Ovarian Cancer Research Pivots Toward Combination Therapies

Despite success with other cancers, immunotherapy alone has not shown much success in treating ovarian cancer, so researchers are now testing combinations of immunotherapy drugs — such as PD1 and PDL-1 inhibitors – with other agents to see if it enhances effectiveness.

“Ovarian cancer is a highly unmet medical need. Most cases are diagnosed in advanced stages, and most cases recur,” Bradley J. Monk, MD, professor and director of the Division of Gynecologic Oncology at Creighton University at St. Joseph’s Hospital and Medical Center in Phoenix, told OncLive, a sister publication of Oncology Nursing News. “We need agents such as immuno-oncology agents to help patients live better and longer.”

Aside from microsatellite instability-high (MSI-H) or mismatch-repair deficient endometrial cancers, there are currently no FDA-approved immunotherapy agents in this space. Previous studies have evaluated a variety of monotherapies for this patient population — including nivolumab (Opdivo), pembrolizumab (Keytruda), avelumab (Bavencio), durvalumab (Imfinzi) and atezolizumab (Tecentriq) – however, they induced insignificant clinical outcomes.

“I am sorry to say that the single-agent activity of these PD-1/PD-L1 molecules is only between 10 to 15 percent,” Monk said. “Therefore, we are now studying combinations.”

There are 5 phase III clinical trials that are testing combination regimens that include at least one checkpoint blockade drug. Of the 5 trials, 2 are investigating combination regimens that include avelumab and three are looking into atezolizumab.

“The idea is to enhance the activity of these checkpoint inhibitors — converting what we call cold tumors to hot tumors, and there are two strategies,” said Monk. “The first is to add immunogenic chemotherapy and an anthracycline, such as pegylated liposomal doxorubicin, or carboplatin/paclitaxel. The other strategy is adding a PARP inhibitor.”

The JAVELIN Ovarian 200 trial, which has enrolled 550 patients with platinum-resistant, recurrent ovarian cancer, will be the first randomized trial to have its results reported. This study is investigating outcomes in patients treated with avelumab alone compared with avelumab plus pegylated liposomal doxorubicin and with pegylated liposomal doxorubicin alone.

In the JAVELIN Ovarian 100 trial, 950 patients with untreated, epithelial ovarian cancer are expected to enroll. Patients will be randomized to receive either avelumab plus carboplatin and paclitaxel or chemotherapy alone in the frontline setting.

The other three trials will be looking into triplet combinations using chemotherapy, bevacizumab — an anti-VEGF therapy – and atezolizumab.

“It’s a very exciting time, and very ambitious,” Monk said.

For now, there are no safety contradictions that researchers are concerned about, though investigation is still in the early stages. More research is needed not only to figure out the potential safety and adverse effect profile, but also the best ways, in general, to use immunotherapy agents in ovarian cancer treatment.

“It is exciting, but it will only be personally satisfying if we can bring these medicines to patients and prove that they are both efficacious and safe,” Monk said.