PARP Added to Chemotherapy Results in Positive Responses for Pancreatic Cancer

Eileen M. O'Reilly, MD

Antitumor activity in patients with germlineBRCA/PALB2-mutant pancreatic ductal adenocarcinoma (PDAC) was reported with the chemotherapy doublet of gemcitabine plus cisplatin with or without the addition of veliparib (ABT-888), according to Eileen M. O'Reilly, MD, who presented the findings at the 2020 Gastrointestinal Cancers Symposium.¹Of note were higher rates of grade 3/4 hematologic toxicities in the group receiving therapy with the addition of the PARP inhibitor.

The overall response rate (ORR) in the patients randomized to the veliparib plus chemotherapy triplet was 74.1% compared with 65.2% in the patients receiving the gemcitabine/cisplatin doublet (P= .55),¹O’Reilly, director of Medical Initiatives at the David M. Rubenstein Center for Pancreatic Cancer Research, and section head of Hepatopancreaticobilary & Neuroendocrine Cancers at Memorial Sloan Kettering Cancer Center in New York, said during the meeting. The disease control rate was 100% and 78.3% in the 2 arms, respectively (P= .02).

“We saw encouraging progression-free survival [PFS] in both arms, and if you reference an unselected population, that [PFS] would be about 5 to 7 months,” O’Reilly said. “The combination came at the expense of more hematologic toxicity, with more anemia, thrombocytopenia, and neutropenia, and more dose reductions and delays; although the dose intensity in both arms was relatively similar over time.”

Findings were published simultaneously in theJournal of Clinical Oncology.²In the published paper, O’Reilly and colleagues concluded that the data “establish cisplatin and gemcitabine as a standard-of-care regimen in germlineBRCA/PALB2+pancreatic ductal adenocarcinoma.” 

Median PFS was not significantly different between the 2 arms—10.1 months (95% CI, 6.7-11.5) with the triplet versus 9.7 months with the doublet (95% CI, 4.2-13.6;P= .74). The median overall survival (OS) was also similar between the 2 arms, at 15.5 months with the triplet (95% CI, 12.2-24.3) and 16.4 months (95% CI, 11.7-23.4) with the doublet (P= .61).

Eligibility criteria for the study included untreated stage III/IV disease, confirmed pathogenic germlineBRCA/PALB2mutation, and an ECOG performance status of 0 to 1.

In the combined population, 42 patients (84%) had stage IV disease, 24% had aBRCA1mutation, 70% hadBRCA2mutation, and 6% had aPALB2mutation. Metastasis to the liver was identified in 74%. Demographics were well balanced between the arms.

Both arms in the study were considered experimental. In the triplet arm (n = 27), patients received cisplatin 25 mg/m²plus gemcitabine 600 mg/m²on days 3 and 10 and veliparib 80 mg twice daily on days 1 through 12, all given for 3 weeks, with an option for veliparib maintenance. In the doublet arm (n = 23), cisplatin and gemcitabine were given at the same doses as in the triplet arm on days 1 and 8 of each 21-day cycle.

Five to 7% of patients with pancreas cancer have a germlineBRCA/PALB2mutation, she said. These genes code for proteins critical for homologous recombination repair of DNA. “Previous work identified that cisplatin, gemcitabine, and veliparib had a high response rate and an encouraging survival signal, prompting this study,”^3,4O’Reilly said.

Reasons for choosing cisplatin and gemcitabine as the chemotherapy backbone include that cisplatin is very active inBRCA-mutated pancreas cancer, O’Reilly said. “These are the only prospective randomized data we have with platinum-based therapy in germline-mutated pancreas cancer; I think it comes with a high level of evidence. Nonetheless, I also think that FOLFIRINOX [leucovorin, fluorouracil, irinotecan, and oxaliplatin] is an option. [The chosen therapy] will probably depend on the patient in front of you because there certainly are some lack of toxicity advantages. For the most part, cisplatin and gemcitabine is a well-tolerated regimen.”

Exploratory analyses across the combined cohorts showed a median PFS of 6.8 months (95% CI, 2.8-10.1) and a median OS of 14 months (95% CI, 8.1-18.5) in patients with germlineBRCA1mutations, and 11.3 months (95% CI, 9.8-12.8) and 20.2 months (95% CI, 12.3-24.4), respectively, in those with germlineBRCA2mutations.

The 2-year survival rate in the combined cohort was 31% (95% CI, 17.7%-44.4%); the rate at 3-years was 18% (95% CI, 8.1%-30.7%). These OS rates represent some of the longest reported in any randomized trial in pancreatic cancer, according to O’Reilly.

In light of emerging data from the POLO trial,⁵exploratory analyses were performed in participants who received 4 or more months of platinum therapy and then continued or received treatment with a PARP inhibitor as the next line of therapy. In this subset of 10 patient combined from both arms, 8 with stage IV disease, the median OS was 23.4 months (95% CI, 6.5-53.9).²

Grade 3/4 cases of anemia occurred in 52% of those treated with the triplet versus 35% of the doublet recipients; thrombocytopenia was reported in 55% and 9%, respectively; and neutropenia in 48% and 30%, respectively. Dose reductions for hematologic toxicity were required in 90% of patients in the triplet arm and 17% of the doublet arm. The rate of nonhematologic toxicities was similar between the 2 treatment arms.

Based on the excellent response rates in both arms and the higher rate of hematologic toxicity in the triplet arm, “the doublet is our recommendation for moving forward. We believe these data define a reference regimen for germlineBRCA/PALB2mutated pancreas cancer,” she said.

In their published study, the investigators wrote, “combined data from the POLO trial and from this trial suggest that platinum-based therapy followed by sequential maintenance PARP inhibitors (or continuation of cytotoxic therapy) represents an optimal first-line treatment approach in germlineBRCA/PALB2+PDAC.”

References:

1. O’Reilly EM, Lee JW, Zalupski M, et al. A randomized, multicenter, phase II trial of gemcitabine (G), cisplatin (C) +/- veliparib (V) in patients with pancreas adenocarcinoma (PDAC) and a known germline (g)BRCA/ PALB2 mutation.J Clin Oncol.2020;38(suppl 4;abstr 639). meetinglibrary.asco.org/record/181908/abstract.
2. O’Reilly EM, Lee JW, Zalupski M, et al. Randomized, Multicenter, Phase II Trial of Gemcitabine and Cisplatin With or Without Veliparib in Patients With Pancreas Adenocarcinoma and a Germline BRCA/PALB2 Mutation [published online January 24, 2020]. J Clin Oncol. doi: 10.1200/JCO.19.02931.
3. Lowery MA, Kelsen DP, Capanu M, et al. Phase II trial of veliparib in patients with previously treated BRCA-mutated pancreas ductal adenocarcinoma. Eur J Cancer. 2018;89:19-26. doi: 10.1016/j.ejca.2017.11.004.
4. O’Reilly EM, Lee JW, Lowery MA, et al. Phase 1 trial evaluating cisplatin, gemcitabine, and veliparib in 2 patient cohorts: Germline BRCA mutation carriers and wild-type BRCA pancreatic ductal adenocarcinoma. Cancer. 2018;124(7):1374-1382. doi: 10.1002/cncr.31218.
5. Golan T, Hammel P, Reni M, et al. Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl J Med. 2019;381(4):317-327. doi: 10.1056/NEJMoa1903387.

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