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Michael Birrer, MD, PhD, discusses the effect that PARP inhibitors have had on the treatment of ovarian cancer, and the potential for combinations with these agents.
Michael Birrer, MD, PhD
The explosion of PARP inhibitors in ovarian cancer has provided new and exciting options for the treatment of patients, explains Michael Birrer, MD, PhD.
Investigators are now looking to combine PARP inhibitors with immunotherapy agents, antiangiogenesis agents, and targeted agents. For example, a phase II study is evaluating the combination of niraparib (Zejula) and bevacizumab (Avastin) in the maitnenace setting for patients with advanced ovarian cancer following response on frontline platinum-based chemotherapy (NCT03326193).
Additionally, results from the phase II MEDIOLA trial presented at the 2018 Society of Gynecologic Oncology Annual Meeting showed that combination therapy with the PARP inhibitor olaparib (Lynparza) and the PD-L1 inhibitor durvalumab (Imfinzi) induced objective responses in more than 70% of patients with relapsed, platinum-sensitive, BRCA-mutated ovarian cancer.
In an interview with OncLive®, Birrer, director, the University of Alabama at Birmingham Comprehensive Cancer Center, discussed the effect that PARP inhibitors have had on the treatment of ovarian cancer, and the potential for combinations with these agents.Birrer: This is a new class of drugs, which most of us consider to be targeted therapy. It is perhaps not as targeted as EGFR inhibitors, but it is close. These are agents that inhibit the PARP protein and are fairly specific. The PARP protein is important because it is involved in single-stranded DNA repair. If you inhibit the ability of a cell to repair single-strand breaks, they become double-strand breaks, and double-strand breaks are lethal unless repaired. Double-strand breaks are repaired by BRCA1/2. This is a great example of what is called synthetic lethality; it is very specific for cells that have homologous recombination deficiency (HRD), such as ovarian cancer, and it should not affect many other cells in the body. It is a very selective therapeutic approach.
Another benefit is that these are oral, so it makes it easy for patients. Also, PARP inhibitors focus on tumor cells and HRD. We have biomarkers such as sequencing BRCA1/2, panel sequencing, or HRD assays, which can pretty much identify the patients who will benefit the most.
PARP inhibitors have all the aspects of modern oncology—they are a form of targeted therapy, are associated with good biomarkers, have a great toxicity profile, and they come as a pill. There is a lot of level 1 evidence to tell us which patients will benefit the most. Level 1 means that it has been seen in randomized clinical trials. We now know that patients who benefit the most are patients who have either germline or somatic BRCA1/2 mutations. However, patients who have mutations in other genes within the Fanconi anemia pathway, possibly patients who have alterations of BRCA1/2—not through mutation but through methylation or downregulation of the gene from microRNA— also benefit. It maybe will not be as much as BRCA1/2 mutations, but they still benefit.
Finally, these HRD assays have been developed that show a snapshot of the tumor in terms of the structure of its DNA. Therefore, [these assays] are looking at the loss of heterozygosity (LOH) patterns in the tumor cells. When there is a high degree of LOH, it is considered to be a surrogate for HRD.
The caveat here is that even after all of that testing, there are patients who do not have any of these indicators of response, but they still seem to gain some benefit from PARP inhibition. While these biomarkers are helpful, they are not perfect. This is a very hot area. There are multiple trials combining 1 of the 3 major PARP inhibitors with immune checkpoint inhibitors. The idea here is that a tumor cell that has HRD is a tumor cell that is going to have a lot of defects or abnormalities in its DNA. Those abnormalities may create what is called neoantigens. These are new mutated peptides that the body has not seen before. They would be great targets for checkpoint inhibitors, hence the combination of PARP inhibition and immune checkpoint inhibitors. Those trials are anything from small phase II studies, to now much larger studies trying to look at both safety and efficacy of the combinations. That is the second combination that has created a lot of excitement. The rationale there is that when you use an antiangiogenic agent and the tumor is starved of blood, it becomes hypoxic. Under hypoxia, there are some data to suggest that DNA repair becomes abnormal. Hence, you could hypothesize that under the influence of the antiangiogenic agent, a tumor may develop a pseudo-HRD phenomenon. In which case, it would then become more sensitive to PARP inhibition.
There are combinations using several PARP inhibitors along with either bevacizumab as a VEGF-targeted agent, or oral tyrosine kinase inhibitors (TKIs). TKIs have not been particularly effective for ovarian cancer, but there is hope that the combination will be.
Drew Y, de Jonge M, Hong S-H, et al. An open-label, phase II basket study of olaparib and durvalumab (MEDIOLA): Results in germline BRCA-mutated (gBRCAm) platinum-sensitive relapsed (PSR) ovarian cancer (OC) . Presented at: SGO Annual Meeting; March 24-27, 2018; New Orleans, LA. Late-breaking abstract.