Plenary Coverage: ASCO Chief Medical Officer Dr. Richard L. Schilsky Discusses LBA4

Plenary Coverage: ASCO Chief Medical Officer Dr. Richard L. Schilsky Discusses LBA4 with Dr. Hedy Kindler.

Welcome to the ASCO Daily News podcast. I'm Dr. Richard Schilsky, Senior Vice President and Chief Medical Officer of ASCO. I'm pleased to be joined by Dr. Hedy Lee Kindler, Professor of Medicine at the University of Chicago Medicine where she is Associate Vice Chair for Clinical Research in the Department of Medicine as well as Director of the Mesothelioma Program. Dr. Kindler presented abstract LBA4, olaparib as maintenance treatment following first-line platinum-based chemotherapy in patients with a germline BRCA mutation and metastatic pancreatic cancer, Phase III POLO trial during the plenary session. Dr. Kindler, welcome to the podcast.

Thank you for inviting me to share the results of our study.

The five-year survival rate for people with metastatic pancreatic cancer is still less than 5%. So there's a real sense of urgency to develop new treatments. The POLO trial evaluated the efficacy of maintenance treatment with olaparib, a PARP inhibitor in patients with metastatic pancreatic cancer and a germline BRCA1 and/or BRCA2 mutation. What did the study show?

Well, in this study, patients with metastatic pancreatic cancer with germline BRCA1 or 2 mutations who had received at least 16 weeks of a first-line platinum-based chemotherapy were randomized 3 to 2 to olaparib tablets or a placebo. The primary endpoint was progression-free survival by blinded independent central review.
This study showed that maintenance olaparib provided a statistically significant and clinically meaningful improvement in progression-free survival. The progression-free survival was 7.4 months with olaparib and 3.8 months for placebo, with a hazard ratio of 0.53 and a p-value of 0.038. Progression-free survival on olaparib was the same irrespective of whether patients had stable disease or a complete or partial response to first-line chemo.

From six months onwards, more than twice the proportion of olaparib arm patients were progression-free compared with the placebo arm. 23% of patients had a response to olaparib. And what is truly remarkable is that the median duration of response to olaparib treatment in these patients with metastatic pancreatic cancer was over two years. The interim survival data at 46% maturity showed no difference between arms. And final survival results will be evaluated at 46% maturity.

Health-related quality of life was preserved with olaparib treatment and showed no difference between arms. And maintenance olaparib was quite well-tolerated with an AE profile similar to that seen in other tumor types.

So those are really quite exciting results. One question I had in looking at the study design is that, as you mentioned, patients in the trial all received four months of standard chemotherapy and were then randomized to continue treatment with placebo or olaparib. The question is, is it standard practice to stop active cancer treatment after four months? Would there be some rationale to adding olaparib to standard chemotherapy rather than using it as maintenance?

Actually, they did not. Patients had at least 16 weeks of first-line platinum-based chemotherapy with no maximum limit to the duration. Actually, about a third of patients received more than six months of chemotherapy. This was up to the treating physician and the patient. And remember, in their cord 11 trial, the median number of cycles was 10. Continuing on folfirinox does increase cumulative toxicity, principally myelosuppression and neuropathy. So it is a very reasonable thing to want to switch to a potentially less toxic treatment.

Understood. Thanks for that clarification.

So you asked about whether one could combine olaparib with standard chemotherapy. Unfortunately, myelosuppression at greater than anticipated rates is the common experience of combinations of olaparib and other PARP inhibitors with chemotherapy. For example, in a phase I trial of olaparib plus gemcitabine, which had a pancreatic cancer expansion cohort, it was not possible to administer gemcitabine above a dose of 600 mg per meter squared or olaparib above a dose of 100 mg bid. So it's quite unlikely that a combination of the highly myelosuppressive, folfirinox, could be administered safely with olaparib.
So if I'm understanding you correctly though, there were a proportion of patients in this study who continued chemotherapy beyond four months but also then had olaparib added during that period of time?

They had chemotherapy for four months or greater and then, they stopped chemotherapy and at that point, were randomized to receive either monotherapy with olaparib or placebo. There was no combination of chemotherapy plus olaparib.

Sorry, for not being able to follow this as clearly as you've laid it out. So what was the trigger to discontinue the chemotherapy then leading them to the randomization to olaparib or placebo?

That was investigator and patient choice. Some patients wanted to receive only four months of chemotherapy and switch over, others wanted to continue chemotherapy for longer. Remember, there is no standard of care, particularly at the time that the study was initiated, for maintenance chemotherapy. And so, four to six months of chemotherapy, at the time of the study design, was considered a very reasonable option.

Were all of the patients not progressing at the time of randomization?

Correct. All patients were required to have stable or responding disease at the time of randomization.

OK, so I wanted to ask you about the germline mutations in BRCA1, BRCA2. We commonly think of BRCA mutations as being associated with breast or ovarian cancer and maybe a few other cancer types, but how often is it that a patient with pancreatic cancer will be a carrier of a germline BRCA mutation?

Studies have shown that between 4% and 7% of pancreatic cancer patients harbor a germline BRCA1 or 2 mutation.
In view of the results of this study, now, do you feel that all patients with metastatic pancreatic cancer should be tested for a germline BRCA mutation?

Well, given the treatment implications demonstrated in the POLO trial, I think it is incumbent upon oncologists to offer all pancreatic cancer patients the option of germline testing. This is supported by an ASCO provisional clinical opinion from January of 2019, which recommended that patients with pancreatic cancer undergo risk assessment for hereditary syndromes that increase pancreatic cancer risk.

It states that germline genetic testing for cancer susceptibility, including testing for BRCA mutations, may be discussed with individuals diagnosed with pancreas cancer even if family history does not clearly suggest an inheritable cancer-related syndrome. Similarly, the NCCN now recommends germline testing for all patients with pancreas cancer due to data that demonstrates that germline mutations can occur at a similar rate in pancreas patients with or without a family history of any type of cancer.

Thanks. So one final question for you. Given the difficulty that we've had in developing effective new treatments for pancreatic cancer patients, given the lack of effective targeted therapies, this study would seem to open up new possibilities. But as someone who's an expert in the field, what do you see as being on the horizon in pancreatic cancer research?

This is an exciting trial because it's the first phase III randomized study to establish a biomarker-driven approach in the treatment of metastatic pancreas cancer. And while I hope that it will open the door to a new era of personalized care for this disease, I think we've been burned many times before. It's so common, in this disease, to see superimposable KM curves. And so, when one sees a hazard ratio of 0.53, it's genuinely exciting. But I really would not hazard a guess as to where we are going next. It's fraught with too many problems.

Understood. Again, today, my guest has been Dr. Hedy Kindler of the University of Chicago Medicine. Hedy, thank you so much for being on the podcast with me.

Thank you, Rich.

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