BRCA was the key to success


CHICAGO — Pancreatic cancer trials don’t report complete responses, until now: two patients’ metastatic pancreatic cancer achieved a complete response to treatment with olaparib (Lynparza), a drug that targets a mutation most often associated with breast, ovarian, or prostate cancer—BRCA.

Moreover, at 2 years and counting, overall survival data are still not mature, said Hedy L. Kindler, MD, of the University of Chicago, who reported the surprising finding from the phase III POLO trial here at the American Society of Clinical Oncology meeting. The findings are the first to validate “a targeted treatment in a biomarker selected population of pancreatic cancer patients.”

The POLO results were also published online by The New England Journal of Medicine.

The novel finding is the result of even more novel or innovative thinking — test patients with metastatic pancreatic cancer for BRCA1 or BRCA2, the mutations associated with breast, ovarian, and prostate cancers. “We tested for germline mutations, so it only requires a blood test,” she said.

Kindler said 4-7% of persons with metastatic pancreatic cancer also harbor a “germline BRCA1 or BRCA2 mutation.

The POLO investigators screened 3,315 patients and identified 154 who tested positive for BRCA and who had not progressed on standard platinum-based chemotherapy. The patients were randomized 3:2 to olaparib 300 mg (n=92) or placebo (n= 62). Olaparib belongs to a class of drugs call PARP inhibitors — poly(adenosine diphosphate–ribose) polymerase inhibitors.

The primary endpoint of the study was progression free survival. “The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P=0.004),” she said.

Objective response was seen in 23.1% of olaparib patients and 11.5% of controls. The median time to onset of response was 5.4 months in the olaparib arm versus 3.6 months in the placebo group, and the median duration of response was 24.9 months versus 3.7 months, favoring olaparib.

The potential for this treatment is probably best illustrated with patient stories, and ASCO spokesperson Suzanne Cole, MD, of U.T. Southwestern, had a dramatic one to share. “I want to share some information about one of Dr. Kindler’s patients,” she said. “This patient with pancreatic cancer inherited BRCA, as had his brother, and he saw that brother die, so he asked if he could get into the POLO study. He was on chemo for 4 months and hadn’t progressed, so he moved to POLO. He is now alive at 2 and a half years and the tumors in his liver decreased in size. He is free of taking IV chemo. These findings are practice-changing, and I can’t wait to get back to my practice so I can look for this mutation in my own patients.”

But while the hallway buzz here was proclaiming the POLO the “biggest news” at this year’s ASCO, the findings should be cautiously interpreted, since “interim overall survival data (at 46% maturity) showed no difference between arms. Final OS results will be evaluated at 69% data maturity,” she said, adding that she thought that threshold might be reached by year’s end.

And, “grade 3, 4, or 5 toxicities occurred in 40% of people taking olaparib compared with 23% of those taking a placebo. In addition, 5.5% of those taking olaparib and 1.7% of those on placebo discontinued treatment due to toxicity,” Kindler added.

 

Disclosure:

The POLO study received funding from AstraZeneca and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA.

Kindler reported consulting or advisory role with AstraZeneca, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, ipsen, ERYTECH Pharma, Five Prime Therapeutics, Paradox Therapeutics, Aldeyra Therapeutics, Kyowa Hakko Kirin and Astellas Pharma, Research Funding (Institutional) from Aduro Biotech, AstraZeneca, Bayer, GlaxoSmithKline, Merck, MedImmune, Verastem, Bristol-Myers Squibb, Lilly, Polaris, Deciphera, Inhibrx, and Roche/Genentech.

Source:

Kindler HL, et al “Olaparib as maintenance treatment following first-line platinum-based chemotherapy (PBC) in patients (pts) with a germline BRCA mutation and metastatic pancreatic cancer (mPC): Phase III POLO trial” ASCO 2019; Abstract LBA4.

Golan, T et al “Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer” N Engl J Med 2019; Published online June 2 DOI: 10.1056/NEJMoa1903387.

 

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