Promising PARP Inhibitor Strategies Emerging in Platinum-Sensitive Ovarian Cancer

Richard T. Penson, MD, MRCP, associate professor, Harvard Medical School, and clinical director, Medical Gynecologic Oncology, Massachusetts General Hospital

Richard T. Penson, MD, MRCP

Incorporating switch maintenance therapy with PARP inhibitors earlier in the treatment of patients with platinum-sensitive ovarian cancer may control the disease for longer periods of time. This may be a more important goal than response rate or overall survival (OS) in patients who are likely to recur, according to Richard T. Penson, MD, MRCP.

“The earlier PARP inhibitors are given, the more effective they are,” said Penson, associate professor, Harvard Medical School, and clinical director, Medical Gynecologic Oncology, Massachusetts General Hospital. “Switch maintenance is really impressive. Patients think it's a devastatingly emotionally traumatic event to have recurrence of disease. About 60% to 80% of patients are going to get a great response to chemotherapy, but it's so short-lived at about 5.5 months. When you carry a BRCA mutation, you have progression of disease. With a PARP inhibitor, [this delay in recurrence] can extend to 18 months or maybe 2 years.”

Additional strategies continue to be explored with this class of agents, such as in combination with immunotherapies and antiangiogenic inhibitors, he explained.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer, Penson discussed novel strategies with PARP inhibitors and the use of biomarkers to create more personalized treatments for patients with platinum-sensitive ovarian cancer.

OncLive^®: How would you define the emerging role of PARP inhibitors in the management of ovarian cancer?

Penson: A new class, PARP inhibitors, was approved in 2014 and really has changed the standard of care. We went for 8 years without a drug approved in ovarian cancer. There's been an explosion of agents: olaparib, bevacizumab (Avastin), niraparib (Zejula), rucaparib (Rubraca), and then pembrolizumab (Keytruda) [for microsatellite instability—high tumors]. It's an exciting time. There have been trials that define switch maintenance therapy in platinum-sensitive disease. Then, the SOLO-2, NOVA, ARIEL3, and SOLO-3 studies show how effective these agents are as single agents.

How are PARP inhibitors best used?

In terms of how the PARP inhibitors are used, there really was a huge change from what was called Study 19, where olaparib was compared with placebo [in the maintenance setting]. In patients who harbor a BRCA mutation, they are super sensitive to [PARP inhibitors]. The strategy of using switch maintenance therapy really brought the best out of the agents. The earlier we used these agents, the better. SOLO-1 demonstrated a massive advantage, so instead of a 1-year [impressive] PFS rate, it was a 3-year PFS [rate]. If you bring a PARP inhibitor upfront, there is this hope that it may impact cures in the future.

The SOLO-3 trial compares physician’s choice of chemotherapy against the PARP inhibitor olaparib. In patients who received 2 prior lines of therapy, there was an 85% response rate with single-agent olaparib. It's relatively highly selective in patients, but it does speak to how potent these agents are.

What factors do you consider when choosing among therapies for patients?

People often ask how to choose among the PARP inhibitors. There is a real consensus that, in terms of efficacy, they're very similar. Talazoparib (Talzenna) may have substantially more PARP trapping effects and may be a more potent agent, but we have yet to really see that. The agents that are FDA approved are all very similar in terms of efficacy. They are slightly different in terms of toxicity. However, there are other factors that dictate choice. They are all great drugs and it's a substantial clinical advantage for patients that these are now available.

Could you highlight some recent pivotal studies that have examined PARP inhibitors?

In terms of therapeutics, the SOLO-3 trial improved response with standard chemotherapy—single-agent non-platinum—based chemotherapy. These agents are better than non-platinum–based chemotherapy, but they may be best used when in combination with platinum-based chemotherapy and follow it with switch maintenance with a PARP inhibitor.

What are some prospective biomarkers that predict response to PARP inhibitors?

People often forget that one-third of BRCA mutations are somatic. They are quiet; they are not inherited. We're increasingly getting tissue tests and not just germline testing in the blood or saliva.

About half of high-grade serious endometrioid tumors harbor homologous recombination deficiency (HRD); [that is important] to look at.

Lastly, we're looking at a new generation of assays that will pick out how to best integrate combinations of therapy. The truth is maybe 20% to 30% of patients who harbor a BRCA mutation will get a reversal mutation in the time of their [disease course]—one [mutation] that happens to turn off the potential for benefit. Those assays have yet to come but are going to be very important.

What research efforts are exploring emerging biomarkers?

The reality is that you need a combination of assays to really get a [result for] HRD; there are 2 FDA-approved companion diagnostics, but no one is very confident about the thresholds for when [results] are positive; nor have we found the best test yet. In terms of those academic studies on how to put cocktails of drugs together, we're still exploring the best predicted markers.

What does eligibility criteria for PARP inhibitors look like?

Traditionally, we have used platinum-sensitivity as a single patient population. Two-thirds of patients are going to have recurrent disease more than 6 months after completing their first-line therapy and they arbitrarily called platinum-sensitive. Now we are looking at the histology, the genetic markers, and the treatment-free interval in the clinical aspects of how people are expected to [respond]. Patients with clear cell or mucinous tumors are more likely to get benefit from bevacizumab than they are from a PARP inhibitor. We're using an increasing portfolio of predictive markers to choose patients.

Personally, one of the clearest things is the CA-125 test. In patients who are super sensitive [to platinum-based therapy] and get a rapid response, I'm increasingly giving fewer platinum-based treatments [for the long-term]. That means giving 4 cycles of platinum-based therapy and switching to a PARP inhibitor early, reducing toxicity, and getting on with the treatment that's going to have a bigger impact in terms of duration of control of disease than others are with giving patients chemotherapy.

Are there any promising combinations under investigation for those with platinum-sensitive disease?

There is a huge interest in the combination of cediranib and olaparib, which is putting together an antiangiogenic agent with a PARP inhibitor. Combinations of PARP inhibitors and immunotherapies have possibly been less exciting. We're now moving into triplet combinations of immunotherapy, antiangiogenic agents, and PARP inhibitors all together. What is hard is if you [are too select with] your patients, and you have very responsive BRCA-mutant population, you don’t get the 85% response rate that olaparib alone would give.

How much you increase the response rate is not necessarily the bottom line. The bottom line is how long we control the disease for. We are going to be responsive to the evolving genotype of the tumor and to the clinical needs of the patient. It's exciting, but it is a more complicated area.

Where should future research efforts focus?

It's going in two directions. Making great treatment is best for patients, but how we put the right things together to give the newly diagnosed patient the best chance of getting cured is what's on the horizon. The margin of benefit for platinum-sensitive disease, SOLO-1, and years of improvement in PFS have given us hope that we may be able to see. However, it may be impossible in the end to demonstrate an OS advantage, but more patients may be cured by upfront switch maintenance PARP inhibitor therapy.