乌鸦传媒

ATLANTA -- Early findings from a small study showed the promise of rucaparib (Rubraca) maintenance therapy for platinum-sensitive BRCA or PALB2-related pancreatic cancer.

Among 19 evaluable patients who received induction chemotherapy for their advanced disease, the objective response rate with single-agent rucaparib was 37%, which included one complete response and six partial responses (PRs), reported Kim Reiss Binder, MD, of the University of Pennsylvania in Philadelphia, here.

Additionally, 53% achieved stable disease for at least 8 weeks, for a disease control rate of 90%. From the time of rucaparib initiation, median progression-free survival was 9.1 months while median overall survival was not yet reached -- two patients have been on therapy for over a year.

"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," she said during a press briefing at the American Association for Cancer Research (AACR) annual meeting. "This is an interim analysis, but it looks promising."

Roughly 5% to 8% of patients with pancreatic cancer have genes that cause homologous recombination deficiency -- germline or somatic mutations in BRCA1/2, PALB2, and others. These mutations confer heightened sensitivity to platinum-based chemotherapies, and patients can stay on treatment for months or years. Reiss Binder told 乌鸦传媒 that while retrospective studies suggest that BRCA or PALB2–related pancreatic cancer patients live longer when treated with platinum-based chemotherapy, rates of response and disease control have not been studied prospectively.

“My clinical experience is that the vast majority of these patients are inherently platinum sensitive,” she said. “Of course, there are exceptions, but they are relatively rare.”

But in the advanced-disease setting, toxicity builds and quality of life suffers with this continuous, indefinite treatment.

"It's not a workable model," Reiss Binder said.

Platinum sensitivity also predicts response to PARP inhibition, and several of these agents are approved for HRD breast and ovarian cancers. Rucaparib, for example, is approved in recurrent BRCA-mutant ovarian cancer and as a maintenance therapy for patients with platinum-sensitive disease.

Gulam Manji, MD, PhD, and Susan Bates, MD, both of NewYork-Presbyterian and the Herbert Irving Comprehensive Cancer Center at Columbia University in New York City, told 乌鸦传媒 in an email that “single-agent, maintenance therapy of long duration would be a welcome paradigm shift in a sub-select population of pancreatic cancer.”

They pointed to recently announced , which reported improved progression-free survival with olaparib (Lynparza) over placebo as frontline maintenance in germline BRCA-mutated metastatic pancreatic cancer with platinum-sensitive disease.

“Since HRD-associated pancreatic cancer responds well to platinum-based chemotherapy, this trial will determine the true contribution of the ability of PARP inhibitors to sustain the responses afforded by chemotherapy,” said Manji and Bates. “If, as is hoped, the POLO trial delivers a positive result, the results of the ongoing single-arm rucaparib trial could help provide further support for this strategy.”

National Comprehensive Cancer Network guidelines now recommend that pancreatic cancer patients receive genetic testing, and that physicians consider having tumor tissue examined for somatic mutations as well. Reiss Binder’s group therefore designed a trial whereby HRD patients with pancreatic cancer who responded to induction platinum chemotherapy would go on to rucaparib monotherapy, which is taken orally and carries a far more favorable safety profile than chemotherapy.

"The idea is to keep the efficacy going and at the same time give people their lives back," Reiss Binder said.

There were no grade 3/4 adverse events (AEs) or dose-limited toxicities during the maintenance rucaparib period. The most common AEs of any grade included nausea (43.4%), dysgeusia (34.8%), fatigue (26.1%), and increased alanine aminotransferase levels (21.7%).

"Treatment with single-agent rucaparib is extremely well tolerated, has the ability to maintain disease control, and in some cases in a long-term way," Reiss Binder said. "This paradigm for the right group of pancreatic cancer patients is a novel approach to this disease and an area that really needs to be further clinically developed."

The ongoing phase II trial has currently enrolled 30 metastatic or locally advanced but unresectable platinum-sensitive pancreatic patients, defined as no disease progression at 4 months or longer. Chemotherapy was stopped and patients received oral rucaparib at 300 mg twice daily until disease progression or unacceptable toxicity. Four patients stopped chemotherapy due to toxicity or an allergic reaction prior to 4 months, but were allowed to go on to maintenance rucaparib. The majority (13 of 19 patients) received anywhere from 16 and 52 weeks of platinum chemotherapy before starting on rucaparib.

Patients progressing on rucaparib were again treated with chemotherapy, platinum or other, depending on each patient’s prior toxicities, preferences, and other factors.

“It will be important to gather this information at the end of the study — i.e., what treatments did patients go on to receive and did they respond again,” Reiss Binder said.

Most of the evaluable patients (median age 61) were women (84%) and had BRCA2 mutations (68%). Both PALB2 mutation carriers had PRs with rucaparib, as did the one patient with a somatic BRCA2 mutation. Four of 13 germline BRCA2 mutation carriers achieved a response (including the one complete responder). None of the three germline BRCA1 carriers responded.

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