Current and Emerging Therapies in Platinum Resistant Ovarian Malignancies

At the virtual 2021 Great Debates & Updates in Women’s Oncology meeting, Shannon N. Westin, MD, MPH, Department of Gynecologic Oncology and Reproductive Medicine, University of Texas MD Anderson Cancer Center, Houston, provided an overview on the current and emerging therapies for platinum-resistant ovarian malignancies.

“We watch the timelines and we see how long has it been since they [patients] completed their therapy before their reccurance occurs. If we get out a couple of months, two, three months, four, five, six months, we’re looking at platinum resistant disease,” explains Dr Westin.

She notes that treatment-free intervals, along with residual toxicity from prior therapy, the volume of disease at the time of relapse, and a serologic relapse, are all considered when looking at platinum resistance. 

Currently, several single-agent therapies have been effective, such as docetaxel and weekly paclitaxel, which remain the backbone in many of these emerging treatments. However, one treatment options Dr Westin focuses on are angiogenesis inhibitors. 

The AURELIA study observed the efficacy of bevacizumab in patients with ovarian cancer that could not receive platinum treatment. The results of this study showed that, while chemo patients had a median progression-free survival (PFS) of 3.4 months, the median PFS was 6.7 months amongst those receiving chemo plus bevacizumab (0.48 [0.38–0.60], P<0.001). 

Although bevacizumab is FDA approved and is the current standard of care, it does not work for everybody and, patients can develop resistance. Researchers have been looking at a drug called navicixizumab, an angiogenesis inhibitor with a DLL4, which targets the notch pathway - one of the mechanisms of ovarian cancer growth. As a single agent, navicixizumab has activity, but when combined with weekly paclitaxel, it achieved an overall response rate (ORR) of 64% in patients who had not received bevacizumab and 33% in those who had.

Another treatment area Dr Westin highlights is antibody-drug conjugates (ADC) by focusing on mirvetuximab soravtansine and XMT-1536. The FOWARD II trial looked at mirvetuximab in combination with bevacizumab. Patients with platinum-resistant ovarian cancer received mirvetuximab plus bevacizumab with chemotherapy, with the addition of pembrolizumab in the expansion cohort. The ORR was 47% in the overall cohort and 64% in patients with a high FRα. 

Furthermore, XMT-1536 phase 1 preliminary clinical results showed that XMT-1536 demonstrates antitumor activity in patients with platinum-resistant ovarian cancer. 10% of patients achieved complete response, the ORR was 35%, and the disease-control rate (DCR) was 80%.

Other targets of interest include tumor treating fields. These are pads that a patient sticks onto the tumor area and electric fields that exert forces on charged tubulin proteins, which disrupt the formation of the mitotic spindle. Tumor treating fields are currently FDA-approved for only certain cancers. When combined with paclitaxel, they demonstrate a median PFS of 8.9 months, a median overall survival (OS) of 90% at six months and 61% at 12 months (95% CI; range 72-97 and 37-78, respectively), and an ORR of 71%.

“Certaintly that treatment free interval is really important and is essential in guiding are therapy, but I’m hopeful that it’ll become less so as we start picking these more novel targeted therapies and picking that right target, the right treatment for the right patient based on what’s going on in their tumor,” said Dr Westin.

“I can’t wait to give this lecture in a few years when we have some more phase 3 results in this space,” she concluded..—Alexandra Graziano