Olive, Kenneth P

TPS4205 Background: Multiple lines of evidence support the use of platinum-based chemotherapy for patients with homologous recombination deficiency-associated pancreatic adenocarcinoma (HRD PDAC; 15-20%). However, the impact of the specific platinum agent used remains uncertain. Mechanistically, oxaliplatin and cisplatin act distinctly on cancer cells, reflected in disparate toxicity profiles and target disease indications; furthermore, preclinical studies have shown that BRCA2-deficient cell lines and mice demonstrate significantly greater sensitivity to cisplatin compared to oxaliplatin. While oxaliplatin, part of the FOLFIRINOX regimen, represents the most commonly used platinum analogue for PDAC, clinical data shows that cisplatin (in combination with gemcitabine) can produce robust response rates (~70%) specifically in patients with germline BRCA/PALB2-mutated metastatic PDAC. We therefore designed a randomized clinical trial (PLATINUM) through the Alliance for Clinical Trials in Oncology cooperative group to assess the optimal chemotherapy regimen in patients with HRD-associated metastatic PDAC following front-line FOLFIRINOX and to test the hypothesis that a platinum switch strategy will be beneficial. Methods: The study consists of a seamless phase II/III design, with the primary endpoint of the phase III component being overall survival. Eligible patients will have metastatic PDAC, a confirmed pathogenic BRCA1/2 or PALB2 mutation (somatic or germline), and demonstrated disease progression on front-line FOLFIRINOX, with or without subsequent PARP inhibitor maintenance. Patients will be randomized 1:1 to receive (1) the de facto standard of gemcitabine plus nab-paclitaxel; or (2) the experimental 3-drug combination of gemcitabine, nab-paclitaxel, and cisplatin (NABPLAGEM), which has been previously studied in non-biomarker-selected patients with advanced biliary tract cancer (SWOG1815) and metastatic PDAC. Both treatment arms will use a once every other week dosing schedule. A total of 100 patients will be enrolled, which provides 90% power to detect an effect size of hazard ratio 0.5 (median OS of 18 vs 9 months) at a one-sided alpha of 0.05. Reports containing efficacy, adverse events, and administrative information will be provided to the Alliance DSMB every 6 months. Planned correlatives include ctDNA analysis for BRCA reversion mutations in all patients, as well as whole genome and transcriptome sequencing in an optional biopsy cohort. This study was activated in December 2023. Clinical trial information: NCT06115499 .

Abstract The sparse vascularity of pancreatic ductal adenocarcinoma (PDAC) presents a mystery: What prevents this aggressive malignancy from undergoing neoangiogenesis to counteract hypoxia and better support growth? An incidental finding from prior work on paracrine communication between malignant PDAC cells and fibroblasts revealed that inhibition of the Hedgehog (HH) pathway partially relieved angiosuppression, increasing tumor vascularity through unknown mechanisms. Initial efforts to study this phenotype were hindered by difficulties replicating the complex interactions of multiple cell types in vitro. Here we identify a cascade of paracrine signals between multiple cell types that act sequentially to suppress angiogenesis in PDAC. Malignant epithelial cells promote HH signaling in fibroblasts, leading to inhibition of noncanonical WNT signaling in fibroblasts and epithelial cells, thereby limiting VEGFR2-dependent activation of endothelial hypersprouting. This cascade was elucidated using human and murine PDAC explant models, which effectively retain the complex cellular interactions of native tumor tissues. Significance: We present a key mechanism of tumor angiosuppression, a process that sculpts the physiologic, cellular, and metabolic environment of PDAC. We further present a computational and experimental framework for the dissection of complex signaling cascades that propagate among multiple cell types in the tissue environment. This article is featured in Selected Articles from This Issue, p. 201