Chemo-Free Maintenance Combo Promising in Pancreatic Cancer

Pairing a PARP inhibitor and immune checkpoint inhibitor together may be a viable non-cytotoxic maintenance therapy option for patients with platinum-sensitive pancreatic ductal adenocarcinoma (PDAC), according to findings of a single-center phase Ib/II study.

At a median follow-up of 23.0 months, combining the PARP inhibitor niraparib (Zejula) with the anti CTLA-4 antibody ipilimumab (Yervoy) achieved a 6-month progression-free survival (PFS) rate of 59.6% (95% CI 44.3-74.9), which was superior to a clinically meaningful benchmark of 44% (P=0.045), reported Kim A. Reiss, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, and colleagues.

That PFS rate far exceeded a historical chemotherapy comparison in this setting (22% at 6 months), and met the trial’s definition of superiority, they stated in Lancet Oncology.

However, the trial’s combination of niraparib plus the PD-1 inhibitor nivolumab (Opdivo) yielded an inferior 6-month PFS rate (20.6%, 95% CI 8.3-32.9) compared to the clinically meaningful benchmark (P=0.0002).

Previous studies, such as POLO and one evaluating rucaparib (Rubraca), have demonstrated that maintenance PARP inhibition can be effective in pancreatic cancer patients with pathogenic BRCA1, BRCA2, or PALB2 variants.

“The results of this study, wherein two combinations of a PARP inhibitor and immune checkpoint blockade were tested, highlight the feasibility and safety of non-cytotoxic maintenance treatments for a broader population of patients with pancreatic cancer,” said Reiss and colleagues. It also highlights “CTLA-4 antibodies as a potentially more relevant checkpoint molecule than PD-1 or PD-L1,” they stated.

In an accompanying comment, Michele Reni, MD, and Giulia Orsi, MD, both of Vita e Salute University, San Raffaele Scientific Institute in Milan, Italy, acknowledged that the study provides further support for the use of PARP inhibitors in PDAC, but cautioned that “drawing firm conclusions on the incremental contribution of an immune checkpoint inhibitor is trickier.”

“Although the authors included an unplanned intention-to-treat analysis, they censored three of five initially excluded patients who should instead have intuitively been considered as having not responded,” they observed. “Accordingly, the 59.6% progression-free survival at 6 months appears to be overestimated. Keeping in mind the 24% rate of premature discontinuation of ipilimumab, extreme caution in the appraisal of the possible advantages of adding an anti-CTLA-4 to PARP inhibitor is warranted.”

Reni and Orsi also stated that “the proposed combination does imply remarkable financial toxicity, which could be an obstacle to the implementation of this regimen in different health-care systems worldwide.”

The open-label trial included 91 locally advanced or metastatic PDAC patients (predominantly metastatic, around age 64) whose cancer had not progressed after at least 16 weeks of platinum-based therapy. A majority were male and white. Of those, 84 were evaluable for the primary endpoints of 6-month PFS and safety. Patients were randomized 1:1 to receive either of the two study combinations.

For the niraparib-ipilimumab group, median PFS reached 8.1 months (95% CI 5.5-10.6) and median overall survival reached 17.3 months (95% CI 12.8-21.9), with an objective response rate (ORR) of 15.4% (95% CI 5.0-30.5).

In the niraparib-nivolumab group, median PFS and OS were 1.9 months (95% CI 1.4-2.3) and 13.2 months (95% CI 8.1-16.7), respectively, with an ORR of 7.7% (95% CI 1.5-19.5).

In planned subgroup analyses, Reiss and colleagues found that patients without DNA damage repair mutations, but a known family history of BRCA1– or BRCA2-related cancers, had a median PFS of 6.2 months and median OS of 18.7 months in the ipilimumab group (n=15), and a median PFS of 1.8 months and median OS of 15.4 months in the nivolumab group (n=18).

For patients with BRCA1, BRCA2, or PALB2 variants, median PFS in seven patients in the ipilimumab group was 10.4 months and median OS was 38.0 months. In the seven patients in the nivolumab group, median PFS was 3.7 months, and median OS was 12.2 months.

In the ipilimumab group, 50% (23 of 45 patients) had a grade ≥3 treatment-related adverse event (AE), as did 22% (10 of 46 patients) in the nivolumab group. The most common grade ≥3 AEs were fatigue (14%), anemia (11%), and hypertension (9%) in the ipilimumab group; and hypertension (8%), anemia (4%), and thrombocytopenia (4%) in the nivolumab group.

Also, 11% discontinued nivolumab due to AEs, but continued taking niraparib, while 24% discontinued ipilimumab prematurely due to AEs, but continued taking niraparib.

The authors reported no treatment-related deaths.