Navigating Among Maintenance Options in Advanced Ovarian Cancer

Camille Gunderson, MD

As the number of available maintenance options in advanced ovarian cancer increases, selection for these approaches will become more challenging, said Camille C. Gunderson, MD. However, factors can be used to inform appropriate treatment for each patient and emerging data could provide further clarity.

Several frontline strategies can be considered for patients with advanced disease, including intraperitoneal (IP) chemotherapy, dose-dense chemotherapy, and intravenous (IV) chemotherapy. However, determining which approach is optimal for each patient has been controversial as available data appear to be mixed.

“The IP chemotherapy trend has been favored in recent years because of the three large trials that all showed progression-free survival (PFS) and overall survival (OS) benefits,” said Gunderson.

However, data from the phase III GOG-252 trial did not indicate a survival benefit with IP chemotherapy over IV chemotherapy, thus making the choice between approaches even more difficult.

Another ongoing debate has to do with deciding between primary debulking surgery and neoadjuvant chemotherapy. Although there are data to support both interventions, treatment decisions boil down to specific patient factors. For example, for those with BRCA mutations, IP chemotherapy might be optimal, as it has been shown to be effective in past research, said Gunderson.

In an interview at the OncLive^® State of the Science Summit™ on Ovarian Cancer, Gunderson, assistant professor of gynecologic oncology, Stephenson Cancer Center, University of Oklahoma, discussed the various maintenance options available in advanced ovarian cancer, as well as what factors should be considered for selecting each approach.

OncLive: What are some important areas of discussion regarding frontline maintenance in ovarian cancer?

Gunderson: My presentation focused on chemotherapy choices—how to make that selection and what you should be taking into consideration when prescribing treatment for patients with advanced-stage ovarian cancer. This includes treatment of neoadjuvant chemotherapy versus primary debulking surgery as well as adjuvant treatment strategies, such as IP chemotherapy, dose-dense chemotherapy, and conventional IV chemotherapy. Additionally, I discussed the role of bevacizumab (Avastin) after and during chemotherapy for advanced-stage ovarian cancer.

In terms of IP chemotherapy versus dose-dense versus IV chemotherapy in ovarian cancer, what data are being used to choose among these strategies?

There have been 3 large trials that have all shown PFS and OS benefit [with IP chemotherapy]. However, the GOG-252 trial is the [most recent to read out], and it really calls into question the utility of IP chemotherapy because there was no benefit seen in the experimental arm of IP chemotherapy versus the 2 other groups utilized in that study.

In a well-selected candidate, IP chemotherapy still can be helpful in comparison with IV chemotherapy, but it certainly is not for everyone. [This approach] is much more toxic [than IV chemotherapy] and is associated with worse quality of life. Patients with no gross residual disease, particularly those with somatic BRCA mutations—which have been shown to benefit more substantially with IP than IV chemotherapy—[are who] you should consider for IP chemotherapy. But for others, IV chemotherapy seems to be preferable based on the survival data that we have and the toxicities.

Neoadjuvant chemotherapy versus primary debulking is an area of debate. What are the data to support these approaches?

There are certainly data to support either approach. I believe that the biggest takeaway from the 4 randomized trials that we have to date is that there are candidates in which one strategy might be more preferable over the other, depending on the particular situation at hand—not only disease distribution, but also the patient’s comorbidities, surgical fitness, and age.

What is the role of bevacizumab in the adjuvant setting?

Bevacizumab received FDA approval in 2018 for use in combination with chemotherapy after initial surgical resection in women with stage III or IV ovarian cancer. The agent is not approved for neoadjuvant chemotherapy. [Although that] has been investigated in several clinical trials, that’s not part of the label right now.

Could you discuss the role of PARP inhibitors in the maintenance setting?

Olaparib (Lynparza) received FDA approval in December 2018 for patients with either germline or somatic BRCA mutations. [This decision was based on] the provocative data from SOLO-1, which showed a really substantial benefit in PFS and also time to first and second subsequent therapy or death. There have not been approvals for any other PARP inhibitors after frontline chemotherapy yet, although that may happen in the future.

Additionally, we have 3 trials—which will all hopefully be reported this year—of other PARP inhibitors following frontline chemotherapy, and those include the PAOLA-1, PRIMA, and GOG-3005 trials. GOG-3005 includes initial chemotherapy with veliparib followed by placebo versus initial chemotherapy with veliparib followed by veliparib maintenance, both in comparison to conventional chemotherapy with placebo followed by placebo maintenance.

Veliparib is very myelosuppressive, and chemotherapy doses must be adjusted. All PARP inhibitors are myelosuppressive, but veliparib is particularly potent with that toxicity.

Pending the readout of the PRIMA data, do you believe there will be a shift away from the use of chemotherapy and bevacizumab, given that the trial was explored beyond those with BRCA mutations?

I believe that that could very well be the case; that has been the question for a couple of years now. Do you use bevacizumab maintenance or PARP maintenance for patients with deficiency in homologous recombination deficiency (HRD) or a somatic BRCA mutation? Certainly [in those with] germline [BRCA mutations], it has been clear that PARP is the answer but now that there is said to be a benefit with PARP maintenance in all-comers, this will become an even more difficult question.

As it stands, what factors dictate whether a patient should receive bevacizumab or PARP in this setting?

It largely comes down to toxicities, because the safety profiles are very different between bevacizumab and PARP, but there seems to be benefit with both [approaches]. The PAOLA-1 trial will show us bevacizumab and placebo versus olaparib and bevacizumab, so that will be informative. However, we don't have any head-to-head comparison to tell us which one we should choose over the other.

In terms of maintenance strategies, are there certain patients who benefit from continuous maintenance versus switch maintenance?

Again, it comes down to toxicity and how much we believe the patient is benefitting from the PARP inhibitor; that [will determine] whether or not they should be switched to something else or whether it would be a good idea to continue treatment.

What are some challenges that are still faced in the field?

Cost is a huge challenge. Right now, with several different PARP inhibitors and bevacizumab all having several different approvals in the ovarian cancer space, this will be something that is increasingly regulated and will require us to make choices. Do we use bevacizumab only once during a patient's treatment course or, if they receive it in the frontline setting, are they eligible to receive it in later lines? Are there going to be more restrictions in that capacity? That is something that will become even more of an issue in the coming years.

What is your take-home message regarding PARP inhibitors as maintenance therapy in ovarian cancer?

We need to keep our eyes and ears open because we have a lot to learn in terms of selecting the best options for maintenance therapy. We've seen some really eye-opening data in recent years with benefits from PARP inhibitors, even the wild-type and the HRD-negative populations. That was pretty unexpected, so continuing to see what the completed and ongoing studies reveal would be what I recommend.