PARP Inhibitors for Maintenance Therapy in Pancreatic Cancer?

Alexander M. Castellino, PhD

April 02, 2019

ATLANTA — Patients with advanced pancreatic cancer harboring BRCA or PALB2 mutations and who respond to chemotherapy may be candidates for maintenance therapy with the poly ADP-ribose polymerase (PARP) inhibitor rucaparib (Rubraca, Clovis Oncology), according to results reported today at the American Association for Cancer Research (AACR) 2019 annual meeting.

In an interim analysis of an ongoing phase 2 study, objective response rate was 36.8% and median progression-free survival was 9.1 months.

"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," Kim Reiss Binder, MD, assistant professor of medicine in the Division of Hematology Oncology at the University of Pennsylvania in Philadelphia, said in an AACR press release.

"This is a preliminary and early signal, which indicates that we can potentially do better than chemotherapy for a small group of patients [with BRCA and PALB2 mutations]," Reiss Binder told Medscape Medical News.

In Pancreatic Cancer, No Chemotherapy Forever

Reiss Binder noted that between 6% and 8% of patients with pancreatic cancer harbor pathogenic BRCA or PALB2 mutations. These mutations readily respond to platinum-based chemotherapies, but the quality of life with persistent chemotherapy is significantly compromised for patients with pancreatic cancer due to cumulative toxicities, she pointed out.

"This approach often becomes unsustainable," she said. "In these patients we can move toward a model of induction chemotherapy followed by maintenance therapy with rucaparib," she added. Reiss Binder explained that this kind of study opens the door for expanding maintenance therapy to other patients, perhaps with targeted agents or biologic therapies.

"Effective maintenance therapy in this setting means no chemotherapy forever," she said.

Reached for comment, Efrat Dotan, MD, medical oncologist at Fox Chase Cancer Center in Philadelphia, agreed.

In the last few years, new data have emerged to identify a subgroup of patients with pancreatic cancer who harbor mutations in DNA repair mechanism genes (such as BRCA) and have significant response to platinum-based chemotherapy, she explained. Recent data from the Pancreatic Cancer Action Network's Know Your Tumor program found these mutations in about 17% of patients with pancreatic cancer, and demonstrated their improved survival with the use of platinum-based therapy, she noted.

"This maintenance treatment approach [with rucaparib] is highly valuable in providing these patients with a treatment that will keep the disease at check without the toxicities associated with platinum-based chemotherapy," she said.

"Despite the small number of patients, the results are encouraging and warrant further evaluation in a larger clinical trial," she added.

Thierry Conroy, MD, director of the Institut de Cancérologie de Lorraine, Vandœuvre-lès-Nancy Cedex, France, also agreed. "Pancreatic tumors with BRCA and PALB2 mutations are sensitive to platinum-based therapies and this approach for maintenance rucaparib is promising for patients," he said.

However, Conroy and Dotan pointed out that the makers of olaparib (Lynparza, AstraZeneca) recently released a press statement noting that the phase 3 POLO trial for maintenance olaparib was positive for a similar group of patients in the maintenance setting of advanced pancreatic cancer.

Reiss Binder, however, explained that the patient population in POLO was different from her team's study. "POLO enrolled patients exclusively with germline BRCA1 and BRCA2 mutations, while this study enrolled patients with germline as well as somatic mutations in both BRCA and PALB2," she said.

Olaparib is the first PARP inhibitor that will likely be approved for maintenance therapy in pancreatic cancer, but it is also likely to be restricted to patients with germline BRCA mutations, she suggested.

ReissBinder further explained that based on this model — induction chemotherapy followed by maintenance targeted therapy — studies have been designed in advanced pancreatic cancer to evaluate maintenance therapy with the combination of a PARP inhibitor and immunotherapeutic agents such as ipilimumab (Yervoy, Bristol-Myers Squibb) or nivolumab (Opdivo, Bristol-Myers Squibb). "Patients are allowed to enroll regardless of tumor mutational status," she said.

Rucaparib Study Details

Rucaparib is 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," Reiss Binder said.

This ongoing, single-arm, phase 2 study is still enrolling patients who have advanced pancreatic cancer with pathogenic germline or somatic BRCA or PALB2 mutations. After 4 months of chemotherapy with no evidence of progression, patients receive maintenance rucaparib 300 mg orally, twice daily.

Currently, 24 of the planned 42 patients have been enrolled and received a median of 4 months of prior platinum therapy before receiving maintenance rucaparib. Median age of patients was 61 years, 16 were women, and 4 patients had received less than 16 weeks of induction chemotherapy.

Of the 19 evaluable patients, germline BRCA1 and BRCA2 mutations were seen in 3 and 13 patients, respectively. Two patients had germline mutations in PALB2 and 1 had a somatic mutation in BRCA2.   

Treatment-related grade 1 or 2 adverse events included nausea (43.4%), impaired sense of taste/dysgeusia (34.8%), and fatigue (26.1%). There were no dose-limiting or grade 3 or 4 toxicities, Reiss Binder said.

With a median follow up of 257 days, median progression-free survival was 278 days (9.1 months). Median overall survival has not been reached. Of the 36.8% overall response rate (ORR), 1 patient showed a complete response (CR) and 6 patients showed a partial response (PR). Disease control rate (CR + PR + SD [stable disease]) was 89.5% for at least 8 weeks.

Eight patients have been on maintenance rucaparib for more than 6 months and two patients remain on treatment for more than 1 year.

Of the 7 patients who responded to maintenance therapy, 4 had mutations in germline BRCA2, 2 had mutations in PALB2, and 1 had a somatic mutation in BRCA2.

"We observed delayed responses to rucaparib in several patients, with time to reach threshold of part response sometimes taking as long as 24 weeks from therapy start, suggesting activity of this single agent rather than simply delayed platinum effect," Reiss Binder said.

At the time of analysis, two patients were on study for 1 year, and eight patients had been on study for more than 6 months.

This was an unplanned, interim analysis of an ongoing, small, single-arm study. "Our results highlight the importance of germline and somatic testing in pancreatic cancer patients," Binder said. "The presence of certain mutations can guide treatment strategies, and patients should know to ask their oncologist about getting tested."

Dotan agreed. "As we await the full publications of these two studies [POLO and this phase 2 study], we should start thinking of conducting germline and somatic genetic testing in pancreatic cancer to identify patients who fall into this category and may be candidates for DNA-damage-repair-mechanism targeted therapy," she said.

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. Conroy receives travel support from Roche. Dotan has disclosed no relevant financial relationships.

American Association for Cancer Research (AACR) 2019 Annual Meeting: Abstract CT234. Presented April 2, 2019.

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