The Use of PARP Inhibitors and Mechanisms of Resistance in Ovarian Cancer

PARP inhibitors are a common treatment for ovarian cancer, but mechanisms of resistance have yet to be fully understood.

Shannon Westin, MD, MPH, FACOG, a gynecologic oncologist at MD Anderson Cancer Center, discusses the use of PARP inhibitors in ovarian cancer and mechanisms of resistance.

According to Westin, PARP inhibitors are a common treatment for ovarian cancer, with approvals in both the first and second line. However, as PARP inhibitors become more common, so does resistance. According to Westin, there are several mechanisms of PARP resistance, but questions still remain around how to identify which mechanism a patient has and how to target it.

The most common mechanism of resistance seems to be the cell cycle itself, according to Westin. The upregulation of certain cell cycle regulators indicates that the tumor is becoming dependent on that agent. During the EFFORT study (NCT03579316), adavosertib is used on its own and in combination with another PARP inhibitor in order to overcome resistance.

0:08 | PARP inhibitors really are accepted in almost every piece of the ovarian cancers journey, right? So upfront maintenance, second line maintenance, and even treatment. For some cases, we're seeing more and more people getting PARP inhibitors. And with that we're seeing more and more resistance to PARP inhibitors. And there are a number of different mechanisms of PARP resistance. And I think one area we're still struggling with is how to know what mechanism of resistance the patient has, what do we need to do to target that. But with that being said, where the science is right now, is we're trying to tackle common mechanisms of resistance or common pathways that may be involved. And so, one particular pathway that we've seen that's involved is just the cell cycle. And specifically, when we treat tumors or patients with PARP, we can see upregulation of different cell cycle regulators indicating that the tumor is becoming dependent on that. And so, what we've done in the EFFORT study is target a specific regulator of the cell cycle which is called Wee1 and the drug that does that is adavosertib. And what's interesting about this study is that not only did we explore adavosertib on its own, but we also combined it with a PARP inhibitor to see if that helps to overcome PARP resistance in this population.