Maintenance Rucaparib Controls Some Pancreatic Cancers Free

Patients with advanced pancreatic cancer harboring BRCA pathway mutations who respond favorably to platinum-based chemotherapy may want to consider switching to a PARP inhibitor as a maintenance treatment.

That's according to preliminary trial data presented on April 2 at the American Association for Cancer Research Annual Meeting 2019 in Atlanta, GA, which demonstrated that rucaparib (Rubraca; Clovis Oncology) offered encouraging signs of disease control without the toxic side effects of standard combination chemotherapy.

“Although this is very early data, PARP inhibitors may represent an alternative to perpetual chemotherapy for these patients,” said Kim Reiss Binder, MD, of the University of Pennsylvania's Abramson Cancer Center in Philadelphia, who led the study. “The hope is that they can suppress the disease and give patients their lives back.”

Researchers had previously shown that rucaparib benefited patients with BRCA-mutated pancreatic cancer whose disease progressed despite chemotherapy—but only if their tumors were platinum-sensitive. That observation prompted Reiss Binder to launch a single-arm, 42-person phase II trial testing the clinical benefit of switching patients who responded well to platinum-based drugs to maintenance rucaparib. Trial participants had to have pathogenic mutations—germline or somatic—in BRCA1, BRCA2, or PALB2. Approximately 6% to 8% of all patients with pancreatic cancer harbor mutations in these genes—variants that make their tumors intrinsically sensitive to both platinum and PARP inhibitor therapy.

Most participants in the new trial had received at least 4 months of prior platinum-based therapy before starting a twice-daily maintenance regimen of rucaparib—an approved treatment strategy for women with ovarian cancer.

Among 19 evaluable patients, one had a complete response and six had partial remissions, for an overall response rate of 37%; ten others experienced stable disease for at least 8 weeks. Median progression-free survival (PFS) was 9.1 months from the start of rucaparib treatment, with minimal toxicity. Eight of the 19 patients remained on the drug for at least 6 months; two have continued taking it for more than a year.

For a disease in which the average overall survival is only about a year, “to me, these numbers are so impressive, and they show real progress,” said James Cleary, MD, PhD, of Dana-Farber Cancer Institute in Boston, MA, who was not involved in the study. The trial had no control arm, so some trial participants who responded favorably to the changed maintenance strategy could well have kept their disease in check by continuing chemotherapy, “but at what cost?” said Cleary, who described the chemotherapy regimens as “brutal” and “miserable.”

Because of the toxicities, many patients today take breaks from an effective therapy or drop part of a multiagent chemotherapy regimen. A safe, oral alternative would be “a very good treatment option for patients,” said Alice Chen, MD, of the NCI, who was not involved in the trial.

Rucaparib may not be the only effective PARP-blocking alternative to chemotherapy. In February, AstraZeneca announced that olaparib (Lynparza) had shown a statistically significant, clinically meaningful improvement in PFS compared with placebo in a randomized phase III trial involving patients with germline BRCA-mutated metastatic pancreatic tumors that had progressed on first-line platinum-based chemotherapy. According to AstraZeneca spokesperson Michele Meixell, full data from this trial will be presented at an upcoming scientific meeting.

“It will be interesting to see the results of that trial in comparison to [the rucaparib study] to see if they show any distinctions between the two PARP inhibitors,” Chen said. –Elie Dolgin