Penson Provides a Snapshot View of Switch Maintenance Therapy Selection in Recurrent Ovarian Cancer

Richard Penson, MD, MBBS

Switch maintenance therapy with bevacizumab (Avastin) or PARP inhibitors, such as olaparib (Lynparza), niraparib (Zejula), or rucaparib (Rubraca), has improved outcomes for patients with platinum-sensitive recurrent ovarian cancer, said Richard Penson, MD, MBBS. He added that the field is continuing to move the needle forward with novel targets like WEE1 and ATR, and with combination strategies of PARP inhibitors plus PI3K inhibitors or immunotherapy.

“With maintenance therapy, we have flipped the old concept that palliative chemotherapy compromises quality of life with no advantage to overall survival [OS]. The new antiangiogenic agent bevacizumab [and] PARP inhibitor switch maintenance therapy [represent] the standard,” Penson said. “[In the up-front setting of] platinum-sensitive recurrent ovarian cancer, we have to decide about surgery and which platinum-based combination of chemotherapy to choose. However, from the get-go, we must educate patients about the natural transition to switch maintenance therapy.”

In an interview with OncLive^®, Penson discussed how he makes treatment decisions for maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer. He is clinical director of medical gynecologic oncology at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School.

OncLive^®: Platinum-sensitivity status informs treatment selection for patients with recurrent ovarian cancer. Does it also inform maintenance therapy selection or should other factors be considered?

Penson: In ovarian cancer, most patients—about two-thirds—will have what we arbitrarily call a potentially platinum-sensitive recurrence, which means that their recurrence happens more than 6 months [after platinum-based treatment]. We treat [platinum-sensitive vs platinum-resistant] disease very differently.

It is true that because of the incorporation of some of the newer, more exciting therapies into our armamentarium, we don’t solely rely on platinum-sensitive vs platinum-resistant [status to guide treatment decisions]. We think about the genotype of the patient and the tumor. We think about the platinum-free interval as a continual variable rather than 2 distinct groups. We also think about the histology and how the patient responded to previous treatments.

For platinum-sensitive recurrent ovarian cancer, patients will go on to combination platinum-based therapy. We preferentially choose pegylated liposomal doxorubicin with carboplatin, and pretty much everybody gets it with bevacizumab based on an [Society of Gynecologic Oncology] Study Group trial that showed superior progression-free survival and OS with that combination. However, some clinicians, particularly for patients with a shorter, 6- to 12-month platinum-free interval, prefer gemcitabine/ carboplatin. That is very popular and [the regimens] are similar in lots of ways. The fabulous thing [with both is that patients] have no hair loss, little neuropathy, and good tolerability.

The question about whether we choose switch maintenance therapy with a PARP inhibitor or continue with bevacizumab is [dependent] on clinician and patient preference. The data suggest that PARP inhibitors have a greater impact compared with bevacizumab in platinum-sensitive recurrent ovarian cancer.

The OReO study [NCT03106987], which looked at the response to rechallenging, was a little disappointing in that the data were a sobering reminder that when patients had previous switch maintenance PARP inhibitor therapy, they had a 2- or 2.5-month time to progression on placebo. [Olaparib] doubled that, but it is still not very long.

The push is to try other avenues, but rechallenging with PARP inhibitors with subsequent lines of therapy is still a popular option. The OReO trial showed that, in contrast to the NOVA [NCT01847274], ARIEL3 [NCT01968213], and SOLO-1 [NCT01874353] trials, at least one-third of patients who likely had reversion mutations got no benefit from PARP inhibitors. A small group of patients, 5% to 10%, got incredibly durable benefit from rechallenge with PARP inhibitors. Currently, our molecular diagnostics are helpful. The ARIEL4 trial [NCT02855944] showed how powerful the molecular diagnostics were. However, picking out the patients who will be long-term survivors with these new therapies remains challenging.

When a patient with recurrent ovarian cancer sits in front of you requiring switch maintenance therapy, what patient- or disease-related factors do you consider that could play into treatment selection?

For patients with mucinous or clear cell cancers, we will shift them to bevacizumab as their switch maintenance therapy. In patients with stage IV disease, in whom there is a demonstrated OS benefit with up-front bevacizumab, bevacizumab becomes an essential part of the armamentarium. In certain clinical situations, such as patients who have ascites or pleural effusions, the serous effusions reflect the vascular permeability factors that drive leaky vessels and cause accumulation of serous, fluid-filled effusions in the chest or abdomen.

At the other end of the spectrum are patients who will get more benefit from a PARP inhibitor: those with great responses to chemotherapy; with high-grade serous cancers; with homologous recombination deficiency [HRD] or a highly penetrant HRD gene like BRCA; or with a RAD51 gene like PALB2.

What rationale do you use for selecting among the 3 available PARP inhibitors?

We have 3 FDA-approved PARP inhibitors for switch maintenance therapy for patients with platinum-sensitive recurrent ovarian cancer that has responded to combination platinum-based therapy. The original [PARP inhibitor] was olaparib in 2014. It was approved as therapy, but the data were [not] available at that time. The following approvals were for niraparib and rucaparib. They are all very similar [in terms of efficacy].

If we use the 200-mg dose of niraparib, the agents are similar in terms of adverse effect profile as well. We have to be careful about nausea and fatigue. Patients must be informed about the small risk of myelodysplastic syndrome and acute myeloid leukemia. These treatments impact survival and are an essential part of the armamentarium.

What unmet needs regarding patients with homologous recombination proficient (HRP) tumors need to be addressed? Do any emerging agents, combinations, or targets look promising?

When we think about maintenance therapy in the recurrent setting, the patients who have HRP tumors or those who are not likely to benefit from PARP inhibitors are the ones of the biggest need and the ones nearest to developing platinumresistant disease. That is a huge unmet need.

There is a lot of excitement about the different avenues [being explored], such as PI3K inhibitors or immunotherapy in combination with PARP inhibitors, or other approaches to attacking the DNA damage response. The more proficient a tumor is at repairing DNA damage, the harder it is to get a better outcome. If [that proficiency] is compromised, patients will respond better to chemotherapy and PARP inhibitors.

We are interested in WEE1 and ATR, as well as lots of other targets. The best cocktail is not known at the moment, and the challenge is that many of these agents have overlapping toxicities. Therefore, getting the right cocktail of therapies without excess hematologic toxicities is difficult. 

It’s true to say there are many fans of antiangiogenic agents or immunotherapeutics with PARP inhibitors. PI3K inhibitors in combination with PARP inhibitors, for example, are now in phase 3 trials. We are in exciting times, but the next generation of studies that report on these outcomes will help us define the new frontier, [allowing us] to help those who do not sufficiently [benefit from] single-agent PARP inhibitor switch maintenance therapy.

Although these advances with switch maintenance therapy options are welcome for patients with recurrent ovarian cancer, disparities in terms of access to care remain. How can clinicians begin to bridge those gaps?

Perhaps [emerging] out of the COVID-19 pandemic, something important that [is getting attention] in the United States is access to care. [For instance], a friend of mine looked at his disadvantaged minority patients and found that they got a PARP inhibitor as switch maintenance therapy only a quarter as often [as nonminority patients]. There is tragic injustice in terms of effective therapies that aren’t getting to everyone.

Raising awareness and doing educational efforts like this interview with OncLive^® [is key] to making sure people know how to identify the patients who benefit from these drugs and how to best use these drugs against this terrible disease. Getting these new and effective therapies to everyone who can benefit is just as important as driving the next scientific advance.