancreatic adenocarcinomas (PDAC) harboring deficiencies in BRCA1/2 or PALB2 are more susceptible to platinum (Pl) chemotherapy regimens as well as PARP inhibitors. The same is not fully elucidated for PDAC harboring alterations in other genes within the DNA damage repair (DDR) pathway. In this study, we aim to compare outcomes of patients (pts) with advanced PDAC harboring mutations in DDR pathway in genes other than BRCA 1/2 and PALB2 with Pl- versus non-Pl -including chemotherapy regimens in first-line (1L).

Methods: We used Tempus Lens, a platform used to query multimodal data from millions of de-identified patient records in the Tempus Database, to identify pts with advanced PDAC without BRCA1/2 and PALB2 mutations who had Tempus xT (solid tumor) or xF (liquid biopsy) testing (N = 3,175). Pts with clinically reportable copy number losses (0 copies) or gains (8 or more copies), or pathogenic/likely pathogenic single nucleotide variations or indels in one of 67 other DDR genes were classified as DDR-mutated (DDR-mut, N = 783). 1L treatment regimens were categorized as Pl if any agent in the regiment was categorized as a Pl compound, or Non-Pl otherwise. Real-world (rw) objective response rate (rwORR) was defined as the
proportion of pts with a documented complete or partial response after 1L start. Rw time to next treatment (rwTTNT) was defined as the time from 1L start to start of next treatment or death and rw overall survival (rwOS) as the time from 1L start to death or loss to follow up. Median rwOS and rwTTNT were estimated using Kaplan-Meier curves and compared with Cox
proportional hazards likelihood ratio tests.

Results: Among the DDR-mut pts, median age at diagnosis was 66 years (range: 29-86), 55% were White, 7% were Black, 2% were Asian and 36% unknown/other. Mutations in ATM were most prevalent (25%), followed by CHEK2 (8.7%). Of DDR-mut pts included in rwOS, 55% (N = 256) received Pl regimens compared to 45% (N = 212) who received non-Pl regimens. Of those receiving Pl regimens, the majority received a triplet regimen rather than a doublet (84% vs 7%). Although no statistically significant difference was observed in rwOS between Pl and non-Pl regimens in the DDR-mut group, there was a trend toward improved survival starting around 5 months of treatment (median rwOS 11.7 vs 9.8 months, p = 0.471). Interestingly, rwTTNT was longer in pts receiving non-Pl (8.3 months vs 6.4, p = 0.115). rwORR was not different between the two groups (40% vs 37%, p = 0.6).

Conclusions: This is one of the largest cohorts comparing outcomes in DDR-mut PDAC with Pl vs non-Pl regimens. Despite a trend toward improved survival with Pl regimens, this trend was not statistically significant. Furthermore, rwTTNT in the non-Pl regimens was longer. The results of this study should be regarded as investigational and do not include length of treatment, performance status, but suggest that future studies capture this information.

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