CHICAGO — Patients with metastatic pancreatic cancer who carry a BRCA gene mutation could see their disease progression slowed or even halted with olaparib (Lynparza, AstraZeneca), suggest the results from the phase 3 Pancreas Cancer Olaparib Ongoing (POLO) trial.

Hedy L. Kindler, MD

Olaparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes that is already approved for use in ovarian and breast cancer in patients with germline BRCA mutations. The company says it intends to submit the new data in BRCA pancreatic cancer to regulatory authorities.

The results from POLO were presented here at the American Society of Clinical Oncology (ASCO) annual meeting (abstract LBA4), and published simultaneously by the New England Journal of Medicine.

Hedy L. Kindler, MD, medical director, gastrointestinal oncology, University of Chicago, and colleagues conducted the trial in patients who were stable on platinum-based chemotherapy, and who were randomized to olaparib or placebo.

The researchers found that patients given olaparib had a median progression-free survival (PFS) of 7.4 months vs 3.8 months with placebo, equating to a 47% reduction in the risk of disease progression or death.An objective response was seen in more than twice as many olaparib patients than in those given placebo, at a median duration of response of over 2 years with the oral medication.

Indeed, two patients in the olaparib group had complete responses that were ongoing at the time of analysis.

Kindler said in a press conference that, following first-line platinum-based chemotherapy, olaparib "should become a new standard of care in patients with metastatic pancreatic cancer who have a germline BRCA mutation."

She added in the release that findings were "truly remarkable" and the study "opens the door to a new era of personalized care for this difficult-to-treat cancer," with the potential to see "a change in patients' disease trajectory."

Richard L. Schilsky, MD, senior vice president and chief medical officer of ASCO, commented that they are "really exciting data that I'm quite sure will change the face of treatment for at least this population of patients with pancreatic cancer."

Invited to comment, Suzanne Cole, MD, a medical oncologist at UT Southwestern Medical Center, Dallas, said that she "fully" agreed, and that the study represents a "huge step forward."

She said: "This is the first time that a targeted medication has been successful in stopping the growth of metastatic pancreatic cancer in people who carry the BRCA mutation," with many patients having "dormant" disease.

It is our duty to search for this genetic mutation in all patients with metastatic pancreatic cancer. Suzanne Cole, MD

"Now that we have a targeted medication that can benefit patients who have the BRCA mutation when they present with metastatic pancreatic cancer, it is our duty to search for this genetic mutation in all patients with metastatic pancreatic cancer so that we can identify those people who can benefit," she said.

For Cole the results were therefore "practice changing for people who have the BRCA mutation."

"I can't wait to back to clinic on Tuesday and look for it in my own patients."

Cole added that it is "good medical practice to pay attention to what is going on in the family and whether there are cancers that we know are related to BRCA mutations...to tip you off that [you] may need to be searching for the BRCA mutation in your own patient."

Kindler noted that the standard of care for metastatic pancreatic cancer is currently chemotherapy with either FOLFIRINOX or gemcitabine plus nab-paclitaxel. These are associated with a median PFS of approximately 6 months and with a median overall survival of just 8 to 12 months.

Moreover, less than 50% of patients end up receiving second-line therapy, and there are currently no targeted treatments for patients on the basis of a disease biomarker have been validated in a phase 3 trial.

It is estimated that between 4% and 7% of patients with metastatic pancreatic cancer have gBRCAm, and they have been shown to have an increased benefit from platinum-based chemotherapy.

The goal of maintenance treatment in this subgroup of patients would therefore be to delay their disease progression after chemotherapy, without worsening their health-related quality of life.

Study Details

With a phase 2 trial having shown that olaparib had antitumor activity in heavily pretreated pancreatic cancer, the researchers examined the efficacy of maintenance olaparib in patients from 119 sites in 12 countries.

The team included metastatic pancreatic patients who had deleterious or suspected deleterious gBRCAm and had received at least 16 weeks of first-line platinum-based chemotherapy without progressing.

They were randomized in a 3:2 fashion, with no stratification factors, to olaparib 300 mg twice daily or placebo, starting 4 - 8 weeks after the last dose of first-line chemotherapy.

No crossover was allowed and the intervention was continued until the occurrence of objective radiologic disease progression or unacceptable toxicity, at which point subsequent therapy was given at the investigators' discretion.

After screening 3315 patients, 247 (7.5%) were found to have gBRCAm. Of those, 93 had disease progression, were ineligible, or declined randomization.

The remaining 154 patients were randomized to olaparib (n = 92) or placebo (n = 62). The median age was 57 years. A slightly higher proportion of olaparib patients were male, at 58% vs 50% of those given placebo.

The median time from diagnosis to randomization was approximately 7 months.

The most common first-line, platinum-based chemotherapy was FOLFIRINOX and its variants, which was given to 81% - 86% of patients for a median of 5 months.

Median PFS, as assessed by blinded independent central review, was significantly longer with olaparib than placebo, at 7.4 months versus 3.8 months, or a hazard ratio for disease progression or death of 0.53 (P = .004).

Importantly, there were no differences in PFS between patients who had experienced a response on platinum-based chemotherapy and those who had had stable disease, and the results were unaffected by baseline characteristics.

By the data cutoff, 41 patients given olaparib and 30 in the placebo group had died.

An interim analysis at 46% data maturity suggested that there was no difference in overall survival, at 18.9 and 18.1 months, respectively, although a further analysis once the data reaches 69% maturity, or 106 events, is planned.

Kindler commented that it is nevertheless "remarkable that we haven't reached a survival endpoint in a disease where patients usually live around a year."

An objective response was seen in 18 patients treated with olaparib and six given placebo, which equated to a response rate of 23% and 12%, respectively, on blinded central review, or an odds ratio of 2.30.

The median time to response was 5.4 months with olaparib and 3.6 with placebo, and the median duration of response 24.9 months and 3.7 months, respectively.

Two patients in the olaparib group had a complete response, which were ongoing at the time of cutoff.

Cole recounted that, in one of those patients, the pancreatic cancer had already spread to his liver at the time of diagnosis.

She explained: "He had inherited the BRCA mutation, as had his brother, and he had recently seen his brother die of metastatic breast cancer within a few months of his diagnosis."

As a consequence, he enrolled onto the POLO trial and received chemotherapy for approximately 4 months, at which point he was able to move over to olaparib.

"He has now been alive for two and a half years and not only have the tumors in his liver stabilized," Cole said, "they've decreased in size."

Noting that olaparib is an oral medication, she added that the patient "has had a really excellent quality of life because he has been free of taking intravenous chemotherapy over this time."

Serious adverse events were recorded in 24% of olaparib patients and in 15% of those given placebo. Adverse events leading to discontinuation were seen in 6% and 2% of patients, respectively.

There was no significant difference in the change in health-related quality of life scores from baseline on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire between the two treatment groups.

Eileen O'Reilly, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center and co-author on the study commented in a press release. "This study defines a new treatment option for certain people with pancreatic cancer," she said.

"We expect it will lead to an application to the US Food and Drug Administration to expand olaparib's approved indications to include people with pancreatic cancer who have an inherited BRCA mutation."

Wells A. Messersmith, MD, University of Colorado School of Medicine, was invited to discuss the POLO trial.

He said that the rationale was "sound" as there is "clearly an unmet need in this for both effective therapies and maintenance strategies, and effective targeted personalized approaches are clearly needed."

Messersmith said that the study design was "reasonable," especially given that it was started in 2014 and that finding gBRCAm patients was a "major challenge."

Moreover, the PFS achieved is "considerable in the context of pancreatic cancer."

The curves, however, "never really flattened, meaning that, as with many targeted approaches, resistance is inevitable."

He also underlined that the lack of overall survival benefit is "humbling, especially given the low rates of subsequent PARP inhibitor exposure," and he does not expect a survival benefit on the final analysis.

Messersmith added that the placebo-based design is "questionable" as pancreatic cancer is aggressive and so the idea of stopping therapy altogether is "not attractive."

Moreover, the trial does not answer the question of how to treat patients with somatic BRCA mutations, as they were not included, and he noted that there is a risk of "financial toxicity" with using PARP inhibitors in this context.

He nevertheless believes that germline testing should be standard for advanced pancreatic cancer, future trials should look at other mutations, and olaparib should be an "option" for patients.

This study received funding from AstraZeneca, Myriad Genetic Laboratories, and Merck Sharp & Dohme Corp. Kindler reported consulting or advisory roles with AstraZeneca, Merck, Bristol-Myers Squibb, Boehringer Ingelheim, ipsen, ERYTECH Pharma, Five Prime Therapeutics, Paradox Therapeutics, Aldeyra Therapeutics, Kyowa Hakko Kirin, and Astellas Pharma; and research funding (institutional) from Aduro Biotech, AstraZeneca, Bayer, GlaxoSmithKline, Merck, MedImmune, Verastem, Bristol-Myers Squibb, Lilly, Polaris, Deciphera, Inhibrx, and Roche/Genentech. Pascal Hammel disclosed consulting or advisory roles with Celgene, Shire, VECT-HORUS, Amgen, and Halozyme; consulting or advisory roles (institutional) with ERYTECH Pharma, Speakers' Bureau for Celgene, and Shire; paid travel, accommodations, and expenses from Merck Serono, Ipsen, Halozyme, Shire, and Lilly; and honoraria from Celgene.

2019 American Society of Clinical Oncology (ASCO) Annual Meeting: Abstract LBA4. Presented June 2, 2019.

N Eng J Med. Published June 2, 2019. Abstract

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