ATLANTA—Maintenance therapy with the PARP enzyme inhibitor rucaparib either shrank or stopped tumor growth in 17 of 19 patients with advanced BRCA- or PALB2-mutated pancreatic cancer, according to interim analysis of data from a phase II clinical trial conducted by researchers at University of Pennsylvania's Abramson Cancer Center.
Treatment provided clinical responses and nominal adverse side effects in patients who had not progressed following at least 4 months of platinum-based chemotherapy. The results were presented during the annual meeting of the American Association for Cancer Research (Abstract CT234). The researchers hope to eventually test their findings in a group of 42 patients.
Several subjects experienced complete or partial response to rucaparib, suggesting that therapy has the potential to provide an alternative to continuing intensive chemotherapy, according to Kim Reiss Binder, MD, Assistant Professor of Medicine in the Division of Hematology Oncology at the Hospital of the University of Pennsylvania.
“The data is extremely preliminary, but the fact that we are seeing complete and partial responses for some of these patients is very exciting, as this is a population that doesn't have many options. Patients with advanced pancreatic cancer often only have chemotherapy as an option,” she told a press briefing. “To be able to offer a targeted therapy with much less toxicity, even if only for a subset of our patients, would be a wonderful thing.”
The median progression-free survival rate at the time of the analysis was 9.1 months, and the overall response rate was 37 percent, including one complete response and six partial responses. The disease control rate was 90 percent for at least 8 weeks, the investigators reported. Eight patients remained on rucaparib therapy for 6 months, and two patients have remained on rucaparib therapy for more than 1 year.
“I would like to highlight that, for some patients, the threshold of partial response was not reached until they had been on treatment for 4-6 months,” said Reiss Binder. “This suggests that their tumors are responding truly to single agent rucaparib therapy rather than [a] delayed platinum effect.”
Common adverse side effects included nausea, dysgeusia, and fatigue. “While this subgroup of pancreatic cancer patients responded well to platinum-based chemotherapy, prolonged treatment leads to cumulative toxicity, so this approach often becomes unsustainable. We wanted to investigate more tolerable maintenance options, as there are no approved treatments in this setting,” Reiss Binder noted.
“Other than the recent tissue-agnostic approval of pembrolizumab for patients with microsatellite instability-high tumors, there really is no other targeted therapy that has shown promise for patients with pancreatic cancer,” she explained. “We are proposing a new, novel strategy to treat these patients for whom the standard of care is indefinite chemotherapy until progression, clinical decline, or death.” But she cautioned that the interim analysis was not planned and the findings require “substantial” validation.
Approximately 5-8 percent of patients with pancreatic cancer harbor pathogenic BRCA or PALB2 mutations, and such mutations often coincide with susceptibility to platinum-based chemotherapies. PARP inhibitor monotherapy has been approved by the FDA as maintenance therapy in multiple BRCA-related malignancies, including advanced ovarian and breast cancers with BRCA mutations (germline and/or somatic). Rucaparib, an oral, small molecule inhibitor of PARP1, PARP2, and PARP3, has also been approved for patients with recurrent ovarian, fallopian tube, or primary peritoneal cancers.
“Our results highlight the importance of germline and somatic testing in pancreatic cancer patients,” Reiss Binder said. “The presence of certain mutations can guide treatment strategies, and patients should know to ask their oncologist about getting tested.”
The single-arm clinical trial is currently enrolling patients with advanced BRCA- or PALB2-mutated pancreatic cancer who have not progressed on platinum-based chemotherapy. Chemotherapy was halted prior to rucaparib.
The researchers allowed patients to enroll without completing the full 4 months of platinum therapy if there was a legitimate medical reason, and four of the 19 patients were unable to complete a full 4 months due to either toxicity or allergic reaction, and two patients did not have measurable disease at the time of enrollment. Although 4 months of platinum-based therapy was required for participation, 13 subjects had been treated for up to 1 year.
Exclusion criteria included prior treatment with a PARP inhibitor and evidence of disease progression on platinum chemotherapy. Measurable disease was not required for enrollment, because the researchers did not want to exclude patients with advanced disease who responded well clinically to platinum therapy.
Among the 19 patients, 13 had germline BRCA2 mutations, three had germline BRCA1, two had germline PALB2, and one had somatic BRCA2 mutations. The participants were predominantly female (84.2%).
Each subject received 600 mg of rucaparib, twice daily, until progression or unacceptable toxicity. All patients were evaluated for toxicity, but overall, treatment was well-tolerated without dose-limiting toxicities.
“This study is a prime example of precision medicine,” said pancreatic cancer specialist and researcher Laleh Melstrom, MD, Assistant Professor of Surgical Oncology at City of Hope Comprehensive Cancer Center in Duarte, Calif. She noted that the current standard of care for metastatic pancreatic cancer is indefinite systemic chemotherapy, and that results in cumulative toxicity over time.
“Now it appears that there will be an additional option for this subset of patients with pancreatic cancer. They may obtain stability of their disease with platinum-based chemotherapy and subsequently be treated with rucaparib.”
She told Oncology Times that evidence suggests this approach will likely become the standard of care for such patients in the future, but more work needs to be done.
“Similar efforts are needed for the vast majority of patients with this disease because between 92 and 94 percent of them do not have this mutation. Pancreatic cancer is unique and complex in that nearly 80 percent of pancreatic tumor mass is composed of the extracellular matrix or fibrosis rather than the tumor cells alone.
“To target this disease, tumor cells need to be reached with our therapies through the fibrosis. Additionally, pancreatic tumors are notoriously devoid of active antitumor immune cells. Strategies to change this tumor microenvironment are also underway.”
She advised patients to ask their physicians about undergoing genetic testing and sequencing of their tumors to identify potential mutations, and then to follow through with seeking eligibility for clinical trials.
“It is only with trials that the field can move forward and that survival can be prolonged. Patients are our greatest allies in their own care and advocacy. If there is a patient with a BRCA1/2 or PALB2 mutation, they should seek a trial that offers a PARP inhibitor,” she concluded.
Kurt Samson is a contributing writer.