Rucaparib Maintenance Shows Early Efficacy in Pancreatic Cancer

Kim A. Reiss Binder, MD

Maintenance therapy with rucaparib (Rubraca) maintained disease control and was well tolerated in patients with platinum-sensitive, advanced BRCA1/2- or PALB2-mutant pancreatic cancer, according to preliminary interim findings of a single-arm, phase II trial presented at the 2019 AACR Annual Meeting.

Of 19 evaluable patients who were treated with the PARP inhibitor, results showed that the median progression-free survival (PFS) was 9.1 months at a median potential follow-up of 257 days, and the median overall survival was not reached at a median potential follow-up of 244 days.

“In this interim analysis of 19 patients with pancreatic cancer and BRCA1/2 or PALB2 mutations, treatment with rucaparib is extremely well tolerated, has the ability to maintain disease control, and in some cases in a long-term way, and can result in additional shrinkage of tumors,” said lead study author Kim A. Reiss Binder, MD, assistant professor of medicine in the Division of Hematology Oncology at the University of Pennsylvania, in a press conference during the meeting.

Pathogenic mutations BRCA1, BRCA2, or PALB2, which result in homologous recombination deficiency (HRD), are present in 5% to 8% of all patients with pancreatic cancer. HRD leads to heightened sensitivity to platinum-based therapy and potentially PARP inhibitors, Reiss Binder said, due to synthetic lethality.

“A substantial portion of people with pancreatic cancer will have a pathogenic mutation in one of the homologous recombination genes, either BRCA1/2 or PALB2, and that results in a homologous recombination deficiency,” Reiss Binder explained. “As of this year, the [National Comprehensive Cancer Network] is recommending that all patients with pancreatic cancer undergo genetic testing, and somatic testing should be considered for everyone as well.”

Patients with pancreatic cancer who harbor BRCA1/2 or PALB2 mutations are likely to experience durable responses to platinum-based therapy, striking the rationale to test PARP inhibitors in this patient population.

“In pancreatic cancer, the PARP inhibitors rucaparib and olaparib [Lynparza] have shown preliminary evidence of efficacy as well with an excellent toxicity profile compared with chemotherapy,” said Reiss Binder.

Therefore, rather than administering indefinite chemotherapy, investigators hypothesized giving it as induction treatment followed by PARP inhibition as maintenance therapy.

“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,” said Reiss Binder. “What if we can find the right people? What if we can find a group for whom chemotherapy is used … as an induction and then once the disease stabilizes, we continue with a less toxic maintenance option.”

In the ongoing, single-arm, phase II study (NCT03140670), patients with BRCA1/2 or PALB2-mutated advanced pancreatic cancer who received platinum chemotherapy ≥4 months and did not experience disease progression then discontinued chemotherapy and were treated with oral, single-agent rucaparib at 600 mg twice daily until progression or unacceptable toxicity.

To be eligible for enrollment, patients must have an ECOG performance status of 0 to 1, and also had received ≥16 weeks of platinum chemotherapy without disease progression unless a legitimate adverse event prevents the full 16 weeks to be administered. Those who received a prior PARP inhibitor or progressed on platinum-based therapy were excluded.

Enrollment is planned for 42 patients, and 30 patients have been enrolled thus far, said Reiss Binder. The primary endpoint is PFS.

Of 19 evaluable patients, median age is 61 (range, 35-81), and 84.2% (n = 16) of patients were female. Most patients were Caucasian (94.7%). Three patients (15.8%) harbored a BRCA1 mutation, 13 (68.4%) had BRCA2, 2 patients (10.5%) had PALB2, and 1 patient (5.3%) harbored a somatic BRCA2 mutation. Four patients were treated with platinum chemotherapy for <16 weeks, 13 for 16 to 52 weeks, and 2 patients received treatment >52 weeks.

Results also showed that the disease control rate was 89.5% and the overall response rate was 41.1%. Two patients had no evidence of disease at start of study and are being measured for disease progression rather than response, and 2 patients developed new lesions. Responses were determined based on RECIST v1.1 criteria.

Reiss Binder noted that follow-up time is measured from the start of rucaparib monotherapy. Twelve patients currently remain on study and 7 have come off. At the time of the analysis, 2 patients have been on study >1 year, and an additional 8 patients have been on >6 months.

Regarding safety, the all-grade possible treatment-related adverse events (AEs) were nausea (n = 10), dysgeusia (n = 8), fatigue (n = 6), alanine aminotransferase (n = 5), diarrhea (n = 4), vomiting (n = 3), aspartate aminotransferase (n = 3), and anemia (n =2). No grade 3/4 AEs nor any dose-limiting toxicities were reported at the time of the analysis. A dose reduction for grade 2 nausea occurred in 1 patient.

While these data are preliminary, Reiss Binder said that maintenance PARP inhibition looks to be a strategy worth pursuing in this space, and should be investigated in other pancreatic cancer populations.

“This maintenance paradigm for the right group of pancreatic cancer patients is a novel approach to this disease and an area that needs to be further clinically developed,” she concluded.

Rucaparib is currently approved by the FDA as a monotherapy for the treatment of adult patients with ovarian cancer with a deleterious BRCA mutation following ≥2 prior chemotherapies, and as a maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy.

Reiss Binder KA, Mick R, O’Hara M, et al. A phase II, single arm study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic mutation in BRCA1, BRCA2 or PALB2. Presented at: 2019 AACR Annual Meeting; March 29 to April 3, 2019; Atlanta, GA. Abstract CT234.

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