Study IDs 'Standard' Chemo for BRCA, PALB2 Pancreatic Cancer

SAN FRANCISCO -- Gemcitabine (Gemzar) plus cisplatin should be considered a standard for metastatic pancreatic cancer patients with germline BRCA or PALB2 mutations, experts here said.

In a randomized phase II trial of 50 such patients, the combination yielded an overall response rate of 65.2% and a disease control rate of 78.3%. For patients also receiving the investigational PARP inhibitor veliparib, 74.1% responded and the disease control rate reached 100%, reported Eileen O'Reilly, MD, of Memorial Sloan Kettering Cancer Center in New York City.

"Both arms were very active, and substantially exceeded the prespecified thresholds. The doublet is our recommendation for moving forward," she told the audience at the Gastrointestinal Cancers Symposium. "We believe these data define a reference regimen for germline BRCA-mutated and PALB2-mutated pancreas cancer."

O'Reilly noted that both arms were considered "experimental," with the hypothesis being that adding veliparib would increase the response rate and durability of response, and potentially have an impact on survival.

However, veliparib didn't improve survival outcomes. Median progression-free survival was an "encouraging" 9.7 months with the doublet and 10.1 months with the triplet (P=0.73). And median overall survival (OS) was 16.4 months without veliparib and 15.5 months with it (P=0.60).

In general, the triplet came at the expense of hematologic toxicity, with more anemia (52% vs 35%), thrombocytopenia (55% vs 9%), and neutropenia (41% vs 30%) reported in the veliparib arm.

Combined analysis of the two arms showed that 31% of patients on trial were alive at 2 years and 18% remained alive at 3 years.

Germline BRCA1/2 or PALB2 mutations are present in about 5% to 7% of patients with pancreatic cancer, and these mutations are thought to confer heightened sensitivity to platinum-based chemotherapies.

"We have always anecdotally felt that they should be receiving platinum, but this I think absolutely confirms that our patients that have BRCA and PALB2 mutations need to receive a platinum-based chemotherapy," Rachna Shroff, MD, of the University of Arizona Cancer Center in Tucson, told MedPage Today.

She called gemcitabine/cisplatin a "very reasonable" choice for patients with BRCA or PALB2 mutations, but a "fantastic option" for patients where tolerance is a concern.

"I think the toxicity profile is better than FOLFIRINOX, when you cross-compare trials," Shroff said. "I have, historically -- even before the POLO data came out -- done exactly that, assess performance status, assess toxicities, and used a gemcitabine and cisplatin backbone if I did not feel FOLFIRINOX was going to be safe or tolerated. So I think that is absolutely implemented in my practice and should be implemented in people's practice."

In an effort to compare the results to POLO (which led to the recent approval of olaparib [Lynparza] as maintenance therapy in BRCA-mutant pancreatic cancer with platinum-sensitive disease), O'Reilly and colleagues conducted an exploratory analysis of patients that received at least 4 months of platinum therapy plus a PARP inhibitor. This revealed a median OS of 23 months, very similar to that seen in POLO.

Their analysis pooled individuals from the veliparib arm that had continued on with the drug as maintenance if they had limited hematologic toxicity, as well as those from the doublet arm that received a PARP inhibitor following study completion.

Shroff called the results "practice-changing," in that they confirm the importance of using platinum-based chemotherapy in these patients, as well as the role of PARP inhibitors. And she added that the trial is further proof of principle of the importance of doing germline-genetic testing on all advanced pancreatic cancer patients to identify those with these susceptibility genes.

"As POLO taught us, it's not everybody with family history," she said.

For the phase II trial, the group randomized 50 patients with locally advanced or metastatic pancreatic cancer 1:1 to 600 mg/m² gemcitabine and 25 mg/m² cisplatin on days 1 and 8 of 3-week cycles, or gemcitabine and cisplatin on days 3 and 10 of 3-week cycles plus 80 mg veliparib twice daily on days 1-12 (with the option of continuing as maintenance). The primary endpoint was overall response rate, and secondary endpoints included progression-free survival, disease control rate, and OS.

Dose reductions and delays were more frequent in the veliparib group (90% vs 17%), "although the dose intensity on both arms was ultimately relatively similar over time," O'Reilly said.

The majority of patients had stage IV disease (84%), three-fourths had liver metastases, and about half had an Eastern Cooperative Oncology Group (ECOG) performance status of 0. Roughly one-fourth of the cohort had BRCA1 mutations, 70% had BRCA2 mutations, and 6% had PALB2 mutations.

Comment