Questions Remain for Targeted Therapy Beyond PARP Inhibition in Ovarian Cancer

Ramez N. Eskander, MD

Ramez N. Eskander, MD

Targeted therapy has effectively been established as an option for patients with ovarian cancers. However, beyond PARP inhibition in theBRCA-mutated or homologous recombination deficient population, questions remain about how to best treat these patients, Ramez N. Eskander, MD, said at the 2019 SGO Annual Winter Meeting.

There are 3 principle emerging treatment strategies for ovarian cancer: antiangiogenic therapy, PARP inhibitors, and immunotherapy, said Eskander, assistant clinical professor in the department of reproductive medicine at the University of California, San Diego School of Medicine. “I try to figure out how these treatments are going to play together,” he said. “Is one going to emerge as preferential over the others, or is there going to be a combinatorial approach that's going to involve all 3?”

Eskander said checkpoint inhibitors have demonstrated limited efficacy as single agents in ovarian cancer. However, investigators are exploring a variety of combinations in hopes of augmenting the immune response including chemotherapy plus immunotherapy, immunotherapy plus antiangiogenic therapy, immunotherapy plus PARP inhibitors, and the triplet approach of immunotherapy, PARP, and antiangiogenic agents.

“We don't have a rational idea which of these is going to win,” he said. “But we're exploring all of them in parallel.”

Data from the TOPACIO and MEDIOLA trials showed that the combination of PARP inhibitors and anti-PD¬—1 agents may not offer the answers investigators hoped for.

In the phase I/II TOPACIO study, women with platinum-resistant/refractory ovarian cancer were assigned to the combination of niraparib (Zejula) and pembrolizumab (Keytruda). Among 36 patients with platinum-resistant disease, 6 patients had partial response (PR) and 12 had stable disease.

In the phase II MEDIOLA, 32 patients with recurrent platinum-sensitive ovarian cancer with germlineBRCAmutations in second-line or later therapy were treated with olaparib (Lynparza) and durvalumab (Imfinzi). Eligible patients had no prior exposure to a PARP inhibitor or immune-oncology agent.

Overall, 23 patients responded to treatment, including 6 (19%) complete responses and 14 PRs. At 12 weeks, the disease control rate was 81%, short of the 90% target.

In a presentation made at the 2018 ESMO Congress, that combination induced 5 (15%) PRs among 35 women withBRCA-mutated recurrent ovarian cancer who received at least 3 prior therapy regimens. Thirteen patients had stable disease lasting at least 4 months.

Eskander said that the absolute numbers for ORR were lower than expected for this combination. Similarly, chemotherapy plus anti-PD—L1 therapy may not be the solution.

“Looking at combining chemotherapy plus immuno-oncology, we believe that chemotherapy itself may be immunogenic,” he added. “But there is synergy between nab-paclitaxel plus anti-PD—L1 therapy in mouse tumor models. Incorporation of a combination of cytotoxic chemotherapy plus anti-PD–L1 can increase the percentage of tumor-infiltrating lymphocytes that are CD8-positive.”

Investigators had high hopes for the phase JAVELIN 100 Ovarian trial evaluating avelumab (Bavencio) in combination with and/or following platinum-based chemotherapy in previously untreated patients with ovarian cancer. However, that study was cancelled due to futility in December 2018.

Similarly, the phase III JAVELIN Ovarian 200 trial of avelumab alone or in combination with pegylated liposomal doxorubicin (PLD) failed to provide a statistically significant improvement in overall survival or progression-free survival versus PLD alone in patients with platinum—resistant/refractory ovarian cancer, missing its primary endpoint. The ORR for the combination was 13.3% compared with 3.7% for avelumab monotherapy and 4.2% for PLD alone.

Eskander said that VEGF may be involved in reducing TILs and associated with an immunosuppressive phenotype by inhibiting T cell function and promoting regulatory T cell activity. Inhibiting VEGF may reverse these effects and improve the efficacy of immunotherapy.

He cited data from a melanoma study evaluating ipilimumab (Yervoy) plus bevacizumab (Avastin) with on-treatment biopsy showing that, compared with ipilimumab alone, the combination increased CD8 T cells within the tumor and macrophage populations.

Investigators are evaluating the combination of anti-VEGF therapy and immunotherapy in women with stage III-IV ovarian, fallopian tube, or primary peritoneal cancer with macroscopic residual disease postoperatively or who will undergo neoadjuvant therapy followed by interval surgery in the global phase III IMagyn050 (NCT03038100) trial.

Patients will be assigned to paclitaxel/carboplatin/bevacizumab with or without atezolizumab (Tecentriq). The estimated completion date is April 2020.

Investigators are also considering the combination of PARP inhibitors and immunotherapy. Eskander said the hypothesis behind the combination is that PARP inhibition results in increased DNA damage, thereby increasing the number of tumor neoantigens and creating a more antigenic environment in which to stimulate the immune microenvironment. The theory is being explored in the Javelin Ovarian 100 PARP (NCT03642132), ATHENA (NCT03522246), FIRST (NCT03602859) and ENGOT-OV41/GEICO 69-O/ANITA (NCT03598270) trials.

Eskander noted that there are 7 phase III targeted therapy trials in ovarian cancer scheduled to report results in the next 2 years.

“This is a very crowded space right now. There are multiple studies that are going on in parallel that are looking at agents including antiangiogenic agents, PARP inhibitors, as well as immune-oncology to determine whether or not we're going to be able to identify a winning combination,” he said. “I think in the next year or 2, we're going to continue to see the results of these trials emerge and hopefully we'll get a better understanding of what direction subsequent studies may go."

Reference:

Eskander RN. The role of immunotherapy in ovarian cancer. Presented at: the 2019 SGO Annual Winter Meeting; January 17-19, 2019; Lake Tahoe, CA.