Part 2: Overcoming PARP Inhibitor and Platinum Resistance in Patients With Ovarian Cancer

In part 2 of this 2-part podcast series, David O'Malley, MD, Ohio State University, discusses strategies for overcoming PARP inhibitor and platinum resistance in patients with ovarian cancer. This talk was given in a virtual session at the recent Great Debates & Updates in Women's Oncology meeting titled "Therapeutic Approaches to Front Line Ovarian Cancer."

The next meeting will be held September 21-23, 2022. For more information and to register visit the conference homepage.

Transcript:

Let's just spend a few minutes on really looking at the different pathways to restore this PARP resistance. And maybe we shouldn't even be restoring PARP resistance, but instead, talking about moving it up earlier in the lines of therapy to benefit those patients which may not be benefiting as greatly. For example, the homologous recombination proficient patients.

A wonderful review paper from a few years ago, differentiated the ways to overcome PARP resistance. We have restoration of homologous combination activity. And we look at both direct and indirect.

In the indirect, we really look at anti vascular pathways, as well as the RAS/RAF/MEK inhibitor, but also the PI 3-kinase and mTOR pathways. And those are all parallel, hopefully promoting restoration to homologous recombination pathway leading to apoptosis.

We could spend all day talking about what is PARP resistance, patients who have been exposed to or patients who have progressed, but that's a discussion for a different day.

I did want to mention one trial that we've gotten permission to discuss with regards to a WEE1 inhibitor combined with a PARP inhibitor. And this will be within the GOG, GOG-3067, and this will be a phase 1 leading to a phase 2 trial. We'll discuss more about this trial in the future, but this is continuing to look for sites right now. And anybody who's interested, please let me know.

Let’s now talk a little bit about where do we go from platinum resistant patients?

Well, we just talked about the challenges with regards to response rates of 10% or less. Well, I will tell you, in drug development, we're really not interested in a drug unless we see a 25% response rate or we see the potential for synergy with other chemotherapy drugs.

So, how do you make a decision based on what you have available, which is not very exciting? Pegylated Liposomal Doxorubicin, single-agent Gemcitabine, single-agent Topotecan. When we're looking at the single agent activities, it's pretty modest. I think our patients would hope for better than a 10% response rate—when we look at clinical trials, maybe 25%.

This is one of the things we've done at OSU. We've set up, and this is just an example, all these trials are not active right now, but just again, what we've set up. And we really look at, first thing I do is test the tissue. Does the tumor have a molecular change that would make them eligible for a clinical trial? That's the first thing we do.

The second thing we do then is say, "are they an option for weekly Paclitaxel?"

If they're eligible for weekly Paclitaxel, that becomes the next. Then we look at the number of prior therapies to make a determination about what should be how to sequence these. I'd encourage each of you to put a similar algorithm together. If you have more than 1 platinum resistant ovarian cancer clinical trial, it may be something to consider in your standard of care arms.

Continuous platinum resistant ovarian cancer continues to be a significant burden. Obviously, all of these drugs ultimately have drug resistance, so overcoming that drug resistance. We continue to have an unbelievable exciting opportunity here in oncology. We're in an unprecedented time of drug development, but we need to move these earlier phase trials into drugs which are approved for our patients so we can utilize them. That really needs to be at the key of our science. Let's move these drugs in so they are available for our patients, not just do experiments.

Obviously, our best opportunity for success is really looking at tumor biology, molecular changes, and how do those respond to some selective pressures that are both inherent and external?

Now let's change gears for a quick second and talk about disparities. I love to hear what each one of these wonderful members of our group here are doing. We’ll talk a little bit about outcomes, adherence and genetic disparities.

We know, and from looking at our data, we know that black patients are more likely than white patients to experience treatment delays and discontinue treatment early. They are more likely to have optimal cyto reduction. We know that they're more likely not to receive guideline-concordant care, as well as adhering to those cares.

What else? Dose reductions. A higher percentage of dose reductions. The scariest thing is even when we control for as many things we can control for, particularly our stage, black patients do worse in their survival. We need to figure out why that is.

Well, we know one reason is when we look at patients that adhere to ovarian cancer guidelines, if we adhere, patients do better.

But, what are some of the risk factors? Low volumes. We need to make sure all of our patients are treated at high volume centers, but we haven't put people, gyn oncologists, throughout the entire US. Getting those patients, all of our patients, to high volume centers can be tough.

What do we need to do to bring our expertise to patients in underserved areas? And obviously what can we do to support those patients, to make sure that they have the necessary means to have the guideline therapy? Insurance also seems to impact that.

How about what can we do to increase accessibility? What can we do to make sure that we are adhering to guideline therapy? Possibly patient navigators, particularly for non-English speaking. Use of satellite clinics, remote, we now have the ability for remote. All of these things are so important.

How about testing for ovarian cancer? We need to make sure all of our patients have genetic testing. With that, when we look at non-white patients, they have a lower occurrence of having genetic testing. Imagine the opportunity we're missing. It's so important to make sure every single one of our patients are counseled they should have genetic testing. Obviously they have the autonomy to make their own decisions. So I'm really looking forward to the discussion with the panel to what are some other ideas that we can come up with to overcome these disparities in our treatment of ovarian cancer. Thank you very much.