Expert Shares Significance of PFS Benefit With PARP Maintenance in BRCA+ Metastatic Pancreatic Cancer

Michael J. Hall, MD, MS

Michael J. Hall, MD, MS

Olaparib (Lynparza) improved progression-free survival (PFS) compared to placebo in patients withBRCA-mutant metastatic pancreatic cancer, based on data from the phase III POLO trial presented at the 2019 ASCO Annual Meeting.

This randomized, double-blind, placebo-controlled phase III trial randomized 154 patients 3:2 to receive either the PARP inhibitor or placebo as maintenance therapy. Patients had to have a germlineBRCA1orBRCA2mutation and responded to frontline platinum-based chemotherapy for at least 16 weeks.

The primary endpoint of this study was PFS by blinded independent central review. The median PFS was 7.4 months in the olaparib arm versus 3.8 months in the placebo arm (HR, 0.53; 95% CI, 0.35-0.82;P= .004).

The secondary endpoints included overall survival (OS), time from randomization to second progression or death, objective response rate (ORR), disease control rate, safety, and tolerability. At the time of analysis, the data had not matured enough for OS and second progression or death measurements. The ORR was 23.1% with olaparib and 11.5% with placebo.

In terms of safety, no new adverse events (AEs) were found in the olaparib arm. Forty percent of patients experienced grade 3 or higher AEs in the olaparib arm versus 23% in the placebo arm. Overall, 5.5% versus 1.7% of patients discontinued treatment due to AEs with olaparib versus placebo, respectively.

Investigators also looked at the health-related quality of life (QoL) and saw no difference between the 2 arms.

In an interview withTargeted Oncology, Michael J. Hall, MD, MS, chair and associate professor in the Department of Clinical Genetics, Fox Chase Cancer Center, and co-researcher for the POLO trial, discussed the findings from the interim analysis of olaparib versus placebo in patients withBRCA-mutant metastatic pancreatic cancer. He highlighted the next steps to come from this research and some of the barriers that need to be overcome in terms of genetic testing for pancreatic cancer, and for all patients with cancer.

TARGETED ONCOLOGY: What was the rationale for looking at a PARP inhibitor as maintenance in this setting?

Hall:Pancreas cancer is 1 of the most dismal tumors in all of oncology, particularly in gastrointestinal oncology, and what we have discovered over the years is that the only option to control disease once it spreads outside of the pancreas, which is 80% of patients when they present, is to use big time multi-agent chemotherapies that are toxic. What’s challenging about that is you’re already taking someone who is often very sick from the disease to be able extend their life sometimes by 6 to 8 months, you’re giving them very toxic chemotherapies. That’s not necessarily something that’s attractive to a patient. They want extended disease-free survival and QoL; they want to have both.

The idea behind this was that there were some preliminary data several years ago that showed that in [patients with] pancreas tumors that have a germlineBRCAmutation, and at that point we knew the range was maybe 5% to 15%, we knew that those tumors responded differently than the other pancreas tumors. They seemed to be especially sensitive to platinum-based agents. Talia Golan, MD, who is the senior author on the study, had a paper in theJournal of Clinical Oncologythat showed that platinum agents were great in this subgroup of patients with pancreas cancer.

Overtime, we understood it was the deficiency in homologous recombination andBRCAthat was driving this sensitivity, so when the PARP inhibitor class of agents was developed, naturally this became something [of interest]. I think a lot of people first looked at pancreas cancer and said there is no way an oral agent will ever be able to control this disease if FOLFIRINOX (folinic acid, fluorouracil, irinotecan, and oxaliplatin) can only hold off PFS by a few months, how can this oral agent ever do this? That was a real gamble. I think there were a lot of nay-sayers that felt it probably wouldn’t work. The trial was born of that.

TARGETED ONCOLOGY: How was this trial designed?

Hall:To get on this trial, there were a few different steps. First, you had to undergo germlineBRCAtesting. I’ll talk a little later on in regard to germline versus somatic, but over 3000 people worldwide were screened for this study to find the roughly 90 patients that went on the olaparib arm and the roughly 60 patients who went on the placebo arm. That was the first part.

Among that group, you had to be a responder to platinum therapy. We know that’s a big part of understanding who is going to respond to PARP inhibitors, so on this trial you actually had a choice of whether it was platinum-based like oxaliplatin, some were on gemcitabine, but frankly most people were on a modified FOLFIRINOX regimen since that is the standard US regimen. You had to be a responder on that for at least a particular amount of time. Once you were a responder for at least 16 weeks or more showing a response, your doctor could actually leave you on that regimen as long as they wanted and as long as you continued to respond, but there was a minimal requirement to demonstrate response.

Once that response was demonstrated, then people were randomized 3:2 to olaparib versus placebo. Everyone asks why 3:2, but that’s because the developers of the trial knew it was not going to be attractive to someone who had an aggressive disease to consider being randomized to placebo, so we tried to make the numbers a little better to go on the study drug. We ultimately randomized around 90 patients to the olaparib arm and around 60 patients to the placebo arm.

TARGETED ONCOLOGY: What were the findings that were presented at ASCO from the POLO trial?

Hall:PFS was our major endpoint. What we saw and what we presented was that we saw a nearly doubling of PFS with a hazard ratio of progression of 0.53, which I think blew everyone away. ThePvalue is very nice, and it demonstrates this is something that works.

There are other endpoints that we are going to be waiting for, so we will be waiting for OS. It’s going to take a while, though, because some of the responders are still responding for a very long period of time. The median duration of response right now is about 24 months. That shows you that for the people where it is working, we are seeing [good responses].  To get the 106 deaths for OS, that may take some time.

We’ve done some subgroup analyses on the PFS, I think the 1 of the high points of that isBRCA1andBRCA2responded roughly the same way. We didn’t see any differences in the subgroups, and I thought the other exciting thing was roughly 50% of people had either a partial response or complete response before they went on the study and roughly 50% were at stable disease. Those 2 groups actually responded the same way, which shows you it’s not just about picking out super responders and giving an icing-on-the-cake drug. It’s about demonstrating some response, and then the olaparib takes over on that. That’s super exciting.

Toxicity data was exactly as we predicted. Olaparib had somewhat more toxicity than being on placebo, naturally, but we didn’t see any extremely high rates of grade 3/4 toxicities, so that fit what we were estimating.

We also did some health-related QoL analyses. The punchline of that was that olaparib had no significant decline of health-related QoL compared to being on a placebo or nothing. I think that’s a strong [finding] because the last thing you would want to do is give someone a maintenance therapy, but you just make them sick again. That’s not what we saw, and we are very happy about that.

TARGETED ONCOLOGY: Where do we go from here?

Hall:We need to wait for the rest of the data to come out. We need the rest of the data to mature, so I think that will be exciting. The other question is what about somaticBRCA? We know germlineBRCA[mutations are in about] 6% to 7% [of patients], but somatic is probably another 3% to 4% of patients. The FDA approval will first be for the germline as the study showed, but the questions will be asked, and the research will be done looking at somaticBRCA. There are also other genes and mutations in theBRCAfamily, likePALB2gene, theCHEK2gene,ATM—they are all part of the Fanconi anemia pathway. Those are mutations based on some research from other groups, and we know those mutations are common. The question is if we can also get the same response.

There is this bigger group of people that are called the homologous recombination deficient pancreas cancers. The rough number is about 30% of pancreas cancers that are homologous recombination deficient. Can we use olaparib in that group as well? Can we combine olaparib with other agents? I think that’s the future. That’s what we will see at ASCO 2020, 2021.

TARGETED ONCOLOGY: What is your key message to share with community oncologists?

Hall:One thing that comes out of this that’s going to be important is that mutations, just like in the ovarian cancer world, mutations in pancreas cancer are very common. If you do a gene panel test in 10% to 15% of all-comers, you’re going to find clinically relevant mutations in this population that are not only potentially important in the coming years for people with pancreas cancer, but it’s going to be important for their family members.

This testing is, at least in the United States right now, is widely available. It’s not that expensive, and the NCCN has it in the guidelines now. It’s approved to do germline testing in pancreatic cancer. I take care of these patients, and I know there are barriers. These people are sick. They are often focused on other things, and that makes it tough to say, “I want you to think about this other thing, like getting a hereditary test.” That brings up a whole bunch of issues. People are still afraid of germline testing. They feel like the government is going to get a hold of their data or their family members might be upset if they find out they have this. There are a lot of barriers that doctors have to address, but I think these kind of data demonstrate that these barriers have always been there, we haven’t addressed them as much as we probably should have, but now if we want to take care of our patients, we need to move beyond this idea of genetic exceptionalism that we treat the germline in a special way. We need to talk to our patients about why it’s important to get these tests done, how it’s going to benefit their family, and how it is going to benefit their care.

One of the other things we found in this study with these data that I worked on in a project with the lead investigator Talia Golan, MD—we looked at people who came into this study knowing they were aBRCA-positive individual versus people found to beBRCA-positive for this study, and what we found was a striking racial ethnic disparity. Most of the African American patients in this study had no idea there wereBRCAmutations in their family before they got on the study. That says something about access, awareness, and potential sociological views of genetics. These are more barriers we need to overcome if we are going to provide good, equitable care to all patients in the field. Whenever we see disparities in the field, we all cringe and say why are these disparities existing and how can we make them better? I think one of the challenges going forward is how can we make sure our Latino, African American, or Caucasian patients all are equally aware that these mutations are out there and that these are things that can benefit them. There is also information that is important for them and their family members. That’s a poster I’m in the process of getting published right now.

Reference:

Kindler HL, Hammel P, Reni M, 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. J Clin Oncol. 2019;37(suppl; abstr LBA4).