The advent of effective combination chemotherapies has changed the treatment landscape for metastatic pancreatic cancer, extending median survival and leading to durable responses in a subset of patients. However, perpetual chemotherapy is cumulatively toxic, leading to progressive bone marrow suppression, fatigue, neuropathy, and a steep decline in quality of life.
At the Special Conference on Pancreatic Cancer, sponsored by the American Association for Cancer Research (AACR) and held virtually this year, Kim A. Reiss, MD, reviewed available data and discussed future directions for maintenance therapy in metastatic pancreatic cancer, including combination treatments and expanding beyond germline BRCA carriers.1
Kim A. Reiss, MD
“Chemotherapy simply is not designed to be given indefinitely,” said Dr. Reiss, Assistant Professor of Medicine at the Hospital of the University of Pennsylvania, Philadelphia. “This compels us to consider an alternative model for the subset of our patients with durable disease control and to investigate what is different about this group that might shape our therapeutic approaches.”
Rationale Behind Maintenance Treatment
As Dr. Reiss explained, a proposed novel model involves the use of cytotoxic chemotherapy as induction treatment, aimed at reducing disease burden and stabilizing patients, followed by a “less abrasive” switch maintenance. This approach maintains disease control while sparing patients the cumulative toxicity that inevitably develops from long-term chemotherapy treatment, she said.
“Our hypothesis is that subsets of patients with pancreatic cancer who have durable responses to cytotoxic chemotherapies are in fact biologically unique and that this biology might be exploited to develop effective maintenance therapy options,” said Dr. Reiss. “This will not be a one-size-fits-all approach, as there are likely to be a variety of unique and possibly overlapping mechanisms for the observed phenotype.”
The First Target: BRCA Mutations
According to Dr. Reiss, patients with BRCA mutations represent the first unique biologic subgroup for whom successful maintenance therapy has been developed. Among patients with pancreatic cancer, 5% to 8% have a pathogenic mutation in BRCA or PALB2 gene, which predicts for responses to platinum chemotherapies and to PARP (poly [ADP-ribose] polymerase) inhibitors across several tumor types.
“As a class, PARP inhibitors are much less toxic to patients and lack cumulative toxicities, even with persistent exposure,” said Dr. Reiss. “Additionally, platinum sensitivity is largely required for sensitivity to PARP inhibitors. These features make PARP inhibitors an ideal strategy for patients with pancreatic cancer as maintenance therapy,” she added.
The POLO trial, which randomly assigned patients with germline pathogenic mutations in BRCA1 or BRCA2 and metastatic pancreatic cancer to receive olaparib or placebo, established the first ever maintenance therapy for patients with pancreatic cancer.2 Prior to enrollment, patients were required to have had 4 months of chemotherapy with a platinum-based regimen without evidence of progressive disease. The trial demonstrated a doubling of progression-free survival between the groups (hazard ratio = 0.54).
“Importantly, there was no difference in quality of life between patients who received olaparib and those who received placebo, highlighting the tolerability of this maintenance therapy, particularly when compared with cytotoxic agents,” said Dr. Reiss.
Of note, the 23% of patients who had a RECIST response to olaparib therapy had a progression-free survival of more than 2 years, whereas 25% of patients on study experienced rapid disease progression within 8 weeks of starting olaparib therapy.
“Even within the apparently narrow group of BRCA mutation carriers, there is large biologic variability that is not yet entirely understood,” Dr. Reiss observed. “It is critical for us to work to understand these unique differences, so we can further refine our identification of patients who may benefit the most from maintenance therapy.”
Rucaparib Maintenance
As Dr. Reiss reported, a second maintenance trial, the single-arm RUCAPANC2 trial, is currently ongoing at the University of Pennsylvania.3 In addition to those with germline BRCA mutations, patients with PALB2 mutations and those with pathogenic somatic mutations were able to enroll. This trial includes serial collections of peripheral blood mononuclear cells and circulating tumor DNA. It also will collect archival tumor tissue from patients’ diagnosis, biopsy at study start, and biopsy at disease progression on rucaparib.
The RUCAPANC2 trial has subtle differences in inclusion criteria in regard to platinum sensitivity as well, said Dr. Reiss. She believes these inclusion criteria differences may translate to differences in observed drug efficacy.
An interim analysis of the first 19 patients enrolled on the study showed expected responses in germline BRCA carriers, partial responses in patients with PALB2 mutations, and a partial response in a patient with a somatic BRCA mutation. “Although these data are very early, they indicate this therapeutic strategy might be expanded beyond just patients with germline BRCA mutations,” said Dr. Reiss, who noted that final data analysis is currently underway and pending.
Beyond PARP Inhibitor Monotherapy
According to Dr. Reiss, an important next step is to improve upon the effect of PARP inhibitor monotherapy in patients with BRCA-related disease, both in the primary maintenance setting and at the development of PARP resistance.
The combination of PARP inhibition plus ATR inhibition has been shown to significantly prolong overall survival compared with either drug alone in both PARP-resistant and platinum-resistant ovarian cancer models.4 These
observations formed the basis for the POLAR trial, a phase II maintenance study that will randomly assign patients with BRCA or PALB2 mutation and platinum-sensitive disease to receive either olaparib monotherapy or a combination of high-dose olaparib plus low-dose ceralasertib.
The primary goal of this first cohort is to establish whether the addition of ATR inhibition improves upon monotherapy PARP inhibitor maintenance treatment, said Dr. Reiss. All patients will undergo a biopsy at disease progression.
The primary goal of the second cohort is to establish whether ATR inhibition can overcome primary resistance to monotherapy PARP inhibitors. Secondly, for patients who developed resistance to low-dose ATR inhibition and high-dose PARP inhibition, investigators will address the question of whether high-dose ATR inhibition plus low-dose PARP inhibition can overcome this resistance. This study, which will be led by Dr. James Cleary at the Dana-Farber Cancer Institute, is planned to open at six centers, including the University of Pennsylvania, at the end of 2020, Dr. Reiss reported.
Phenotype Capture: The PARPVAX Trial
Finally, an alternative way to capture patients who may benefit from maintenance therapy is to identify a particular clinical phenotype that may indicate a biologic deficiency. For example, said Dr. Reiss, patients who are durably and profoundly platinum-sensitive may have a DNA repair deficiency that would also render them sensitive to PARP inhibition.
The phase II PARPVAX trial is enrolling patients with advanced pancreatic cancer who have had at least 4 months of platinum-based chemotherapy without evidence of resistance. Patients are taken off platinum therapy at the time of clinical response to treatment and are randomly assigned to either niraparib with ipilimumab or niraparib with nivolumab. Whole-genome sequencing is performed on all patients in the germline, and biopsies are collected at enrollment and 4 weeks later to assess immunologic shifts in the tumor microenvironment after exposure to PARP inhibition and checkpoint blockade. Additionally, said Dr. Reiss, blood for broad germline sequencing, tissue samples, peripheral blood mononuclear cells and circulating tumor material are collected serially for future analyses. The primary endpoint of the trial is progression-free survival in each arm.
“Arguably, the most critical part of the PARPVAX trial is the collection of patient samples, so we maximize our learning about patients who respond and those who do not,” said Dr. Reiss. “By working to understand the biology of particular groups more deeply, we can alter the model and change the course of patients’ lives.”
DISCLOSURE: Dr. Reiss has received research funding from Lilly Oncology, Bristol Myers Squibb, GlaxoSmithKline, and Clovis Oncology.
REFERENCES
1. Reiss KA: The end of perpetual chemotherapy? Hope for a new era in the treatment of pancreatic cancer. AACR Virtual Special Conference: Pancreatic Cancer. Plenary Session 2. Presented September 29, 2020.
2. Golan T, Hammel P, Reni M, et al: Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med 381:317-327, 2019.
3. Reiss KA, Maxwell KN, Nathanson K, et al: A single arm phase II study of rucaparib maintenance in patients with advanced pancreatic adenocarcinoma and a known deleterious BRCA1, BRCA2 or PALB2 mutation who have achieved stability on platinum therapy. 2018 Gastrointestinal Cancers Symposium. Abstract TPS531. Presented January 19, 2018.
4. Kim H, Xu H, George E, et al: Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models. Nat Commun 11:3726, 2020.
