Galeterone and gemcitabine in advanced pancreatic ductal adenocarcinoma.

Abstract

e16433 Background: Advanced pancreatic cancer (PC) has limited chemotherapeutic options and a dismal prognosis. Mutant KRAS, present in 90% of cases, activates the MAPK and PI3K pathways, driving chemoresistance and metastatic spread (PMID 40829181). In pre-clinical work, galeterone (GAL), a novel steroidal anti-androgen, alone or combined with gemcitabine (GEM) depleted pan-KRAS and critical mediators of the eukaryotic translational initiation complex, and inhibited MiaPaca-2 xenograft growth (PMID 28881737). In a phase 2 multi-arm trial in patients with advanced PC, GAL monotherapy was tolerable but minimally effective. We herein report results from the GAL plus GEM arm. Methods: Patients with locally advanced or metastatic PC who progressed after at least 1 prior line of systemic therapy were eligible. Galeterone was administered orally at 2550mg daily and gemcitabine intravenously at 1000mg/m2 weekly for 3 weeks on 28-day cycle. The primary endpoint was radiographic response rate per RECIST v1.1, and secondary endpoints included progression-free survival, overall survival (OS) and adverse events (AEs). We used a Simon’s optimal two-stage design with a null hypothesis of P 0 = 0.05 and one-sided alternative of P 1 = 0.20 with an early stopping rule for futility. The study closed after enrollment of 9 patients due to sponsor withdrawal of funding. Results: The median age of enrolled patients was 66 (range 48-69). Six were male and 3 were female. Four patients were White, 2 were Black, 1 Asian, and 2 with unknown race. Eight identified as non-Hispanic and 1 as Hispanic. Five out of 9 patients withdrew before the 1 st radiographic assessment; 2 transitioned to hospice due to progressive PC, 1 died due to PC, 1 withdrew after treatment-unrelated stroke, and 1 withdrew due to nausea possibly related to treatment. Most (8/9) received 2 prior lines of therapy. For the 4 evaluable patients, 3 had stable disease at the 1 st 8-week assessment and 1 patient had partial response. Stable disease duration ranged from 2.3 to 7.7 months. The partial response lasted 9.2 months. Median time on treatment for all enrolled patients was 1.2 months, and median OS was 3.3 months (range 0.6 – 14.2). Treatment-related AEs (TRAEs) for GAL were mostly grade 1-2 and included fatigue, nausea, vomiting and dizziness; 2 patients experienced grade 3 fatigue. There were no new or unexpected safety signals with gemcitabine. Five patients required dose-reduction of gemcitabine due to hematologic toxicity. Conclusions: GAL plus GEM was overall well-tolerated but with limited efficacy in an all-comer population. Two participants however with prior progression on GEM had prolonged disease control with this regimen suggesting a signal of efficacy in a subset of patients. Future work aims to evaluate more potent GAL analogues and develop predictive biomarkers for response with a focus on its ability to inhibit RAS signaling and the translational initiation complex. Clinical trial information: NCT04098081 .