Benefit of PARP Inhibitors May Extend to Certain Tumors With IDH Mutations
March 21, 2020 12:00am
By Rachel Narozniak, MA
Advances in checkpoint inhibitor therapy have gained speed in cancer care; however, ovarian cancer has yet to see any approved indications for immunotherapy agents, said Lana E. Kandalaft, PharmD, PhD, to an audience at the European Society for Medical Oncology 2018 Immuno-Oncology Congress.
Lana E. Kandalaft, PharmD, PhD
Advances in checkpoint inhibitor therapy have gained speed in cancer care; however, ovarian cancer has yet to see any approved indications for immunotherapy agents, said Lana E. Kandalaft, PharmD, PhD, to an audience at the European Society for Medical Oncology 2018 Immuno-Oncology Congress.1
In order to use immunotherapy in this tumor type, Kandalaft, director of the Centre of Experimental Therapeutics in the Department of Oncology at the Centre Hospitalier Universitaire Vaudois of the University of Lausanne in Switzerland, said, “We need to identify better biomarkers for predicting responses to checkpoint blockade inhibition [in ovarian cancer].”
Immunogenicity of Ovarian Tumors
The presence of T cells in ovarian tumors, said Kandalaft, is associated with better survival times, as evidenced by several studies that analyzed the connection between CD3 or CD8 lymphocytes and ovarian cancer outcomes.2One such study found that patients whose tumors contained T cells had a 5-year survival rate of 38% versus 4.5% in patients whose tumors lacked T cells.3
Adding to this, Kandalaft said that ovarian tumors can be divided into 3 immunophenotypes, but “the data that we have on checkpoint inhibition is [tumor] agnostic. No one has personalized the treatment or looked at the phenotype to give checkpoint blockade inhibition.”
The tumor phenotypes that she described are immunogenic tumors, or “hot” tumors, containing T cells, and non-immunogenic tumors. The latter can be further divided into 2 subgroups: immune-excluded tumors, where T cells do not properly home into the tumor, and immune-ignorant tumors that have no T cells at all.
To date, published overall response rates (ORRs) to immune checkpoint inhibitor monotherapies in ovarian cancer have been poor.
“If you look at the immunogenic phenotype, although it has T cells, there are also suppressors that are co-upregulated,” said Kandalaft. This means that checkpoint inhibition may need to be combined with other inhibitory or activating receptors to have the desired effect on the ovarian tumor.
Methods to Improve Response to Immunotherapy
One approach she suggests is to combine 2 checkpoint blockade inhibitors as in the phase II NRG-GY003 trial comparing nivolumab (Opdivo) monotherapy with nivolumab plus ipilimumab (Yervoy) in patients with persistent or recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. An interim analysis showed that responses were observed in 12.2% of patients in the nivolumab group and 31.4% in the combination group (P = .034),4demonstrating that combination immunotherapy with CTLA-4 and PD-1–targeted agents was superior to PD-1 monotherapy alone.
Another strategy combines intravenous interleukin-2 with adoptive cell therapy using tumor-infiltrating lymphocytes in patients with progressive platinum-resistant ovarian cancer. Of the 6 patients treated, 4 had stable disease lasting 3 months and 2 had stable disease lasting 5 months; 5 patients had a decrease in their target lesion.5
For immune-excluded tumors, Kandalaft said combining anti-VEGF therapy with immune checkpoint inhibitors may be successful in overcoming the T cells’ inability to enter the tumor. Past study results have revealed that the level of VEGF, an angiogenic and immunosup- pressive factor, was higher in tumors without T cells.3This is due to the abnormality in the endothelial cells where high levels of VEGF-A are secreted by the tumor leading to morphological changes to the tumor endothelial cells and low adhesion molecules that cannot penetrate into the tumor.
This is being investigated in the phase III randomized ATALANTE trial in which patients with relapsed, platinum-sensitive ovarian cancer are being treated with platinum-based chemotherapy plus bevacizumab (Avastin), an anti-VEGF monoclonal antibody, followed by bevacizumab plus atezolizumab (Tecentriq) or placebo maintenance. An interim safety analysis showed no safety issues at the 2018 American Society of Clinical Oncology Annual Meeting, and the trial is still recruiting at this time.6
With the immune-ignorant phenotype, Kandalaft said there is “a T-cell priming defect,” which means immunogenicity needs to be induced in order for immunotherapy to be effective. One way of achieving this involves causing immunogenic cell death with chemotherapy, radiation, or PARP inhibition.
This strategy was investigated in the phase III JAVELIN 200 study of avelumab (Bavencio) in combination with pegylated liposomal doxorubicin, which failed to meet its primary endpoints of progression-free survival (PFS) and overall survival. However, Kandalaft pointed out that study results indicated “potential clinical activity” with the chemotherapy/antiPD-L1 combination, and that will be the basis of further analysis.7
PARP inhibition may induce cell apoptosis in cells harboring defects in their homologous recombination or double-stranded DNA repair functions commonly seen in BRCA1/2-mutated tumors. The phase I/II MEDIOLA trial of durvalumab (Imfinzi) in combination with the PARP inhibitor olaparib (Lymparza) resulted in an ORR of 72% with 19% complete responses.8
Another strategy for immune-ignorant tumors involves the expansion of tumor-specific T cells. Kanadalaft referenced her own research into whole tumor antigen dendritic cell vaccines in which monocytes were collected from the tumor and differentiated into dendritic cells; the dendritic cells were then matured with lipopolysaccharide and interferon-g and injected intranodally. The vaccine induced T-cell responses to autologous tumor antigen and achieved tumor lysis in patients with platinum-treated, immunotherapy-naïve, recurrent ovarian cancer; these responses were also seen in combination with immunotherapy.9Not only was the vaccine associated with an improved PFS, but it also enhanced preexisting and induced newly detected T-cell responses against neo-epitopes.
In addition to identifying predictive biomarkers to immunotherapy, Kandalaft said clinical trial designs need to be tweaked to accelerate the integration of checkpoint inhibitors with standard-of-care therapies earlier in the treatment paradigm. Current clinical trials are testing these combinations in patients who have relapsed but not in those with a new diagnosis.
“Perhaps if we try to include checkpoint inhibition in these early stages, then we will potentially see better responses,” Kandalaft said.