PARP Inhibitors and the Challenges of Developing Ovarian Cancer Therapeutics

Jonathan Ledermann, MD

Michael Birrer, MD, PhD

Ovarian cancer is notoriously difficult to treat because it is usually diagnosed at an advanced stage, and because of the high variance in the types of mutations that are found in individual tumors. This creates hurdles for the development of efficacious treatments.

Cancer Network presents an interview with two prominent ovarian cancer researchers from both sides of the Atlantic. Dr. Jonathan Ledermann is professor of medical oncology at the UCL Cancer Institute in London, England. He treats gynecological cancers and is heavily involved in ovarian cancer clinical trials. Dr. Michael Birrer is a professor of medicine at the Harvard Medical School and is part of the Dana-Farber/Harvard Cancer Center where he also treats gynecological cancers and leads an effort to molecularly characterize gynecological cancers.

-Interviewed by Anna Azvolinsky, PhD

CancerNetwork: I would like to start the dialog between both of you about the development of PARP inhibitors in ovarian cancer. Dr. Ledermann, could you briefly describe the mechanism of action of PARP inhibitors and their rationale for use in ovarian cancer?

Dr. Ledermann: PARP inhibitors really represent a new class of drugs for the treatment of cancer and are particularly interesting in the treatment of ovarian cancer. Initially those with germline BRCA mutations but we now recognize that PARP inhibitors may be active in a much broader range of ovarian cancers. PARP is a key enzyme, involved in the regulation of the response of DNA to damage and the repair of single-stranded breaks by excision repair. So inhibitors of this enzyme, PARP inhibitors will inhibit this process of DNA repair and that leads to an accumulation of double-stranded breaks. Now, there are normally other mechanisms that the cell has to effectively repair those double-stranded breaks. Homologous recombination is the most common pathway. And in normal cells, that is what happens in the presence of a PARP inhibitor. But in cells that have deficiency of homologous recombination the cell can’t repair the damage and this leads to chromosomal instability and cell death. Now, tumors that are deficient in the BRCA gene or have mutations in the BRCA gene have this impairment in homologous recombination and therefore are particularly susceptible to PARP inhibitors. But as I said earlier, it does seem that there is a broader group of ovarian cancers that also have homologous recombination deficiency, and they are therefore susceptible to inhibition by PARP inhibitors.

CancerNetwork: Do you think that patients would still have to be screened for those mutations, or is it almost a given that ovarian tumors have mutations in some aspect of the DNA repair pathway?

Dr. Ledermann: Well, we know that mutations in the BRCA gene probably occur at about 15 to 20 percent of ovarian cancers so this is a relatively small percentage overall, but nevertheless significant. There are deficiencies in the functional aspects of BRCA in a much larger population of patients, probably in the region of between 40% and 50% of all patients. So potentially, the group of patients, particularly those with high-grade serous cancers (those are the ones that have HRD [homologous recombination deficiency])-about 40% to 50% of those patients may be susceptible to PARP inhibitors.

CancerNetwork: Despite promising results at ASCO last year, with one of the PARP inhibitors, olaparib, showing positive progression-free survival (PFS) benefit, the phase II trial was stopped in mid December because this PFS benefit was not likely to translate to an overall survival benefit. I would like to get both of your perspectives on this and then what the future holds for other PARP inhibitors in development.

Dr. Ledermann: Mike Birrer will want to comment on this, but can I just correct you on a point of fact. The phase II trial was not stopped. In fact it is still going. There are still patients on treatment, and it has not been unblinded. What the company that manufactures olaparib, which is one of the PARP inhibitors, said in their press release was they were not going to continue development of olaparib in high-grade serous ovarian cancer because, as you said, the interim analysis of survival didn’t show the benefit they wanted to see in relation to the benefit in PFS that I reported at the ASCO conference. But the trial is still continuing and a final analysis will be done probably toward the end of this year.

CancerNetwork: I see. So maybe both of you could comment on some of the other PARP inhibitors and what the prospect is for this class of drugs for ovarian cancer?

Dr. Birrer: So perhaps I can address that. And let me just go back for a moment to touch the highlights because I think John summarized the whole field quite well. I think the excitement of this field and this set of drugs, the fact that this is an entirely new class of drugs that clearly demonstrate activity in that they address or inhibit DNA repair. That actually synergizes with or interacts nicely with the kinds of drugs we already use for ovarian cancer, namely, the platinums. We've understood that ovarian cancer is particularly sensitive to platinum compounds because platinum damages DNA, and obviously inhibiting PARP, which is a way that cells can attempt to repair that DNA is going to be important, and so there is a lot of hope that not only as a single agent, but a combination between these two will be at least additive if not synergistic. The challenge for the future, as was just summarized, is trying to identify what percentage of ovarian cancers actually would benefit from treatment from PARP inhibitors, and there is a lot of work going on there and will continue despite the sort of slowdown in terms of clinical development of at least one agent.

I would say in summarizing the trials, not only was the consolidation trial strongly positive but there were a number of other trials prior to that which showed very impressive single agent activity in BRCA1 germline-mutated patients which got us all very excited. A little of what the problems we have gotten into is more beyond just the development of PARP inhibitors. Ovarian cancer patients now, for a variety of reasons-better supportive care, better surgery, better treatment-actually have a median survival that extends quite far. And the use of overall survival as an end point becomes somewhat problematic for companies because it takes a long time to see that signal and initially that signal may be complicated because patients may cross over, they will get multiple therapies and so the natural inclination has been to try to use PFS as a surrogate. And there is a lot of debate about this, but I think that there is pretty good evidence that PFS will parallel overall survival in many cases. The difficulty is the regulatory bodies at least in the United States are not willing to accept that yet and so not only have PARP trials gone into this but other biologic trials that are using PFS.

PFS as an end point have reported positive trials but the FDA and regulatory agencies are not, it’s not clear that they are going to accept that for registration of the drug . Now, having said that, as Jonathan said, the consolidation trial was positive, it is ongoing. I don’t think the decision by the company is by any means an end to this. For instance, even that agent that was involved, the company has not said definitively that they are not going to develop it. And then there are a number of other companies-at least one large company and two smaller companies-that have very well characterized, by preclinical data, PARP inhibitors that are in various points of clinical testing. At least two of them coming very rapidly into phase I/phase II, and then another agent from a larger company is all the way through phase I and will be through phase II very rapidly, and they are collaborating with the Gynecological Oncology Group to try to bring that into an upfront phase III trial. So I think we will be seeing and hearing a lot more about PARP inhibitors in the next year or two.

CancerNetwork: Dr. Ledermann, do you have any perspective about the overall survival/PFS debate?

Dr. Ledermann: Well, I think the first thing to say is that this is an interim analysis that was done by the company. It was done so they could plan their phase III program a little bit more clearly. So we don’t know what the final results of the survival analysis are going to be. But I think this is the sort of first real foray with nonchemotherapy drugs and maintenance, if you like, for ovarian cancer. And the data that we have for maintenance chemotherapy is not that strong either. Some of those studies showed improvements in PFS, which has not translated to overall survival. So as far as the translation between PFS benefit using maintenance therapy into an overall survival benefit, it is still a very new area for everybody and we are seeing that with bevacizumab too.

I think the problem that the companies have is, as Mike Birrer put it, the regulators are the ones that are driving this in a sense, particularly in the United States where if there is not a survival benefit, regulators take a very poor view of the PFS. But, there is no getting away from the fact that olaparib was a very, very active drug in this population of patients. The hazard ratio of PFS, the different was 0.35, which is really very big indeed. So, this drug is definitely active, and I am sure that the whole class of drugs are active. It is perhaps that we don’t know exactly which group of patients to use them in and exactly how we should use them. Whether it should be with chemotherapy because of the possibilities of synergy, whether it should be as a maintenance therapy, or whether it should be in certain subsets of patients where we might actually see a better activity. So I think that there is a lot more work that needs to be done, but it is really important that work continues with this class of drugs because they really are a new and very active group of agents.

CancerNetwork: Do you think that part of the problem of the development of these PARP inhibitors in ovarian cancer is the fact that there are challenges in developing therapeutics for these smaller patient populations?

Dr. Birrer: I do think that that is part of it. And I think that is part of a much broader issue that is, a lot of people and a lot of companies are struggling with in oncology in general. We are fairly rapidly moving toward more personalized medicine, and as you get more targeted therapies and diagnostics are able to identify the patients that are going to benefit from it, there is no doubt that patients benefit. There is less toxicity and more efficacious drugs are being developed, but the markets tend to get smaller. For PARP inhibitors and ovarian cancer, it cannot be as small as we thought.

As Jonathan has described in detail, we first started with germline BRCA1/2 mutated patients. We now know that we are probably missing about one-third of those. So the percentages go from about 8% to 15% or 20%. And then there are somatic abnormalities and abnormalities in other genes so that this percentage in ovarian cancer may be as high as 30% or 40% or 50%. But, one needs to recognize, that in some ways, ovarian cancer is considered a rare tumor to begin with. Now you are talking about a percentage of those. So that is a challenge that all of the companies are going to have to address. I think that it will be reflected to a certain extent in the way that drugs are developed, probably pricing, and hopefully, the regulatory agencies will be able to recognize this and make it a little less burdensome for the companies to develop drugs of this nature.

CancerNetwork: Thank you both so much for joining us.

Dr. Ledermann: Thank you.

Dr. Birrer: My pleasure.