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Clovis' Rubraca Benefits BRCA1/2, PALB2-Mutated Pancreatic Cancer Patients as Maintenance Therapy


NEW YORK – In a Phase II trial of rucaparib (Clovis Oncology's Rubraca), researchers found that the PARP inhibitor was effective as a maintenance treatment for pancreatic cancer patients beyond those with BRCA1/2 germline mutations.

In an investigator-sponsored study published on Monday in the Journal of Clinical Oncology, researchers from the University of Pennsylvania Abramson Cancer Center evaluated rucaparib in 46 advanced pancreatic cancer patients with germline or somatic mutations in BRCA1, BRCA2, or PALB2. Nearly all patients had adenocarcinoma of the pancreas, but the study also included one patient each with the pancreatic cancer subtypes acinar carcinoma and squamous cell carcinoma.

Lead author Kim Reiss, an assistant professor of hematology-oncology at Penn's Perelman School of Medicine, said they hoped to explore whether a PARP inhibitor was effective for a wider range of patients than those included in the Phase III POLO study, which evaluated another PARP inhibitor olaparib (AstraZeneca's Lynparza) as a maintenance therapy for pancreatic cancer.

Based on the results of the POLO study, the US Food and Drug Administration in December 2019 approved olaparib for metastatic pancreatic cancer patients who had responded to a first-line platinum-based chemotherapy regimen and not progressed for at least four months. Additionally, patients must have germline mutations in BRCA1 and BRCA2, and alongside the drug, the FDA also approved Myriad Genetics' BRACAnalysis CDx to identify those with these germline mutations.

"It's a small group of patients overall who have these alterations and so it's really key to maximize the number of patients who may be eligible for this type of treatment," Reiss said. "What we've done is we've expanded beyond what POLO showed us, which is that there was a benefit to PARP inhibitors in adenocarcinomas with germline BRCA1/2 mutations, and we've opened the door to allow this therapy to be used in a larger group of patients."

According to one estimate, approximately 1 percent or fewer of pancreatic cancer patients have BRCA1 mutations, while up to 2 percent harbor BRCA2 mutations. While about 1 to 2 percent of patients with pancreatic cancer have a germline pathogenic PALB2 variant, and 0.5 percent will have a somatic pathogenic variant in BRCA or PALB2, Reiss said.

The current standard-of-care maintenance therapy for pancreatic cancer patients is chemotherapy, Reiss said, or olaparib for the small portion of patients with germline BRCA1/2-mutated pancreatic cancer. However, long-term chemo and its side effects can be tough for patients even at low doses.

Reiss said she and her colleagues were concerned they would have difficulty recruiting participants for this trial since patients would have to go off their chemotherapy, even if it was working, to join this study. "We thought, would patients be willing to risk that? The[re] was an overwhelmingly positive response," she said. "That brought home in a heartbreaking way how hard chronic chemotherapy is and that we really do need to open a space and study more intensely the patients who might benefit from this kind of strategy."

Researchers didn't have difficulty enrolling patients in the study. In fact, patients enrolled in the single-institution study from all over the US, Reiss said. One patient from France and a patient from Mexico flew to Penn monthly for clinical trial visits, she added.

This pancreatic cancer trial met its primary objective of six-month progression-free survival, which was 59.5 percent among the 42 evaluable patients. The one-year progression-free survival was 54.8 percent.

In the study, the median progression-free survival among the 42 evaluable patients was 13 months and median overall survival was 23.5 months. The overall response rate among 36 patients with measurable disease was 41.7 percent, with three complete responses and 12 partial responses. The median duration of response was 17.3 months. The disease control rate, which also includes patients with stable disease, was 66.7 percent.

The researchers also analyzed the response rate and progression survival by mutation type. Of patients with germline BRCA2 mutations, 42 percent (11 of 27 patients) saw a response. Three out of six patients with germline PALB2 mutations responded, and one out of two patients with somatic BRCA2 mutations had a response to rucaparib. However, none of the seven patients with a germline BRCA1 mutation responded to the treatment.

Patients with germline BRCA2 mutations also saw a greater benefit in progression-free survival compared to germline BRCA1 patients, 18 months and 3.7 months, respectively. The median progression-free survival for PALB2 patients was 14.5 months.

The extent of patients' tumor burden may have been a factor in how well they responded to rucaparib. The 15 responders had a lower baseline disease burden by total sum of lesions than non-responders. The authors noted that the seven patients with BRCA1 mutations had "significantly higher baseline disease burden" by median tumor size than the patients with BRCA2 mutations, which may explain the lower response rate.

This study was not registrational, Reiss said. In addition, Clovis Chief Medical Officer Lindsey Rolfe said in an email that the company does not plan to further explore rucaparib's activity as a maintenance treatment for pancreatic cancer. 

"We are pleased to see the investigators reported disease control and RECIST responses in the rucaparib population not only in patients with germline BRCA1/2 mutated tumors, but also in somatic BRCA1/2-mutated disease and in patients with germline PALB2 mutations," Rolfe said in the statement. "While we do not currently have plans to investigate rucaparib as a maintenance therapy for pancreatic cancer, Clovis is committed to understanding how rucaparib may benefit certain patient populations with high unmet need." 

In January, Clovis executives laid out the timeline for ongoing rucaparib trials. The company is exploring rucaprib's activity in patients with solid tumors that have a mutation in homologous recombination repair (HRR) genes, patients with metastatic castration-resistant prostate cancer with HRR deficiency, and in combination with nivolumab (Bristol Myers Squibb's Opdivo) for ovarian cancer patients. Some of these trials are expected to report results later this year or sometime in 2022.

In the company's Phase II LODESTAR trial focused on solid tumors, one arm is exploring rucaparib in patients who have mutations in BRCA1/2, PALB2, and certain other genes, Rolfe said.

Since 2018, rucaparib has been approved in the US and in Europe as a second-line maintenance treatment for platinum-responsive ovarian cancer patients with BRCA1/2 mutations. Last year, the FDA also approved it for BRCA1/2-mutated, metastatic castration-resistant prostate cancer patients.

As to whether this investigator-initiated study provides insights into rucaparib's efficacy in pancreatic cancer patients compared to olaparib, Reiss cautioned that the differences in trial design between this study and the POLO olaparib study make direct comparisons difficult. The authors pointed out in their paper that in the POLO trial, olaparib showed a shorter progression-free survival (7.4 months) and lower response rate (23 percent) than this rucaparib trial, but the latter study results may have been bolstered by a fitter patient cohort.

The POLO study included patients with metastatic disease, whereas the rucaparib study also included patients with locally advanced disease, who tend to have lower disease burden. Platinum-responsive patients tend to fare well on PARP inhibitors, and the rucaparib trial had more stringent criteria in terms of excluding patients with any clinical signs of platinum resistance. The rucaparib study was also conducted at a single institution and was not a randomized-controlled trial.

"The differences in the study are far too great to be able to make any kind of direct efficacy comparison," Reiss said. "We are trying to build on what POLO presented and trying to broaden the group and those patients who might be eligible to receive such a therapy."

The question raised by this study that Reiss and her team will follow up on is why some patients appear to be "hyper-responders," while others progress quickly on the same treatment. As of the data cutoff, eight patients were still alive and in active follow-up for more than two years after starting rucaparib and half hadn't experienced disease progression. "We want to know what the differences might be even in this narrow group of mutation carriers, so we can target [them] more effectively," Reiss said.