Investigators Still Seeking Options Beyond PARP Inhibitors in Ovarian Cancer

Jason Harris
Published: Friday, Jan 18, 2019

Ramez N. Eskander, MD

Ramez N. Eskander, MD

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

Eskander, assistant clinical professor in the department of reproductive medicine at the University of California, San Diego School of Medicine, said there are 3 principle emerging treatment strategies for ovarian cancer: antiangiogenic therapy, PARP inhibitors, and immunotherapy. “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 germline BRCA mutations 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 with BRCA-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.


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