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Richard Penson, MD, MBBS, discusses how he makes treatment decisions for maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.
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, who added that the field is continuing to move the needle forward with novel targets like WEE1 and Akt, or 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 or 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, clinical director of Medical Gynecologic Oncology at Massachusetts General Hospital and an associate professor of medicine at Harvard Medical School, discussed how he makes treatment decisions for maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.
Penson: In ovarian cancer, most patients—about two-thirds—are going to 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-resistance] 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 are going to 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 AGO Study Group trial that showed superior progression-free survival and overall survival 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 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 rechallenging with response, 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 likely had reverse mutations got no benefit from PARP inhibitors. There was a small group of 5% to 10% of patients who 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 are going to be long-term survivors with these new therapies remains challenging.
Let’s imagine a patient in front of us, and we are going to polarize to extremes. For patients with mucinous or clear cell cancers, we are going to shift them to bevacizumab as their switch maintenance therapy. Patients with stage IV disease where there is a demonstrated OS benefit with up-front bevacizumab, that agent becomes an essential part of the armamentarium. There are certain clinical situations, such as patients who have ascites or pleural effusions, in which 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.
In the other extreme, patients with great responses to chemotherapy, high-grade serous cancers, or patients with homologous recombination deficiency [HRD] or a highly penetrant HRD gene like BRCA or RAD51 gene like PALB2 are the ones who will get more benefit from a PARP inhibitor.
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 available at that time. [That approval was] followed by niraparib, [which was followed by] 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.
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 platinum-resistant 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 stay there are many fans of antiangiogenic agents or immunotherapeutics with PARP inhibitors. PI3K inhibitors, for example, in combination with PARP inhibitors are now in phase 3 trials. We are in exciting times, but the next generation of studies that report on these outcomes are going to help us define the new frontier of helping those who are not sufficiently helped by single-agent PARP inhibitor switch maintenance therapy.
Something important that, perhaps out of the COVID-19 pandemic, has been emphasized in the United States is access to care. 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 non-minority 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 and how to best use the 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.