Homologous Recombination Deficiency and PARP Inhibition in Ovarian Cancer

Gordon Mills, MD, PhD

As part of our coverage of the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago, we are speaking with Gordon Mills, MD, PhD, chair of the department of systems biology and professor of medicine and immunology at the University of Texas MD Anderson Cancer Center in Houston, about ways to incorporate homologous recombination markers into clinical practice for ovarian cancer.

-Interviewed by Anna Azvolinsky

Cancer Network: First, what is the link between ovarian cancer and homologous recombination deficiency? Do most ovarian tumors harbor this defect?

Dr. Mills: I think it’s important to remember that when we talk about ovarian cancer, we frequently focus on high-grade serous ovarian cancer, the most common and most lethal type of ovarian cancer. Homologous recombination deficiency is actually very common in high-grade serous ovarian cancer. If you look at the most clear indication of homologous recombination deficiency-loss of BRCA1 or BRCA2 cancer genes, either in the inherited germline or the tumor itself-that number is close to 25% of ovarian cancers. If, however, you look at the pathway more broadly and look at any defects in enzyme involved in homologous recombination, those numbers increase the percentage to somewhere between 50% and 70%. Indeed, at least in part, the abnormalities in homologous recombination deficiency have contributed to the very outstanding responses to platinum therapy and very striking new data with PARP (poly [ADP-ribose] polymerase) inhibitors.

Cancer Network: What are the ways to test for this deficiency of homologous recombination in patients with ovarian cancer? Is this something that is now readily done in the clinical setting?

Dr. Mills: There are a number of approaches to test for homologous recombination deficiency. I think the one that is done most commonly right now is testing for the breast cancer genes, BRCA1 and BRCA2. These tests are quite widely available either from commercial resources or within hospitals. Testing for additional genes in the pathway and in a number of pathways is done through a number of commercial resources; the only other clinically relevant test is the homologous recombination defect assay, which is commercially available from Myriad Genetics. [Dr. Mills has disclosed that he holds part of the technology associated with that particular assay and patent.]

In terms of the use of PARP inhibitors, the first two PARP inhibitors that were approved required testing for BRCA1/2 deficiency as a co-clinical test from the US Food and Drug Administration (FDA) for approval. However, the most recent approval of niraparib came through without any restrictions in terms of having additional tests done to indicate that there may sensitivity. This was due to an observation that there were strong responses in patients with BRCA1/2 abnormalities, responses that were intermediate in patients with the homologous recombination defect assay. But, even the patients without either of those abnormalities had a modest improvement in progression-free survival with PARP inhibitors. The FDA decided in this case that the benefit was sufficient to warrant approval of the drug without requiring any additional biomarker testing. This is controversial, since the amount of benefit in those patients without either abnormalities in the pathway or in the homologous recombination defect assay are really quite modest, and whether this warrants the toxicity of the PARP inhibitors in these circumstances will require additional study.

Cancer Network: You mentioned the clinical utility of testing for homologous recombination deficiency. What else do we know about understanding how homologous recombination deficiency as a marker can guide clinical practice? Are these markers prognostic and do they tell clinicians about potential eligibility of other types of therapies, including those under development?

Dr. Mills: Patients that have defects in homologous recombination-and the data are clearest with BRCA1 and BRCA2 abnormalities-do have an improved prognosis. However, that improvement in prognosis is not sufficient to warrant changing management for those individuals. I think that the exciting opportunity here is to go beyond using PARP inhibitors alone in patients in a recurrent or maintenance setting and to move those upfront to where they may have more activity. That will require a completely new set of clinical trials, and it’s my expectation that the benefit is going to be most marked in those individuals with clear evidence of homologous recombination deficiency.

The PARP inhibitors that we use, although they have a very high response rate, the vast majority of patients will still recur. We need to add something to the active drug, the PARP inhibitors, a rational combination to identify ways to give patients a greater benefit. Whether that will be restricted to patients with a homologous recombination deficiency or all ovarian cancer patients is probably going to depend on the particular combination. In either case, it will be very important both upfront and as we look at combination therapies, to determine which patients optimally benefit and if they are the patients with defects in homologous recombination who should be tested for genetic changes with the functional homologous recombination defect assay that I mentioned earlier. Also, a number of new homologous recombination defect assays have been recently released, including one from the Sanger Institute called HR Detect that may be even more effective in identifying patients with abnormalities in homologous recombination.

Cancer Network: What are the important questions that still need to be addressed? Are there gaps in our knowledge on what we know and how we define homologous recombination deficiency? Are there other genes that we have not identified yet, or is there anything else that still needs to be addressed or studied further in regard to this biomarker?

Dr. Mills: I think that there is an enormous amount that we need to understand. Although the response rate to PARP inhibitors is really quite remarkable, particularly in those with defects in homologous recombination, it is clear that the majority of these patients will still recur. We need to understand the mechanisms of resistance to PARP inhibitors to potentially identify patients who are going to recur quickly and who will not benefit significantly from them. But even more important is to understand the mechanisms sufficiently enough to be able to come up with rational combination therapies to increase both the frequency of benefit and the duration of benefit from PARP inhibitors. We have this wonderful first step for a drug that is highly effective in a significant population of patients, and we now need to convert that step into prolonged responses. Hopefully that will approximate cures or will greatly extend the survival of ovarian cancer patients.

Cancer Network: Thank you so much for joining us today, Dr. Mills.

Dr. Mills: Thank you. I am pleased to talk to you and I hope that this will help both my colleagues and patients. I think it is important to emphasize that the activity of PARP inhibitors in high-grade serous ovarian cancer is one of the most exciting events that has happened in this disease over the more than 30 years that I have been working in this setting.