Maintenance Rucaparib Shows Efficacy in Advanced Pancreatic Cancer Harboring BRCA1, BRCA2, or PALB2

The PARP inhibitor rucaparib (Rubraca) has proven to be a safe and effective maintenance option for patients with platinum-sensitive, advanced pancreatic cancer that harbors pathogenic variants such as BRCA1, BRCA2, or PALB2, according to results from a phase 2 study (NCT03140670) published in the Journal of Clinical Oncology.¹

Among 42 evaluable patients, the progression-free survival (PFS) rate at 6 months was 59.5% (95% CI, 44.6%-74.4%). The median PFS achieved with this approach was 13.1 months (95% CI, 4.4-21.8), while the median overall survival (OS) was 23.5 months (95% CI, 20-27). At 12 months, the PFS rate was 54.8% (95% CI, 39.7%-69.9%).

Among 36 patients with measurable disease, maintenance rucaparib induced an objective response rate (ORR) of 41.7% (95% CI, 25.5%-59.2%); this included 3 complete responses (CRs) and 12 partial responses. The median duration of response (DOR) was 17.3 months (95% CI, 8.8-25.8). Moreover, the disease control rate (DCR) was 66.7% (95% CI, 49.0%-81.4%). Responses were observed in 41% (n = 11/27) of patients with germline BRCA2, 50% (n = 3/6) of those with germline PALB2, and 50% (n = 1/2) of those with somatic BRCA2 pathogenic variants.

“This is another step forward for PARP inhibitors and for the treatment of tough-to-treat pancreas tumors,” Kim Reiss, MD, lead study author and an assistant professor of Hematology-Oncology at Perelman School of Medicine of Penn Medicine, stated in a press release.² “It’s a safe option that not only has the potential to maintain responses, but also to shrink pancreatic tumors and, in some cases, achieve CRs for those carrying these mutations.”

Patients with pancreatic cancer who harbor pathogenic variants such as BRCA1, BRCA2, or PALB2 have been shown to be very sensitive to treatment with platinum-based chemotherapies. In May 2020, the PARP inhibitor olaparib (Lynparza) was FDA approved as a maintenance therapy for patients with platinum-sensitive, metastatic pancreatic adenocarcinoma that harbors germline BRCA1 and BRCA2 pathogenic variants.

However, efforts are now dedicated to expanding the group of patients with pancreatic cancer who can potentially derive benefit from PARP inhibitors, beyond those who harbor germline BRCA pathogenic variants. Moreover, investigators seek to refine clinical and biological biomarkers that could predict for benefit with these agents in patients with this disease.

In the phase 2 trial, investigators sought to determine whether maintenance therapy with rucaparib in patients with platinum-sensitive, advanced pancreatic cancer and a germline or somatic pathogenic variant in either BRCA1, BRCA2, or PALB2, could induce a 6-month PFS rate of at least 60%.

The open-label, single-arm, single-stage, phase 2 trial enrolled patients who were at least 18 years of age, who had locally advanced or metastatic pancreatic cancer, and confirmed, or likely, pathogenic germline or somatic variants in BRCA1, BRCA2, or PALB2.

Initially, patients were required to have received at least 16 weeks of treatment with platinum-based chemotherapy without showcasing evidence of platinum resistance, but the study protocol was amended to permit patients who had a contraindication to platinum therapy to enroll without prior exposure. Additional eligibility criteria required patients to have acceptable organ function, an ECOG performance status of 0 or 1, and a life expectancy of at least 12 weeks. Notably, those who had previously received a PARP inhibitor were excluded.

Study participants received oral rucaparib monotherapy at a twice-daily dose of 600 mg on days 1 through 28 of each 28-day cycle until either disease progression or intolerable toxicity. The primary end point of the study was 6-month PFS rate, while secondary end points included safety, ORR, DCR, DOR, and OS.

Among the 42 evaluable patients enrolled to the study, the median age at diagnosis was 61.5 years (range, 35-81) and more than half, or 57%, were female. In terms of pathogenic variants, 64% had germline BRCA2 mutations (n = 27), 17% had germline BRCA1 mutations (n = 7), 14% had germline PALB2 mutations (n = 6), and 5% had somatic BRCA2 mutations (n = 2). The median time from diagnosis to study start was 5.6 months (range, 2.5-62.5). Eighty-six percent of patients had measurable disease (n = 36), and 95% had metastatic disease at study start (n = 40).

Moreover, 34 patients had received 16 weeks or more of platinum therapy (range, 0-139), while 6 patients received less than 16 weeks due to either intolerance (n = 5) or allergy (n = 1) to platinum. Notably, 2 participants were noted to have severe neuropathy due to prior exposure to nab-paclitaxel (Abraxane) and they enrolled to the study without having received platinum therapy.

At the time of data cutoff, 66.6% of patients had progressed (n = 28), and 47.6% had died (n = 20).

Additional data indicated that patients with BRCA2 mutations had a longer PFS with maintenance rucaparib than those with BRCA1 mutations, at a median of 18 months (95% CI, 12.0-23.9) vs 3.7 months (95% CI, 0-8.6), respectively (P = .002). In the 6 patients with PALB2 mutations, the median PFS with rucaparib was 14.5 months (95% CI, 0.7-28.3).

No significant difference in OS was observed between the subgroups of patients with BRCA2 and BRCA1; here, the median OS was 25.3 months (95% CI, 19.8-30.7) vs 14.5 months (95% CI, 12.8-16.2), respectively (P = .34).

Moreover, among 36 patients with measurable disease, the median PFS with maintenance rucaparib was 7.5 months (95% CI, 0.0-20.0), while the median OS was 23.1 months (95% CI, 18.4-27.2). In 6 patients without measurable disease, the median PFS and OS had not been met (P = .09, for each).

When broken down by pathogenic variant, the ORR with maintenance rucaparib was 40.7% in those with germline BRCA2 mutations (n = 11/27), 50.0% in those with germline PALB2 mutations (n = 3/6), 50.0% in those with somatic BRCA2 mutations (n = 1/2), and 0% in those with germline BRCA1 mutations (n = 0/7). Notably, a response was noted in a patient with squamous cell carcinoma of the pancreas in the setting of a germline PALB2 pathogenic variant.

The most frequently experienced adverse effects (AEs) with rucaparib included anemia (74%), nausea (48%), increased alanine aminotransferase (ALT; 47%), fatigue (45%), thrombocytopenia (39%), and dysgeusia (37%). However, most of the reported AEs were grade 1 or 2 in severity.

The most common grade 3 AEs comprised anemia (22%), fatigue (4%), increased ALT (4%), thrombocytopenia (4%), nausea (2%), vomiting (2%), and WBC count decreased (2%). Additionally, 15 patients required temporary dose holds due to toxicities, 9 patients needed dose reductions due to AEs, and 1 patient withdrew study consent because of grade 3 fatigue. However, no other patients discontinued treatment due to AEs, and no grade 4 AEs were reported.

“These latest results show us another effective and less toxic maintenance therapy option for [patients with] pancreatic cancer, and underscore the importance of genetic counseling and testing, which can potentially steer the treatment course in a better direction,” study author Susan Domchek, MD, the executive director of the Basser Center for BRCA at Penn Medicine, added in the release.

References

1. Reiss KA, Mick R, O’Hara MH, et al. Phase II study of maintenance rucaparib in patients with platinum-sensitive advanced pancreatic cancer and a pathogenic germline or somatic variant in BRCA1, BRCA2, or PALB2. J Clin Oncol. Published online May 10, 2021. doi:10.1200/JCO.21.00003
2. A break from chemo: PARP inhibitor shrinks tumors in pancreatic cancer patients with mutations. News release. Penn Medicine. May 10, 2021. Accessed May 12, 2021. https://bit.ly/2QdvGGh