Selected Podcast

PARP Inhibitors in Ovarian Cancer

Martina Murphy M.D discusses PARP inhibitors in ovarian cancer. She examines the use of a PARP inhibitor as first-line therapy, and helps us to understand the relevance of homologous recombination deficiency (HRD) in development of ovarian cancer. She shares the mechanism of action and rationale for PARPi and reviews the FDA-approved uses for PARPi in the management of advanced ovarian cancer.
PARP Inhibitors in Ovarian Cancer
Featured Speaker:
Martina Murphy, MD
Dr. Murphy is a clinical investigator and medical educator with a passion for women's health especially within hematology/oncology. She specializes in gynecologic cancer. Her research focuses in the study and reduction of healthcare disparities & inequity as it pertains to patient related outcomes in cancer care as well as workplace and training environments. She serves as the Program Director for the hematology/oncology fellowship program. 

Learn more about Martina Murphy, MD
Transcription:

The University of Florida College of Medicine is accredited by the Accreditation Council for Continuing Medical Education, ACCME to provide continuing medical education for physicians. The University of Florida College of Medicine designates this enduring material for a maximum of .25 AMA PRA category 1 credit. Physicians should claim only the credit commensurate with the extent of their participation in this activity.

Melanie Cole (Host):  Significant progress has be made in the treatment of patients with ovarian cancer. This is UF Health MedEd Cast with UF Health Shands Hospital. I’m Melanie Cole. And today, we’re discussing PARP Inhibitors in ovarian cancer. We’ll examine the use of PARP Inhibitors as first line therapy and we will understand the relevance of homologous recombination deficiency in development of ovarian cancer. We’re covering the mechanisms of action and rationale for PARP and reviews on the FDA approved uses for it. Joining me Dr. Martina Murphy. She’s an Assistant Professor in the Division of Hematology and Oncology, in the UF Department of Medicine and she practices at UF Health Shands Hospital. Dr. Murphy, it’s a pleasure to have you join us today. Let’s start off by discussing the state of ovarian cancer. What are you seeing in the trends?

Martina Murphy, MD (Guest):  So, it’s important to understand that ovarian cancer while it’s the second most common gynecologic malignancy; it actually has the highest rate of mortality of all gynecologic cancers. And this is really related to the fact that we don’t have any effective screening methods. So, by the time women end up in our clinic; most of them have advanced disease. And unfortunately for many years, we really haven’t had a lot of change in terms of our treatment options. So, what’s important to know is that when women are diagnosed with ovarian cancer; really regardless of stage, the primary treatment is surgery followed by standard chemotherapy. And the good news is that the vast majority of women, somewhere around 70 to 90% of them will actually respond to this treatment and either go into a complete or partial remission. So, that’s good. The trouble is that the vast majority of these women unfortunately about 80% will actually recur at some time. And so that’s where the PARP inhibitors come into play.

Host:  So, tell us about them. And how are you using them for ovarian cancer? What’s the role as you see it now?

Dr. Murphy:  That is such a great question and I’ll be honest; the role is really evolving. So, in order to understand that question, we sort of have to understand a little bit about the way that the medication themselves work. So, PARP stands for poly adenosine diphosphate ribose polymerase. Thankfully we’ve shortened it to PARP because none of us can actually say that in a regular sentence. So, PARP is actually a protein that is very important for repairing DNA or chromosomal breakage and so what we have found is that if we inhibit this protein, DNA damage in cancer cells accumulates and eventually cancer cells will die. So, that is the rationale behind why PARPs actually work in cancer in general.

In ovarian cancer, they have a particular role because a large proportion of women with ovarian cancer have additional mutations that make them unable to – make the cancer cells unable to recover from DNA damage. So, the sort of what we call synthetic lethality of the genetic mutation that the patient has and the addition of the PARP inhibitors makes it such that we have the ability to selectively kill these cancer cells.

Host:  Well as you are telling us about that, what an interesting topic this is Dr. Murphy. What role does the BRCA mutation play in this developing cancer and while you are telling us that and you mentioned recurring cancers; as they are being looked at for new diagnoses in a more advanced stage, help us to understand as I said in the intro, the relevance of the homologous recombination deficiency. So, kind of tie that all and I know it’s a lot but tie that all together for us.

Dr. Murphy:  Yeah. It’s really fascinating and it’s really interesting and important. So, I’m glad that you are asking. So, there are several well established risk factors for the development of ovarian cancer an done of them sort of the most important one I think is the genetic predisposition for the development of the disease that is actually conferred by having a mutation in this BRCA gene. We know that women who have BRCA mutations are far more likely than women without these mutations to develop ovarian cancer in their lifetime. So, what is BRCA and why is it important?

So, the that are proteins are encoded by the BRCA gene, are actually really important for a DNA repair mechanism that’s known as homologous recombination. And this is very complex. We learn all about this in medical school but as a primer, it’s just a- it’s a very complex process of DNA repair where the body is able to repair double stranded DNA breaks and so when people have a mutation in BRCA or other proteins that are involved in this process; we call it homologous recombination deficiency or HRD.

Okay, so that was a little biology 101. So, why does this relate to ovarian cancer and why should we care when we are thinking about how we treat our patients with ovarian cancer? So, what we now know is that approximately half of epithelial ovarian cancers which is the most common form or ovarian cancer; have or exhibit defective DNA repair through alterations in this HRD homologous recombination pathway. And about 20% of patients with epithelial ovarian cancer have that cancer as a direct result of a BRCA mutation and that understanding the way that these genes lead to the development of ovarian cancer helps us understand ways that we can develop drugs to better help attack it.

Host:  Well again, this is so fascinating. So, as you mentioned the rationale for ovarian cancer. For which patients are they indicated. Help us to understand the mechanism of action a little bit more if you would.

Dr. Murphy:  Yeah, so the main value I would say at this point in time of the drugs of PARP inhibitors in clinical practice is actually as a form of maintenance therapy. So, a therapy that’s given after initial standard chemotherapy to essentially help prevent cancer recurrence. So, the idea is to use these oral medications after response to platinum based chemotherapy to help maintain that response and to keep patients from developing recurrence so quickly.

Host:  Are there some people for whom PARP might be indicated for initial treatment?

Dr. Murphy:  So, no, currently PARP inhibitors are actually indicated again, as maintenance following standard chemotherapy.

Host:  Then review for us, the FDA approved uses as they stand now. Where does it stand as to regulatory approval?

Dr. Murphy:  So, there are currently three PARP inhibitors on the market. So, there’s olaparib, rucaparib and niraparib and of those, only olaparib is actually approved for what we call first line maintenance. So, maintenance therapy right after their initial chemotherapy. And to sort of further drill down on that; it’s actually only indicated for first line maintenance in patients with a BRCA mutation. The remainder of the PARP inhibitors can be used for what we call second line maintenance. So, maintenance therapy after platinum based chemotherapy for recurrent ovarian cancer.

Host:  How interesting and what do the studies say Dr. Murphy? Do they support the use of PARP inhibition, irrespective of the BRCA mutation status? Tell us a little bit about that.

Dr. Murphy:  So, it’s a great question. So, what we know is that in all of the studies, patients with a BRCA mutation or other forms of homologous recombination deficiency respond better to these medications than patients who do not have these mutations.

Host:  Well tell us about what you’re doing at UF Health Shands Hospital. Any research you’d like other providers to know about that we haven’t discussed and what you see on the horizon. Give us a little blueprint for future treatments.

Dr. Murphy:  Great question. So, in my practice at UF Health Shands Hospital, first and foremost, any patient who we see in clinic with the diagnosis of ovarian cancer should undergo and does undergo genetic testing specifically to look for a BRCA mutation or other forms of homologous recombination deficiency. In patients who have this mutation, I certainly counsel them and talk to them about the merits of using a PARP inhibitor after they complete their first line chemotherapy. And all of my other patients, I talk to them at the time of recurrence. So, I don’t know that we know the best answer yet as I mentioned before, I think this is evolving but it certainly is something that I talk to all of my patients about. Taking a maintenance medication, a pill that you take every single day, there are some different considerations than standard chemotherapy where there is a definitive start and finish. So, for many patients, they are interested in taking a pill everyday and are willing to deal with any side effects that might come up. But other patients are not. And so there’s a lot of counseling and sort of talking about what matters most to the patient that goes on in clinic.

In terms of things on the horizon; I think what we’re learning more and more and trying to understand better is how to again, extend the time between responses to chemotherapy and disease progression. And so the way that we’re really starting to look at that is combination therapy. So, can we combine PARP inhibitors with chemotherapy or can we combine PARP inhibitors with other forms of treatment like immunotherapy to better deepen the responses that we see in patients with these diseases.

Host:  Do you have any final thoughts for referring physicians?

Dr. Murphy:  I think what I’d like other people to know, referring physicians is that here at UF Health Shands Hospital, we have a phenomenal multidisciplinary team whose primary goal is to help care for women with gynecologic cancers like ovarian cancer. So, I work in concert with my surgical colleagues, my radiation colleagues and my other colleagues in medical oncology. So, the other aspect of that is that we also have several ongoing clinical trials looking at novel ways to treat women with gynecologic cancers to include ovarian cancer and so that’s another really important part of receiving care at UF Health Shands Hospital.

Host:  Well thank you so much Dr. Murphy for sharing you expertise and telling us what’s going on in the world of ovarian cancer. Absolutely fascinating. Thank you again. And this concludes today’s episode of UF Health MedEd Cast with UF Health Shands Hospital. To learn more about this and other healthcare topics at UF Health Shands Hospital please visit www.ufhealth.org/medmatters to get connected with one of our providers. Please remember to subscribe, rate and review this podcast and all the other Uf Health Shands Hospital podcasts. I’m Melanie Cole.