The poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib holds promise as maintenance therapy for advanced, platinum-sensitive, BRCA- or PALB2-mutated pancreatic cancer, according to an interim analysis of an ongoing phase II clinical trial presented at the 2019 Annual Meeting of the American Association for Cancer Research (AACR).¹

A maintenance paradigm is a novel approach for the right group of patients with pancreatic cancer and presents an important opportunity for further development.

— Kim Reiss Binder, MD

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“In a small, preliminary study, several patients with platinum-sensitive pancreatic cancer [and BRCA or PALB2 mutations] had complete or partial responses to single-agent rucaparib maintenance therapy. This suggests that single-agent rucaparib has the potential not only to maintain response, but to shrink the tumors in some cases,” said lead author Kim Reiss Binder, MD, Assistant Professor of Medicine at the University of Pennsylvania’s Perelman School of Medicine, Philadelphia.

“This is a novel strategy for pancreatic cancer. We are building on the model in ovarian cancer but taking it a step farther. In ovarian cancer, the model is to continue PARP maintenance for stable disease. Platinum-sensitive patients with pancreatic cancer do very well on platinum for years, but the cumulative side effects can make the treatment intolerable over time. The idea of using the PARP maintenance strategy is to use a less-toxic option to maintain their response and allow them to get their lives back,” Dr. Reiss Binder said.

Study Rationale

Between 5% and 8% of patients with pancreatic cancer have tumors that express one of the homologous repair genes: BRCA1, BRCA2, or PALB2, resulting in a homologous repair deficiency (HRD). Current National Comprehensive Cancer Network^® (NCCN^®) recommendations call for germline testing for those with pancreatic cancer and consideration of testing for somatic mutations. Data from other studies have demonstrated a relationship between HRD and sensitivity to platinum and PARP inhibitors.

Rucaparib is currently approved by the U.S. Food and Drug Administration as maintenance therapy for patients with ovarian and fallopian tube cancers whose disease has recurred but is still sensitive to platinum-based chemotherapy, as well as for treatment of BRCA1/2 mutation-associated ovarian cancer treated with two or more lines of chemotherapy.

Early studies suggested that some patients with pancreatic cancer and BRCA mutations responded to PARP -inhibition with olaparib and rucaparib, despite progression of tumors on chemotherapy. Platinum sensitivity predicts the efficacy of PARP inhibitors, and patients with pancreatic cancer and BRCA1, BRCA2, or PALB2 mutations have “exceptional and durable responses to platinum therapy,” she explained.

Study Details

The current standard of care for pancreatic cancer is indefinite chemotherapy until disease progression or unacceptable toxicity or death. In an effort to reduce toxicity and improve quality of life, Dr. Reiss Binder and coauthors initiated the phase II study and, at the time of the interim analysis, had enrolled 19 patients with advanced pancreatic cancer and BRCA1, BRCA2, or PALB2 mutations. To enroll in the trial, patients were treated with platinum-based chemotherapy for at least 4 months; if there was no disease progression on chemotherapy, the oral PARP inhibitor rucaparib at 600 mg twice daily was given. No previous PARP inhibitor treatment was allowed.

At baseline, the median age was 61 years (range, 35–81 years); 84.2% were female; 94.7% were white; 84% had BRCA1/2 germline mutations; 10.5% had PALB2 germline mutations; and 5.3% had somatic BRCA2 mutations.

Key Findings

Toxicities considered treatment-related included nausea (43.4%), taste disturbances (34.8%), and fatigue (26.2%). There were no treatment withdrawals due to side effects.

At median follow-up of 8.4 months, the median progression-free survival was 9.1 months from the start of PARP inhibitor therapy. The estimated median overall survival was not yet reached.

Best responses included partial response in 6 patients, complete response in 1 patient, and stable disease in 10 patients; 2 patients had disease progression at first follow-up. Twelve patients remained on study as of data cutoff.

“This treatment had a disease control rate of 89.5%, and in some cases, they were long term. A total of 8 patients have been on therapy for more than 6 months, and an additional 2 patients, for more than 1 year,” she said.

“These responses can be slow to occur. For several patients, it took 4 to 6 months to respond. This suggests that the response is due to the PARP inhibitor rather than the tail end of chemotherapy,” Dr. Reiss Binder said.

Susan Domchek, MD

Dr. Reiss Binder emphasized the preliminary nature of these findings. Thus far, 30 patients of a planned enrollment of 42 have been enrolled.

“A maintenance paradigm is a novel approach for the right group of patients with pancreatic cancer and presents an important opportunity for further development,” Dr. Reiss Binder stated.

The senior author of this paper, Susan Domchek, MD, Executive Director of the Basser Center for BRCA at the University of Pennsylvania, said: “These promising results highlight just how crucial it is for patients with cancer to undergo genetic testing, as specific mutations can help guide doctors to targeted therapies and treatment strategies.” ■

DISCLOSURE: Dr. Reiss Binder has received institutional research funding from Clovis Oncology, Bristol-Myers Squibb, Tesaro, and Lilly Oncology. Dr. Domchek has received honoraria from AstraZeneca, Clovis Oncology, and Bristol-Myers Squibb as well as institutional research funding from Pharmamar, Clovis Oncology, and AstraZeneca.

REFERENCE

1. 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. 2019 AACR Annual Meeting. Abstract CT234. Presented April 2, 2019.