Expanding PARP Inhibitor Benefits in Advanced Pancreatic Cancer

Maintenance therapy with a PARP inhibitor demonstrated activity in mutated advanced pancreatic cancer beyond germline BRCA variants, results of a small phase II trial showed.

A patient cohort with germline and somatic mutations, including PALB2, had a 6-month progression-free survival (PFS) of 59.5%, decreasing only slightly to 54.5% at 12 months with maintenance rucaparib (Rubraca). The overall response rate of 41.7% included patients with germline (g) and somatic (s) BRCA1/2 mutations and those with PALB2 variants. Two-thirds of patients obtained disease control with the PARP inhibitor, according to Kim A. Reiss, MD, of University of Pennsylvania Perelman School of Medicine in Philadelphia, and colleagues.

The results supported and extended those from the practicing-changing POLO trial of olaparib (Lynparza) maintenance for gBRCA1/2 pancreatic cancer, they reported in the Journal of Clinical Oncology. The findings also extended preliminary results reported by Reiss and colleagues.

“I think the biggest takeaway [from the current report] is that we’ve added a number of additional types of patients who might benefit from a maintenance PARP inhibitor,” Reiss told MedPage Today. “The POLO study showed us that those with germline BRCA variants would benefit and that obviously led to an FDA approval. Our study shows benefit also in germline PALB2 patients, patients with somatic variants, and also patients with other histologies.”

“I think what we’re really trying to do here is to expand the group of patients who might benefit from a lower-toxicity maintenance therapy after chemotherapy,” she stated.

Pancreatic cancers associated with pathogenic gBRCA1, gBRCA2, or gPALB2 alterations exhibit deep sensitivity to platinum-based chemotherapy. Olaparib has FDA approval as maintenance therapy for platinum-sensitive metastatic pancreatic cancer associated with gBRCA1/2 pathogenic variants. A great need exists to expand the proportion of patients who might benefit from PARP inhibitors, Reiss and colleagues noted.

One recent study showed a beneficial effect of olaparib in patients with metastatic breast cancer and sBRCA pathogenic variants. Other studies have demonstrated PARP inhibitor activity beyond gBRCA variants in prostate and ovarian cancers with homologous recombination deficiencies.

To continue the investigation of PARP inhibitor activity, investigators enrolled patients with platinum-sensitive advanced pancreatic cancer associated with germline or somatic pathogenic variants in BRCA1, BRCA2, or PALB2. They hypothesized that rucaparib maintenance therapy would lead to a 6-month PFS of at least 60%.

Eligible patients had locally advanced or metastatic pancreatic cancer treated for at least 16 weeks with platinum-containing chemotherapy without evidence of platinum resistance. They received twice-daily oral rucaparib, continued until disease progression or death from any cause.

Data analysis included 42 patients evaluable for the primary endpoint. After a median follow-up of 18 months, the trial met the primary endpoint, as the lower bound of 95% confidence intervals exceeded the hypothesized rate of 44% (95% CI 44.6-77.4%, P=0.042). With a median potential follow-up for overall survival (OS), the median OS was 23.5 months.

The overall response rate in 36 evaluable patients was 41.7%, including three complete responses. Median duration of response was 17.3 months. Two of three patients with complete responses had ongoing responses that exceeded a year, and the third had disease progression after 10.1 months. The disease control rate (response plus stable disease) was 66.7%.

Objective responses occurred in 11 of 27 (40.7%) patients with gBRCA2 variants, three of six with gPALB2, one of two with sBRCA2, and none of seven with gBRCA1. Patients with BRCA2 variants had a significantly longer median PFS as compared with patients who had BRCA1 variants (18.0 vs 3.7 months, P=0.002). Patients with PALB2 variants had a median PFS of 14.5 months. OS did not differ significantly between patients with BRCA2 or BRCA1 variants (25.3 vs 14.5 months, P=0.34).

Objective response was associated with lower disease burden as defined by median total sum of lesions (3.87 vs 5.69 cm, P=0.02). Patients with BRCA1 variants had a higher baseline disease burden as compared with those who had BRCA2 variants (5.8 vs 3.0 cm, P=0.04).

Among 46 patients evaluable for safety, the most common adverse events (AEs) at least possibly related to rucaparib were anemia (74%), nausea (48%), increased alanine aminotransferase (ALT; 47%), fatigue (45%), thrombocytopenia (39%), and dysgeusia (37%). The most common grade 3 (no grade 4) treatment-related AEs were anemia (22%), fatigue (4%), increased ALT (4%), thrombocytopenia (4%), and nausea, vomiting, and decreased white blood cell count (2% each).

“We know that there are still broad biological differences in these patients, even in such a small group, because of the variance in response,” said Reiss. “A small group falls off right away. As you can see by the [survival] curves, there’s a group of patients at the tail end who appear to do extremely well. We need to do more work to figure out who’s who.”

The findings probably apply to other PARP inhibitors, although not all drugs in the class have supporting data in the maintenance setting, she added.