A Randomized Phase II Double-Blind Study of Olaparib versus Placebo Following Curative Intent Therapy in Patients with Resected Pancreatic Cancer and a Pathogenic BRCA1, BRCA2, or PALB2 Mutation

By Kim A. Reiss, MD

@KReissMD

Pancreatic cancer remains a highly lethal diagnosis. Even in the resected setting, up to 70% of patients will recur despite aggressive multimodality therapy, including multi-agent chemotherapy.¹ A small but persistent subset of patients with pancreatic cancer is characterized by pathogenic mutation in BRCA1, BRCA2, or PALB2. Patients with any of these variants are known to respond to poly (ADP‐ribose) polymerase (PARP) inhibitors in the metastatic maintenance setting,^{2, 3} where they provide a prolonged hiatus from cytotoxic chemotherapies. However, PARP inhibitors have never been tested in the curative-intent paradigm for these patients.

In the randomized phase 3 OlympiA trial,⁴ patients with early-stage BRCA-related breast cancer received one year of olaparib versus placebo after completing all their standard curative-intent therapy. This trial demonstrated both a progression-free and overall survival benefit and led to the approval of adjuvant olaparib for this population—providing a compelling rationale to study PARP inhibitors in the curative-intent setting for other BRCA-related solid tumors. The APOLLO study (EA2192) is a randomized, double-blind, phase 2 trial for patients with pathogenic somatic or germline variants in BRCA or PALB2 who have early-stage pancreatic cancer and have completed all curative-intent therapy. Patients must be within 12 weeks of their most recent anti-cancer intervention, whether that be chemotherapy, radiation, or surgery, and must have no signs of recurrent disease at enrollment. Germline and/or somatic testing will be done locally but will be centrally reviewed prior to patient randomization.

Eligible patients are randomized 2:1 to receive olaparib or placebo for twelve 28-day cycles. Patients are monitored monthly for toxicity. Importantly, telemedicine visits are permitted to decrease patient burden. Imaging reassessments occur at regular intervals. Once patients have completed treatment on the study, they will continue to be followed for recurrence as per standard practice.

The primary outcome of the study is relapse-free survival; overall survival is a secondary endpoint. This trial will enroll a total of 152 patients, 102 of whom will receive olaparib and 50 of whom will receive placebo. Patients will be stratified by (1) R1 vs. R0 resection, (2) receipt of platinum-based chemotherapy or not, and (3) receipt of neoadjuvant therapy or not.

Based on prior literature, the expected relapse-free survival of the control group is 22 months. The study is targeting a relapse-free survival of 44 months in the experimental group, with 90% power using a one-sided 0.05 level stratified log-rank test.

Since the trial opened in 2021, 98 out of the planned 152 patients have been enrolled. Also, the study is now open in Israel, in addition to the United States.

The APOLLO trial has the potential to change the standard of care for patients with curative pancreatic cancer and BRCA or PALB2 variants. Genetic testing is standard for all patients with pancreatic cancer, and we encourage you to pursue it for your early-stage patients whenever possible, so that they might be considered for this trial.

Learn more about the APOLLO trial at ecog-acrin.org.

Dr. Reiss (University of Pennsylvania/Abramson Cancer Center) is the study chair for this trial and co-chair of the ECOG-ACRIN Gastrointestinal Cancer Committee.

The study co-chair is Anup Kasi, MD (University of Kansas Hospital/Westwood Cancer Center) and the community co-chair is Xin Yao, MD (ThedaCare Regional Cancer Center).

 The NCTN group study champions are Michael Pishvaian, MD, PhD (Johns Hopkins University/Sidney Kimmel Cancer Center) for Alliance for Clinical Trials in Oncology, Samuel J. Klempner, MD (Massachusetts General Hospital) for NRG Oncology, and Philip Philip, MD (Henry Ford Cancer Institute) and Gabriela Chiorean, MD (University of Washington/Fred Hutchinson Cancer Center) for SWOG.

^{1Conroy T, Hammel P, Hebbar M, et al. FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer. N Engl J Med 2018; 379(25): 2395-406.}

^{2Reiss KA, Mick R, O'Hara MH, et al. Phase II Study of Maintenance Rucaparib in Patients With Platinum-Sensitive Advanced Pancreatic Cancer and a Pathogenic Germline or Somatic Variant in BRCA1, BRCA2, or PALB2. J Clin Oncol 2021; 39(22): 2497-505.}

^{3Golan T, Hammel P, Reni M, et al. Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer. N Engl J Med 2019; 381(4): 317-27.}

^{4Tutt ANJ, Garber JE, Geyer CE, Jr. Adjuvant Olaparib in BRCA-Mutated Breast Cancer. N Engl J Med 2021; 385(15): 1440.}