Updates in Ovarian and Cervical Cancers - Episode 14
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Four general classes of compounds are demonstrating promise in ovarian cancer, states Michael J. Birrer, MD, PhD. These include 1) PARP inhibitors, 2) antiangiogenic agents, 3) antibody drug conjugates, and 4) immunotherapy.
In December 2014, the FDA approved olaparib as the first PARP inhibitor for patients with advanced BRCA-mutated ovarian cancer. The 3 other PARP inhibitors that are farthest along include rucaparib, niraparib, and veliparib. Along with BRCA-mutated ovarian cancer, some of these agents are being assessed for use in patients who are platinum-sensitive. These compounds are being tested in both the treatment and maintenance settings.
There is controversy over the appropriateness of combining PARP inhibitors with a cytotoxic agent. Some researchers suggest that PARP inhibitors and cytotoxic agents have similar mechanisms of action, and thus combining them will result in greater toxicity with minimal added benefit. Other researchers believe that a PARP inhibitor plus a platinum agent may create synergistic activity. With the exception of veliparib, combining a PARP inhibitor and cytotoxic agent is challenging, as this can result in myelosuppression, notes Birrer. There are concerns about the possible long-term toxicity with this combination. One question is whether using drugs that inhibit DNA repair, particularly in combination chemotherapy, in patients who then may live another several years could result in their developing MDS or leukemia. These risks need to be discussed with the patient.
Several antiangiogenic agents are being examined in ovarian cancer, notes Birrer, with bevacizumab being the drug most tested. Additionally, TKIs, including pazopanib and cediranib, have shown activity. Another class in the angiogenic field is Ang II receptor blockers (ARBs), which has several active agents, including some with phase 2 and phase 3 data suggesting activity in ovarian cancer. The delta-like ligand 4, which is part of the notch pathway, is another angiogenic target in earlier developmental stages.
There are a number of very interesting proteins that sit on the surface of ovarian cancer cells, explains Birrer, that can be targeted by antibody-drug conjugates (ADCs). One example of these ADCs being investigated is IMGN853, which targets the folate receptor. Other ADC targets include mucin-16 (MUC16/CA125), which regulates tumor cell growth, tumorigenesis, and metastases; and sodium-dependent phosphate transport protein 2B (NaPi-2b), which is a phosphate transferase.
As with other solid tumors, immunotherapy is also a growing topic of interest in ovarian cancer. PD-1 and PD-L1 agents are now entering into clinical trials in ovarian cancer, notes Birrer. Robert A. Burger, MD, FACOG, FACS, and his colleagues at the University of Pennsylvania already have data demonstrating that ovarian cancer can be positively manipulated by immunotherapeutic approaches.