Frontline Maintenance Requires Careful Consideration in Advanced Ovarian Cancer

Alexander Babatunde Olawaiye, MD

Homologous recombination deficiency (HRD), symptomatic ascites, and heavy disease burden are 3 telltale signs that a patient with advanced ovarian cancer stands to benefit from frontline maintenance therapy, explained Alexander Babatunde Olawaiye, MD. However, he cautioned that not all patients need or want maintenance therapy, necessitating a careful discussion about the risks and benefits of each treatment option.

“Before we put anyone on maintenance therapy, the risks, toxicity, and cost should be weighed very carefully and balanced against the potential benefits that the patient is going to gain from that treatment. If the risk and benefit ratio is heavily [unbalanced], it might be appropriate not to offer such therapy in some patients,” Olawaiye said.

In an interview with OncLive^® during the SGO 2022 Winter Meeting, Olawaiye, director of the Gynecologic Oncology Research Program and an assistant professor of Gynecologic Oncology at the University of Pittsburgh and Magee-Womens Hospital of the University of Pittsburgh Medical Center (UPMC) Hillman Cancer Center, discussed factors that influence optimized frontline maintenance therapy in advanced ovarian cancer.

OncLive®: What was the focus of the debate you participated in during the SGO 2022 Winter Meeting with Angeles Alvarez-Secord, MD, of Duke Health, and Kathleen Moore, MD, of OU Health?

Olawaiye: The debate was about frontline maintenance therapy options for patients with HRD and homologous recombination proficiency [HRP]. I argued in favor of bevacizumab [Avastin], one of my colleagues argued in favor of PARP inhibitors, and my other colleague argued in favor of observation in patients with HRP.

What makes bevacizumab an optimal maintenance therapy for all-comers? What other options are available, and what factors do you consider when making treatment recommendations?

I argued that bevacizumab is an optimal frontline maintenance therapy for all-comers whether patients have HRD or HRP. The reason for that is that the benefit of the therapy no matter how you look at it, whether you look at the progression-free survival or the HR of someone who is treated with bevacizumab maintenance vs someone who is not, the benefit is similar. For the HRP group, that benefit appears to be better than what patients in that category get from PARP inhibitors. In the HRD group, multiple trials have demonstrated significant benefit with PARP inhibitors. Therefore, it makes sense that it should be a standard to treat those patients with PARP inhibitors because of the magnitude of benefit that was seen in all the trials in that group.

When you have more than one choice, this type of discussion is always going to come up. In my opinion, it’s a very good problem to have. We have now at least 2 choices in that category.

Patients can either be treated with niraparib [Zejula] monotherapy if they have HRD or they can be treated with the combination of bevacizumab and olaparib [Lynparza]. If you look across the [pivotal] trials, there are some subtle variations in the characteristics of the patients, but the benefit that was gained by those patients in both trials was very similar.

[The decision of which regimen to choose] boils down to dose, convenience, adverse effect profile, and [other] individualistic considerations vs just giving everybody a blanket treatment. When you have choices, you have to factor everything that can be important to the patient into your choice.

In what situations does it make the most sense to use bevacizumab as maintenance therapy?

We have an unmet need in the HRP group. If you are going to treat those patients with maintenance therapy in the up-front setting, the one maintenance strategy that makes sense is bevacizumab. That being said, the benefit gained by bevacizumab maintenance in the up-front setting of ovarian cancer is modest, at best. My approach is such that either you are going to observe them or give them bevacizumab maintenance. There are patients where part of their treatment strategy from the beginning of therapy makes the bevacizumab addition very important. For instance, in patients with symptomatic ascites at presentation and patients with very heavy disease burden, if you include bevacizumab as part of their treatment, even when they are on chemotherapy, it makes a lot of sense to continue bevacizumab maintenance.

When would you think twice about recommending any maintenance therapy?

In patients where you did not include bevacizumab as part of up-front or adjuvant therapy, if they have HRP, as Dr Angeles-Secord argued, observation is still an option. If we choose to observe patients in those type of scenarios, we’re not shortchanging the patient because there is a cost, and I don’t mean monetary. There’s a cost in time, cost in toxicity, cost in anxiety level, and cost in disruption of lifestyle to being treated. In the GOG-218 study [NCT00262847], after completing chemotherapy, which included bevacizumab, patients were given about 11 to 12 additional treatments of bevacizumab. That is in total about 15 months of going to the hospital every 3 to 4 weeks to get treated. All these costs should weigh into the considerations that you use to counsel the patient about therapy.

What ongoing research are you most looking forward to seeing the results of?

ATHENA [NCT03522246] is another up-front trial in ovarian cancer. ATHENA is combining nivolumab [Opdivo] with rucaparib [Rubraca] in the up-front maintenance treatment of ovarian cancer in one of the study arms. We have seen what olaparib achieved for patients with [somatic and germline] BRCA mutations, and what olaparib achieved was excellent. We have seen what niraparib did for patients with HRD and the same thing with the combination of bevacizumab and olaparib in patients with HRD. All these categories of patients that were treated in SOLO-1 [NCT01844986], PRIMA [NCT02655016], and PAOLA-1 [NCT02477644] experienced benefits with the investigational regimen.

Now the combination of nivolumab and rucaparib is going to be a newcomer to the field, introducing immunotherapy as part of the frontline maintenance management of ovarian cancer. Now, I will say that very carefully, because it’s not the first time that we have done a study that includes an immune agent in frontline treatment or maintenance, but this is the first trial that has looked at a combination of a PARP inhibitor with immunotherapy. That alone is exciting because there may be a new era in frontline maintenance therapy if it shows something that is better than what we have seen with current strategies. Other studies of immunotherapy and a PARP inhibitor in the frontline setting are going to read out soon, but I believe the first of these treatment strategies we’re going to see the results of is most likely going to be ATHENA.

What would like to emphasize to your colleagues regarding the use of maintenance therapy in ovarian cancer?

Ovarian cancer maintenance therapy is necessitated because of how advanced ovarian cancer tends to behave, ie. the prognosis, which is not very good. All these attempts that we’re making with maintenance therapy is to prolong the lives of women diagnosed with this disease. For many years, we [evaluated] so many maintenance therapies; all of them were negative. Since 2014, we now have at least 4 strategies for maintenance. In fact, we have more than 4 because there was another study called VELIA [NCT02470585] that looked at veliparib in combination with chemotherapy followed by veliparib monotherapy as maintenance, which was positive. That drug has been brought to market though. The success that has been achieved in developing maintenance strategies in ovarian cancer since 2014 until now is commendable.

However, there is a cost to treatment, and I don’t mean financial cost alone, although there is financial toxicity as well. There is a burden that a patient bears by getting treated, and there is a certain level of relief and enjoyment that comes without being treated. Individualization is always going to be key in treating patients with cancer. In all the concentrations, individualization will continue to be relevant, but we must consult the patients regarding weighing the risks against the benefits and be diligent in making sure that patients understand what they’re getting themselves into before they embark on [a long treatment course].