Novel Therapies for Newly Diagnosed Advanced Ovarian Cancer

Bradley J. Monk, MD, FACOG, FACS:Although we combine ovarian fallopian tube and peritoneal cancer into 1 entity, I think there are better ways to partition the patients. First of all, histologic subtype. If it hasn’t occurred to you, the early-stage tumors are more commonly clear cell or endometrioid. They are more commonly associated with endometriosis. They are more commonly treated with a primary resection and staging, as compared with the stage III and IV high-grade serous or high-grade endometrioid tumors. That’s more of a bulk-reducing sort of opportunity. In fact, half of those patients actually start with chemotherapy. Then, between in the third and the fourth cycle, they have an interval debulking and get 3 more doses. That’s been the historical past. It’s really been the global paradigm for treating both early-stage and advanced-stage newly diagnosed ovarian cancer.

Then in June 2018, we added bevacizumab. Bevacizumab can be added after surgery, during the chemotherapy phase, and in maintenance. When you do that, it improves progression-free survival by 6.2 months, with a hazard ratio of 0.62. There’s this idea that maybe even in the large-volume patients, there’s a survival advantage of around 10 months.

That was really the first targeted therapy approval in the frontline treatment. Again, only advanced patients and only post surgery, although some individuals will use it before interval debulking with neoadjuvant chemotherapy—although technically that would be off-label.

Then in December 2018, just 6 months later, olaparib was approved in maintenance alone in newly diagnosed advanced patients who responded, with the restriction of having a germline or somatic mutation.

Then the provider had to choose: chemotherapy alone, chemotherapy-bevacizumab, or chemotherapy and olaparib maintenance. Then the pivot point, the fulcrum: There was a molecular signature of germline and somaticBRCA. Then fast-forward to ESMO [European Society for Medical Oncology Congress] 2019.

There were 3 papers that were presented adding niraparib in maintenance beyondBRCA, OK? Because remember, SOLO-1 was onlyBRCA. We kind of liked that—niraparib beyondBRCA, published inTheNew England Journal of Medicine. Or veliparib, a fourth PARP inhibitor, with chemotherapy and in maintenance. We liked that because there’s a bit of an opportunity with the addition of veliparib to chemotherapy. Or the third trial presented at ESMO was olaparib-bevacizumab together. This was very impactful. It created more options. Those 3 frontline trials—maintenance niraparib beyondBRCA, veliparib with chemotherapy in the maintenance setting, and the combination of olaparib and bevacizumab—will ultimately lead to some sort of FDA approval and even make it more complicated.

Because then the provider will have to decide whether to use chemotherapy alone, chemotherapy-bevacizumab, or chemotherapy-veliparib. That will be the first decision. And then after the 6 doses, if the patient is not already part of that maintenance with veliparib or bevacizumab, we’ll either do olaparib alone, niraparib alone, or the combination.

We’ll get into this. The take-home message is 2-fold. Almost all patients with advanced ovarian cancer need maintenance. Even if they have aBRCAmutation, even if they have a good surgery, and even if they respond to chemotherapy, almost all those are going to recur; and they’re going to recur at probably around 12 to 14 months. They need help, OK?

The second is, we have a molecular signature beyondBRCAnow that predicts activity, and that is thisBRCA-like genetic signature—the homologous recombination repair deficiency, or HRD. So in the patient who is HRD-positive, orBRCA, basically it’s mandatory that they get a PARP inhibitor either alone—SOLO-1—or PRIMA, niraparib; or with chemotherapy and in maintenance, veliparib; or together with bevacizumab—PAOLA-1. And again, the take-home message is: molecular testing and maintenance. We will not be doing our patients a service if we give them only chemotherapy and don’t do molecular testing.

This is the new era, again, of maintenance and personalized medicine in newly diagnosed advanced ovarian cancer.

Transcript edited for clarity.