Maintenance Therapy With Rucaparib Shows Clinical Responses in a Subgroup of Patients With Pancreatic Cancer

ATLANTA — Maintenance treatment with the PARP inhibitor rucaparib (Rubraca) was well tolerated and provided clinical responses among patients with advanced BRCA- or PALB2- mutated pancreatic cancer sensitive to platinum-based chemotherapy, according to results from an interim analysis of an ongoing phase II clinical trial presented at the AACR Annual Meeting 2019, March 29–April 3.

“In this interim analysis, we are finding that patients with platinum-sensitive pancreatic cancer appear to benefit from treatment with single agent rucaparib,” said Kim Reiss Binder, MD, assistant professor of medicine in the Division of Hematology Oncology at The Hospital of The University of Pennsylvania. “Several patients had complete or partial responses with rucaparib treatment, suggesting that this therapy has the potential not only to maintain the disease, but also to shrink the tumors in some instances,” she added.

Approximately 6 to 8 percent of patients with pancreatic cancer harbor pathogenic mutations in the genes BRCA or PALB2, noted Reiss Binder. Mutations in these genes often coincide with susceptibility to platinum-based chemotherapies, she added. “While this subgroup of pancreatic cancer patients respond 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 said.

Rucaparib was approved as a maintenance treatment for patients with recurrent ovarian, fallopian tube, or primary peritoneal cancer who respond to platinum-based chemotherapy. “We wanted to determine if this therapeutic strategy could also be utilized in pancreatic cancer patients with platinum-sensitive tumors,” explained Reiss Binder.

This single-arm, phase II clinical trial is actively enrolling patients with advanced BRCA- or PALB2-mutated pancreatic cancer who have not progressed on prior platinum-based chemotherapy. The patients in the interim analysis had received a median of four months of prior platinum chemotherapy. More than 80 percent of patients were female.

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Patients are treated with 300mg of rucaparib twice daily until disease progression or unacceptable toxicity. The primary endpoint of the study is progression-free survival (PFS). Overall response rate (ORR) is also being evaluated.

Nineteen of the 24 enrolled patients were evaluable for analysis as of Dec. 31, 2018.

The median PFS at time of analysis was 9.1 months following initiation of rucaparib treatment. The ORR was 37 percent, which included one complete response (CR) and six partial responses (PR). The disease control rate (defined as the sum of PR, CR, and stable disease) was 90 percent for at least eight weeks. Eight patients remained on rucaparib therapy for at least six months, and two patients have remained on rucaparib therapy for more than one year.

Common adverse events related to the treatment included nausea, dysgeusia (a distortion of the sense of taste), and fatigue.

“Although this is very preliminary data, the fact that we’re seeing sustained clinical responses in some of these patients is very exciting,” noted Reiss Binder. “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.

“Our results highlight the importance of germline and somatic testing in pancreatic cancer patients,” said Reiss Binder. “The presence of certain mutations can guide treatment strategies, and patients should know to ask their oncologist about getting tested.”

As this was an unplanned interim analysis of an ongoing, small, single-arm study, the results require substantial further validation, noted Reiss Binder.

This study is sponsored by the Abramson Cancer Center and is funded by Clovis Oncology. Reiss Binder receives research funding from Clovis Oncology, Tesaro, Bristol-Myers Squibb, and Lilly Oncology.

Abstract Session Type: Clinical Trials Minisymposium Session Number: CTMS03 Session Title: Developmental Therapeutics: Clinical Results of Novels Agents Location: Marcus Auditorium- Bldg A-GWCC Session Time: Tuesday, April 2, 2019, 3:00 pm - 5:00 pm Presentation Number: CT234 Publishing Title:

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 Author Block: Kim A. Reiss Binder, Rosemarie Mick, Mark O'Hara, Ursina Teitelbaum, Thomas Karasic, Charles

Schneider, Peter J. O'Dwyer, Erica Carpenter, Austin Pantel, Mehran Makvandi, David Mankoff, Katherine Nathanson, Kara Maxwell, Stacy Cowden, Mary Jane Fuhrer, Janae Romeo, Gregory L. Beatty, Susan Domchek. University of Pennsylvania, Philadelphia, PA

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Abstract Body:

Background: PARP inhibitors have activity in multiple BRCA-related malignancies and have recently demonstrated dramatic efficacy as a maintenance strategy for platinum-sensitive ovarian cancer. Between 5-8% of patients with pancreatic cancer (PC) have a pathogenic mutation in BRCA1, BRCA2 or PALB2. Therefore, we initiated a single arm phase II clinical trial of maintenance monotherapy rucaparib in patients with advanced PC and a pathogenic germline or somatic BRCA or PALB2 mutation, whose cancer had not progressed following at least four months of platinum-based chemotherapy (NCT 03140670). Methods: Patients were enrolled and treated with rucaparib 300mg PO BID until disease progression or unacceptable toxicity. The primary endpoint is progression free survival (PFS). Patients have previously received >4 months of platinum-based chemotherapy without evidence of disease progression. However, patients with a medical contraindication to receiving the full four months of platinum have been permitted to enroll at the discretion of the primary investigator. Responses were determined using RECIST v1.1.

Results: As of December 31st, 2018, we have enrolled 24 of the planned 42 patients, of which 19 are evaluable for PFS at the time of this interim analysis. For these patients, the mutational distribution includes: 13 germline BRCA2, 3 germline BRCA1, 2 germline PALB2, 1 somatic BRCA2. Patients were predominantly female (84.2%) with a median age of 61 years (range: 35-81). Patients had received a median of four months (range 0.5-32 months) of prior platinum therapy for advanced disease. All patients were evaluable for toxicity. Overall, treatment with rucaparib was well tolerated without dose limiting toxicities. The most common adverse events that were at least possibly related to treatment included nausea (grade 1, 41.6%; grade 2, 4.2%), dysgeusia (grade 1, 33.3%) and fatigue (grade 1, 25%). One patient required dose reduction for nausea. The median PFS was 9.1 months from the start of rucaparib therapy with an ORR of 36.8% (six PRs; one CR). Disease control rate (CR + PR + SD) was 89.5% for at least eight weeks. Two patients (10.5%) had progressive disease at first follow-up scan two months after beginning treatment. Eight patients have been on rucaparib for >6 months and two patients remain on treatment for >1 year (13 months and 15 months). The seven responding patients include those with germline BRCA2 mutations (4 patients), germline PALB2 mutations (2 patients) and somatic BRCA2 mutation (1 patient). Conclusions: Based on these early data, maintenance rucaparib following induction with platinum- based chemotherapy shows encouraging disease control with minimal toxicity in patients with platinum-sensitive advanced PC and a pathogenic mutation in BRCA1, BRCA2 or PALB2.

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