Dennis J. Slamon, MD, PhD
Although PARP inhibitors were intended to treat patients who harbor germline BRCA
mutations, Dennis J. Slamon, MD, PhD, explained that the future of PARP inhibition is likely to lie in combination and at full dose.
Niraparib (Zejula), for example, has shown efficacy in patients with platinum-resistant/refractory ovarian cancer when in combination with pembrolizumab (Keytruda). Data from the recurrent ovarian cancer cohort of the phase I/II TOPACIO/KEYNOTE-162 trial showed an objective response rate of 25% and disease control rate of 67% in the 60 evaluable patients.
However, there is still work that remains, said Slamon.
“PARP inhibitors will lead the way, but [the landscape] is by no means restricted to PARP inhibition,” he said.
In an interview at the 2018 OncLive®
State of the Science Summit™ on Ovarian Cancer, Slamon, director of Clinical/Translational Research, Revlon/University of California, Los Angeles (UCLA) Women's Cancer Research Program, Jonsson Comprehensive Cancer Center, discussed new opportunities for treatment advances in ovarian cancer.
OncLive: Are there new opportunities for drug discovery in ovarian cancer?
: At this meeting, we spoke about how we are using some of the preclinical and laboratory models—both in vitro and in vivo—to try and develop new therapeutic approaches for ovarian cancer. The frustration we have is that we have not yet come up with a lot of new approaches for this disease in the last four and a half decades. We are still treating patients with therapies that were developed back then. The outcome data are not very gratifying in terms of what we are seeing in patients. We need to come up with something more effective. We are using the laboratory preclinical models to try and understand that and develop rational clinical trials based on that molecular information.
What is the next logical step in drug development?
The hottest thing right now in ovarian cancer is PARP inhibitors. PARP inhibitors were initially developed for BRCA
-positive breast cancers or ovarian cancers in patients with an inherited mutation in a critical DNA-repair pathway. Using a PARP inhibitor made the limitations of DNA repair even greater. Those patients whose tumors contained BRCA
mutations were particularly sensitive to PARP inhibitors.
We have learned that the effect of PARP inhibitors goes beyond BRCA
-positive disease. That is particularly true in ovarian cancer. Some of the published data with niraparib has shown efficacy in non–BRCA
-positive patients, with either homologous repair deficiency (HRD) or another DNA repair deficiency, as well as those who do not have [any deficiency] as best as we can measure. Now, we have to determine how to best use [PARP inhibitors]. We talked about those possibilities at this meeting.
What are some of those possibilities?
Many possibilities have been looked at in the treatment of patients with ovarian cancer. One of these possibilities is using PARP inhibitors to their fullest potential. This means using them at their full dose or near full dose. When we introduce a cytotoxic combination to the mix, it should be given at a minimal dose.
A minimal dose would be 10% to 15% of the standard dose—something that is almost unheard of. You would never administer that low of a dose with chemotherapy alone, as it would have almost no effect on the tumor. However, if you have full-dose PARP inhibition on board and you have knocked that pathway out with minimal DNA damage, you can have profound clinical impact on their tumor. You can also spare normal tissues.
How do these efforts compare in the first-line versus the relapsed/refractory setting?
All the testing so far has been done in the relapsed/refractory setting. It needs to be moved up to the frontline setting. It does not necessarily need to be moved to the initial disease setting, although it can potentially be moved there. Now, it needs to be tested in first-line recurrences as opposed to giving our best approved standard care treatments because they have not resulted in a significant increase in cures.
What will the treatment landscape look like over the next 5 to 10 years?
[The landscape] is going to change considerably. PARP inhibitors will lead the way, but [the landscape] is by no means restricted to PARP inhibition. [There will be combinations] of PARP inhibitors with cytotoxics. More importantly, there are some data beginning to come out with combinations of novel targeted therapies. This means that we may have PARP and other targeted pathways where there is a clear molecular interaction. If we knock out both pathways, we can get very important synergistic effects.
What are those targets?
Several of the targets that are being looked at have been things like ATM and ATR. CDK4/6 inhibitors look like they may be playing a role. There are some very interesting preliminary data with checkpoint inhibitors in combination with PARP. There are a lot of options that are happening out there.
Is there anything else that you would like to emphasize?
Ovarian cancer is a disease where we really need new therapeutic interventions. It is not restricted to ovarian cancer either. We are pretty far behind in endometrial cancer. Once a patient fails chemotherapy, we do not have many other effective options for those patients. We need to take these same approaches in that disease. There is going to be a lot that will begin to be put out there is the next 24 to 36 months, which will look pretty exciting.
Konstantinopoulos PA, Waggoner SE, Vidal GA, et al. TOPACIO/Keynote-162 (NCT02657889): A phase 1/2 study of niraparib + pembrolizumab in patients (pts) with advanced triple-negative breast cancer or recurrent ovarian cancer (ROC)—Results from ROC cohort. J Clin Oncol. 2018;36 (suppl; abstr 106).