A new study conducted by researchers from the Dana-Farber Cancer Institute has shown it may be possible in the future to identify which patients will not benefit from a drug combination for advanced ovarian cancer. This could help investigators direct such individuals to trials where treatment might be more effective.
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Clinical trials have shown that for patients with advanced ovarian cancer, a combination of Poly-ADP Ribose Polymerase (PARP) and immune checkpoint inhibition can lead to remission. However, so far, trial investigators have not been able to predict which patients will not respond to the treatment and should seek other options.
About PARP and immune checkpoint inhibition
PARP is a protein that helps damaged cells to repair themselves. As a treatment approach to cancer, inhibiting PARP prevents it from carrying out this repair in cancer cells, which then die as a result.
Immune checkpoints are molecules found on the surface of certain immune cells that become activated or inactivated in the presence of foreign cells as part of launching an immune response against them. In some cases, cancer cells manage to use these immune checkpoints to protect themselves from attack by immune cells. However, pharmacological inhibitors of the checkpoints can stop cancer cells from being able to do this.
“Combined PARP and immune checkpoint inhibition have yielded encouraging results in ovarian cancer, but predictive biomarkers are lacking,” write study author Panagiotis Konstantinopoulos and colleagues in the journal Nature Communications.
Identifying determinants of treatment response
Now, Konstantinopoulos and team have identified two determinants of patient response to the immune-PARP combination. One factor is a specific mutational signature in ovarian cancer cells and the other is the presence of an aggressive immune response in the tumor microenvironment.
The team found that when tumors possessed either feature, patients were significantly more likely to respond to treatment, with the cancer kept under control for long periods. Patients with tumors that did not exhibit these features, however, did not benefit from the treatment.
By taking these factors into account, researchers leading trials of this combination in patients with advanced, chemotherapy-resistant ovarian cancer may select individuals who may respond to this combination of drugs."
Panagiotis Konstantinopoulos, Director of Translational Research at Dana-Farber
Although checkpoint inhibition has been a highly effective approach to many forms of cancer, it has generally failed among patients with ovarian cancer. For instance, treatment with the PD-1 checkpoint inhibitor pembrolizumab produces a positive patient response in fewer than 5% of women with tumors that do not express the PD-1 ligand (PD-L1).
Similarly, the PARP inhibitor niraparib only produces a patient response in 3% of ovarian cancer cases that are nonresponsive to platinum-based chemotherapy and do not possess either the BRCA1 or BRCA2 gene.
However, using these drugs in combination produces significantly more patient benefit. A clinical trial conducted by Konstantinopoulos and colleagues showed that a combination of pembrolizumab and niraparib either completely or partly shrank tumors in 18% of patients with cancer that had not responded to platinum-based chemotherapy.
Furthermore, in 65% of cases, ovarian cancer was held in check. Among some of the participants that responded to the therapy, it was beneficial for more than one year. These findings were particularly important because many of the participants enrolled had previously failed to respond to various different treatments.
However, although the Konstantinopoulos and team were encouraged by the results, they had no way of gauging, before treatment, which patients would respond.
The researchers say that to investigate whether this could be possible, they “performed immunogenomic profiling and highly multiplexed single-cell imaging on tumor samples from patients enrolled in a Phase I/II trial of niraparib and pembrolizumab in ovarian cancer.”
The team profiled the tumor cells’ genome to look for mutations and analyzed “exhausted” T cells within the tumors. This “exhaustion” refers to when T cells that have been primed to fight cancer fail to attack tumor cells. Checkpoint inhibition can be particularly effective when there is an abundance of exhausted T cells in tumors.
The team then investigated whether there was any correlation between the results and patients’ responses to the niraparib-pembrolizumab therapy.
Two determinants could identify patients who will not respond
The team identified two factors that determined patient response. Patients who responded to treatment had tumors that possessed a set of mutations referred to as “mutational signature 3,” which disrupts repair to damaged DNA. Patients also responded if they had tumors with a “positive immune score,” which indicates communication between cancer and immune cells.
Patients with tumors that did not possess either feature did not see any treatment benefit.
"Patients with advanced or metastatic ovarian cancer who are resistant to standard platinum-based chemotherapy agents often have few further options for treatment," says Konstantinopoulos.
"Our findings will help ensure that patients for whom a PARP inhibitor-checkpoint inhibitor combination won't be beneficial can focus on other clinical trials of treatments that may be more effective for them," he concludes.
Färkkilä A, et al. Immunogenomic profiling determines responses to combined PARP and PD-1 inhibition in ovarian cancer. Nature Communications 2020; 11:1459https://doi.org/10.1038/s41467-020-15315-8