Chemotherapy Remains Cornerstone of Recurrent Ovarian Cancer Treatment

Jason A. Konner, MD

Platinum-doublet chemotherapy remains the cornerstone of treatment for patients with platinum-sensitive recurrent ovarian cancer, just as anthracycline- and taxane-based chemotherapy are mainstays for those with platinum-resistant/recurrent disease. However, the availability of bevacizumab (Avastin) warrants careful consideration in terms of which regimen to begin with, explained Jason A. Konner, MD.

“Despite all of the excitement about some of the new targeted therapies, standard chemotherapies remain the bedrock of treatment both in the first-line, adjuvant, and recurrent settings,” said Konner. “The standards of care all wrap around these platinum doublets until platinum resistant/recurrent disease develops. Then, we talk about some nonplatinum therapies.”

Although preliminary data posited mirvetuximab soravtansine (IMGN853) as one such nonplatinum therapy, the agent failed to demonstrate a statistically significant improvement in progression-free survival (PFS) versus chemotherapy in patients with platinum-resistant/recurrent disease in the phase III FORWARD I trial.

For patients with platinum-sensitive disease, commonly used agents include liposomal doxorubicin, taxane, gemcitabine, platinum, and now bevacizumab, according to data from the phase III OCEANS and GOG0213 trials.

In OCEANS,¹ patients with platinum sensitivity who were randomized to receive gemcitabine combined with carboplatin plus bevacizumab followed by maintenance bevacizumab experienced a 54% reduction in the risk of disease progression or death versus chemotherapy plus placebo (HR, 0.46; 95% CI, 0.37-0.58; P <.0001). Further, in the GOG0213 trial,² patients with platinum sensitivity who were randomized to receive bevacizumab plus paclitaxel/carboplatin chemotherapy experienced a 39% reduction in the risk of progression or death versus chemotherapy alone (HR, 0.61; P <.0001).

Findings from the AURELIA trial³ echoed the utility of adding bevacizumab to standard chemotherapy backbones. In the phase III trial, patients with platinum-resistant/recurrent disease experienced a 62% reduction in the risk of progression or death if they received the combination of bevacizumab and investigator’s choice of chemotherapy—pegylated liposomal doxorubicin, weekly paclitaxel, or topotecan—versus chemotherapy alone (HR, 0.38; 95% CI, 0.30-0.49; P <.0001).

“Right now, it's important to recognize that there are FDA maintenance strategies that involve bevacizumab or PARP inhibitors,” said Konner. “Whenever choosing a platinum doublet, you need to keep in mind not only which platinum doublet might be best for your patient, but also what maintenance strategy you might consider for that patient.”

OncLive: What are the key takeaways from major trials in recurrent ovarian cancer?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Ovarian Cancer and Soft Tissue Sarcoma, Konner, a medical oncologist at Memorial Sloan Kettering Cancer, shed light on the current treatment landscape for patients with platinum-sensitive and platinum-resistant/recurrent ovarian cancer.Konner: First, we established the basis for the platinum doublets. We looked at the trials combining paclitaxel and gemcitabine with carboplatin, which showed superiority to carboplatin by itself. Furthermore, we looked at the head-to-head doublet of liposomal doxorubicin and carboplatin versus paclitaxel/carboplatin in the CALYPSO study.

Is there a preferred doublet?

What do you find that most patients prefer?

Once a patient develops platinum-resistant disease, what therapies are available to them?

According to the FORWARD I data, mirvetuximab soravtansine missed the primary endpoint. What does that mean for the agent?

What are the biggest unanswered questions and the steps being taken to address them?

What are some of these subsets?

What research would you like to see moving forward?

Furthermore, we reviewed the trials that established bevacizumab in conjunction with chemotherapy in the treatment of patients with platinum-sensitive recurrence, both with paclitaxel/carboplatin and with gemcitabine/carboplatin in the GOG0213 and OCEANS trials, respectively. We touched on some of the recent European data looking at carboplatin and liposomal doxorubicin in combination with bevacizumab, and the interesting results in comparison with data from the OCEANS trial. There are also the DESKTOP III and GOG0213 data as they pertain to secondary surgical cytoreduction. It really needs to be individualized to the patient. If you want to use bevacizumab, you have to do it from the start. Otherwise, if you're planning on using a PARP inhibitor for switch maintenance, then you could choose your platinum doublet independent of that based on schedule and toxicity, prior treatments, and patient preference. Then you can plan your PARP inhibitor separately. The first platinum doublet that showed a benefit was carboplatin and paclitaxel. It was definitely good news to see something better than single-agent carboplatin. However, patients had just grown their hair back. Their nerves were just recovering from frontline treatment with paclitaxel, so losing their hair again and getting more neuropathy was not desirable. Having gemcitabine as an alternative was a welcome change. In addition, the CALYPSO data, which showed that carboplatin and liposomal doxorubicin is as good as, and maybe even better than, carboplatin/paclitaxel in that setting, were very encouraging. That's one of my preferred regimens, with regard to schedule, toxicity, and efficacy. [At the State of the Science Summit^TM], we talked about two phase III trials. One is the AURELIA study, which [served as the basis for the] current FDA approval for bevacizumab in the platinum-resistant/recurrent setting. In addition, I mentioned data from the FORWARD I trial, which was recently reported and looked at a folate receptor-alpha (FR-α)—targeted antibody-drug conjugate (ADC). It's a good question. There are still some unanswered questions about the trial. It did not meet its primary endpoint of PFS advantage, but it had a high overall response rate. We do know that it's an active drug in ovarian cancer. We don't know what added value it has in addition to the treatments we already have. That question remains to be answered. The manufacturers are going to be looking at various subgroups, specifically patients with high levels of FR-α expression to see if they can identify an advantage in that group. There are many unanswered questions. Despite the advances we've made, outcomes overall leave a lot to be desired. Ideally, patients want their disease to be eradicated; that would be the holy grail. Right now, especially with the forthcoming incorporation of new agents, we have several different types of PARP inhibitors, and potentially immunotherapies, coming down the road. The identification of either molecularly defined or clinically defined patient subgroups who are going to respond best to certain treatments is an important goal as all patients are different. We have to find what is best for individuals. One thing you want to look at is the avoidance of toxicities. Even without a specific molecular definition, you want to identify the toxicities to avoid in your patient. You also have to consider who might be the best patient to receive bevacizumab or who you might expect to have possible perforation. Beyond that, we don't have good molecular definitions. Our hope was if mirvetuximab soravtansine had become available, then we would at least have a biomarker-directed ADC. Unfortunately, that did not work out. I want to focus my efforts on understanding the basic science of ovarian cancer and understanding why some patients respond to one treatment and not to another. Ultimately, looking at trials is very useful, but we're pooling groups of patients. It's the identification of biologic subtypes that's going to be the most meaningful. Right now, we lack a lot of basic science in our understanding of these various subtypes.

Additionally, I would like to see more trials for patients with recurrent disease. Right now, there is a race to the frontline setting in ovarian cancer. We see multiple drugs being tested in the first-line setting with fewer and fewer trials for recurrence. However, as we know, the vast majority of patients recur and those patients need options.

References

1. Aghajanian C, Blank SV, Goff BA, et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J Clin Oncol. 2012;30(17):2039-2045. doi: 10.1200/ JCO.2012.42.0505.
2. Coleman RL, Brady MF, Herzog TJ, et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): a multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2017;18(6):779-791. doi: 10.1016/S1470-2045(17)30279-30286.
3. Pujade-Lauraine E, Hilpert F, Weber B, et al; AURELIA Investigators. AURELIA: a randomized phase III trial evaluating bevacizumab (BEV) plus chemotherapy (CT) for platinum (PT)-resistant recurrent ovarian cancer (OC). J Clin Oncol. 2012;30(suppl 18; abstr LBA5002). doi: 10.1200/jco.2012.30.18_suppl.lba5002.