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

Richard Penson, MD, MBBS, explains how he makes treatment decisions for maintenance therapy in patients with platinum-sensitive recurrent ovarian cancer.

Changing maintenance treatment to bevacizumab (Avastin) or PARP inhibitors, such as olaparib (Lynparza), niraparib (Zejula), or rucaparib (Rubraca), improved outcomes for patients with Platinum-sensitive recurrent ovarian cancer, said Richard Penson, MD, MBBS, who added that the field continues to advance the needle with new targets such as WEE1 and Akt, or combination inhibitor strategies PARP and PI3K inhibitors or immunotherapy.

“With maintenance treatment, we have reversed the old concept that palliative chemotherapy compromises quality of life without any benefit for overall survival. [OS]. New antiangiogenic agent bevacizumab or PARP inhibitor maintenance therapy replaces maintenance therapy [represent] the norm, ”Penson said. “[In the up-front setting of] Recurrent platinum sensitive ovarian cancer, we have to decide on the surgery and which combination of platinum-based chemotherapy to choose. However, from the start, we need to educate patients about the natural transition to switching to maintenance therapy. “

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

OncLive®: Platinum sensitivity status informs treatment choice for patients with recurrent ovarian cancer. Does it also inform the choice of maintenance therapy or are there other factors to consider?

Penson: In ovarian cancer, most patients – about two-thirds – will have what we arbitrarily call a potentially platinum-sensitive recurrence, which means their recurrence occurs over 6 months. [after platinum-based treatment]. we treat [platinum-sensitive vs platinum-resistance] disease very differently.

It’s true that due to the incorporation of some of the newest and most exciting therapies into our arsenal, we don’t just rely on platinum sensitivity over platinum resistance. [status to guide treatment decisions]. We are thinking about the genotype of the patient and the tumor. We consider the platinum-free interval as a continuous variable rather than as 2 distinct groups. We also think about the histology and how the patient has responded to previous treatments.

For recurrent platinum-sensitive ovarian cancer, patients will undergo combination therapy with platinum. We prefer pegylated liposomal doxorubicin with carboplatin and virtually everyone gets it with bevacizumab based on a trial from the AGO study group which showed superior progression-free survival and overall survival with this combination. However, some clinicians, especially for patients with a shorter platinum-free interval of 6 to 12 months, prefer gemcitabine / carboplatin. It is very popular and [the regimens] are similar in many ways. The fabulous thing [with both is that patients] have no hair loss, little neuropathy and good tolerance.

The question of whether we should switch from maintenance therapy to a PARP inhibitor or continue with bevacizumab is [dependent] on clinician and patient preferences. Data suggests that PARP inhibitors have a greater impact than bevacizumab in relapsing platinum-sensitive ovarian cancer.

The OReO study [NCT03106987], which looked at re-exposure with response, was a bit disappointing in that the data was a baffling reminder that when patients had previously received PARP inhibitor maintenance therapy, they had a delay of 2 or 2.5 months to progress under placebo. [Olaparib] doubled, but it is not yet very long.

The push is to try other avenues, but questioning PARP inhibitors with subsequent lines of therapy is still a popular option. The OReO test showed that, unlike the NOVA test [NCT01847274], ARIEL3 [NCT01968213], and SOLO-1 [NCT01874353] trials, at least a third of patients with likely reverse mutations did not gain any benefit from PARP inhibitors. There was a small group of 5-10% of patients who experienced an incredibly long-lasting benefit from the re-injection of PARP inhibitors.

Currently, our molecular diagnostics are useful. The ARIEL4 test [NCT02855944] showed just how powerful molecular diagnostics are. However, choosing which patients to survive in the long term with these new therapies remains a challenge.

When a patient with recurrent ovarian cancer is in front of you and needs maintenance replacement therapy, what factors related to the patient or disease do you envision that might play a role in the choice of treatment?

Imagine a patient in front of us, and we are going to polarize to the extreme. For patients with mucinous or clear cell cancers, we will be switching them to bevacizumab as maintenance replacement therapy. In patients with stage IV disease where there is a demonstrated benefit for OS with upstream bevacizumab, this agent becomes an essential part of the therapeutic arsenal. There are certain clinical situations, such as patients with ascites or pleural effusions, in which the serous effusions reflect the vascular permeability factors that cause vessels to leak and cause a buildup of fluid-filled serous effusions in the chest or the abdomen.

At the other extreme, patients with good responses to chemotherapy, high-grade serous cancers, or patients with deficient homologous recombination [HRD] or a highly penetrating HRD gene such as BRCA or the RAD51 gene like PALB2 are the ones who will benefit the most from a PARP inhibitor.

Do you have a reason to choose between the 3 PARP inhibitors available?

We have 3 PARP inhibitors approved by the FDA for maintenance switching therapy for patients with platinum-sensitive relapsing ovarian cancer who have responded to combined platinum therapy. The original [PARP inhibitor] was olaparib in 2014. It was approved for therapy, but data was available at that time. [That approval was] niraparib monitoring, [which was followed by] rucaparibe. They are all very similar [in terms of efficacy].

If we use the 200 mg dose of niraparib, the agents are also similar in terms of side effect profile. Be careful with nausea and fatigue. Patients should be informed of the low risk of myelodysplastic syndrome and acute myeloid leukemia. These treatments have an impact on survival and are an essential part of the arsenal.

What unmet needs for patients with competent homologous recombination [HRP] tumors need to be treated and are there any emerging agents, combinations or targets that you find particularly promising?

When we think of maintenance therapy for a relapse, patients who have HRP tumors or those who are not likely to benefit from PARP inhibitors are the ones who need it most and who are closest to them. develop a disease resistant to platinum. It is a huge unmet need.

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

We are interested in WEE1 and ATR, as well as many other targets. The best cocktail isn’t known yet, and the challenge is that many of these agents have overlapping toxicities. Therefore, it is difficult to get the right cocktail of therapies without excessive hematological toxicities.

It is true to remain that there are many amateurs of anti-angiogenic or immunotherapeutic agents with PARP inhibitors. PI3K inhibitors, for example, in combination with PARP inhibitors are now in Phase 3 trials. We live in exciting times, but the next generation of studies reporting these findings will help us define the new frontier. to help those who are not sufficiently helped by maintenance treatment with a PARP inhibitor monotherapy.

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

One important element that, perhaps due to the COVID-19 pandemic, has been highlighted in the United States is access to care. A friend of mine looked at his disadvantaged minority patients and found that they received a PARP inhibitor as maintenance replacement therapy only a quarter more often [as non-minority patients]. There is a tragic injustice in terms of effective therapies that do not benefit everyone.

Raise awareness and make educational efforts like this interview with OncLive® [is key] to make sure people know how to identify the patients who benefit from it and how to best use the drugs for this terrible disease. Providing these new and effective therapies to all who can benefit from them is just as important as fostering the next scientific breakthrough.

Martin E. Berry