Part 1: Current Emerging Therapies for Platinum-Resistant Ovarian Malignancies

In part 1 of this 2-part podcast series, David O'Malley, MD, Ohio State University, discusses the current emerging therapies for platinum-resistant ovarian malignancies. 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 here.

Transcript:

Hi, I'm Dave O'Malley from the Ohio State University where I'm honored to lead the division of Gynecological Oncology, as well as the work I do, which is a Clinical Trial Advisor for GOG Partners.

I'm really looking forward to talking about current emerging therapies for platinum-resistant ovarian malignancies. But how about what have we seen most recently? We now have 4 additional trials that have reported out large randomized phase 3 trials. And what do we see in those arms without Bev? Single agent therapy really is about 10% plus or minus about 3% in a response rate. So as low as 4% in the JAVELIN 200, which was with PLD, and up to about 13% in the NINJA trial. So again, consistent with our AURELIA data, but really looking at almost just at about single agent response rates, a little bit above for our current contemporary control. So it's important to keep in mind as we're discussing new agents, that our contemporary control is about 10% plus or minus a few percent.

So clearly platinum resistant ovarian cancer continues to be a large unmet need for our patients because all those who recur will ultimately become platinum-resistant. And how do we kind of look at some of these strategies? Well, a way that we've set this up to evaluate it is looking at weekly Paclitaxel regimens, plus or minus weekly Paclitaxel, then antibody drug conjugates, immune therapies, and then targeting replication stress.

So let's talk about the Taxane first. So the first trial we get to is VB-111. This trial has completed enrollment. Really interesting adenovirus, and it looks to have a dual mechanism, both antivascular as well as immunogenic properties it's taking in the cells. And this large randomized phase 3 trial, I said, has completed enrollment. We're excited to see the results of it. And it was really weekly Paclitaxel plus or minus, I'm going to call that Ofra, okay?

So when we look at this and we look at Ofra and the OVAL study, the exciting preclinical results of 13% response rates as a single agent, but as then we combine it with Paclitaxel, we see response rates significantly increasing. And this is from Dr. Arend's paper from the interim analysis.

Now, we also have the GOG-3044, the PROFECTA-II study, and that is looking at the Pan AKT inhibitor. It's really interesting. A lot of the data, the preclinical and early phase data, is really looking at restoring chemo sensitivity. And when we look at this trial, it's actually recently been amended to include up to 1 to 5 prior chemotherapy regimens. In the past, it's required Bev, but now Bev is optional in this patient population. Again, very interesting mechanism in preclinical work, and this trial is ongoing. So again, looking at targeting the AKT pathway to restore platinum sensitivity.

Let's change gears a little and look at Relacorilant, which is a cortisol suppressing agent. And the theory behind this is that cortisol actually blocks pro-inflammatory cytokines. And by utilizing that, then allowing for chemo resistance. What this agent does is trying to restore chemo resistance. There's a very interesting 3-arm trial that looked at intermittent dosing versus continuous dosing versus the single arm of Nab-paclitaxel. The trade name of that is Abraxane.

And when we looked at these outcomes, you see here that the intermittent dosing seem to differentiate itself versus single agent NAB-paclitaxel. And this led to the design of a larger trial that we'll talk about in a second, but you see here that the response rates are similar, but when we see that the duration response appears to favor the intermittent dosing, probably related with regards to the tolerance.

So as we move forward in that design of the trial, we're obviously going to look at the intermittent dosing compared to a physician's choice. Speaking of novel treatment strategies, the GOG-3029 or INNOVATE-3 is looking at tumor treating fields. And what this is, is arrays, which are placed on the abdominal cavity. And it's actually an electrical current that is passed between those arrays. This apparatus actually has 3 approvals already, 2 in GBM and one in thoracic mesothelioma.

And when we look at the preclinical work here, it's really interesting that it disrupts the mitotic spindle so you have this anti micro tubulin effect. And Dr Vergote originally presented the expansion cohort. This current phase three trial, the INNOVATE-3, has actually also completed enrollment with nearly about 500 patients in this. And again, weekly Paclitaxel plus or minus tumor treating fields. The primary endpoint here is overall survival, as obviously you can't have a placebo controlled trial with the tumor treating fields.

Now, another unique strategy utilizing Taxanes is the GOG-3059 trial, the ACCELERATE trial. So once again, looking at wonderful pre-clinical work by Katherine Fuh, previously at Wash[ington] U[niversity] in St. Louis, really looked at the AXL GAS6 pathway, which basically everything bad that happens in cancer seems to have some relationship with the GAS6 pathway. And what this does, is the mechanism of action is actually a decoy receptor for the Gas6. And this agent's pretty amazing in that it has very little to any toxicity compared to weekly Paclitaxel. So the ongoing phase 3 trial continues to enroll and with weekly Paclitaxel plus minus AXL.

Now, with regards to the antibody drug conjugates, we have 2, really 4, ongoing trials and a series of other trials that are being designed. And what antibody drug conjugates are, are basically an antibody connects to an antigen, that antigen then releases its contents into the cell. It undergoes degradation and then becomes active. Most of the payloads are anti micro tubulin. And so what we see then is they ultimately then active within the cell causing cell death or apoptosis. And then with that, the active ingredients are then released from the cell, the active agent, I should say, not ingredients, are released in the cell and you get bystander effect in those cells that are near.

And with regards to immune therapy, we have multiple trials, and this is really based on some wonderful work. Now, the problem with combining these immune therapies, immune therapy by themselves have been fairly disappointing, but some area of optimism is when we combine it with PARP inhibitors plus anti vascular. And we also have the MEDIOLA data in a platinum sensitive, so I did not include it here, which had quite impressive results.

Now, you could argue that these response rates by themselves, without the immune therapy, may explain these waterfalls, but again, the triplet of PARP inhibitor, immune therapy and anti vascular is very interesting, but maybe more in platinum sensitive than platinum resistant.

GYN-023, which has now activated, this is a forearm trial looking at physician's choice. And then again, using that triplet, Durva, Olaparib, Cediranib. In this case, Cediranib rather than Bev. Versus Durva or Cediranib together versus Olaparib and Cediranib. And the randomization is 1:2:2:2. So when we're looking at this, this is, again, an NRG trial that we will be able to sort out the relative contribution of each one of those combinations as compared to the triplet, seeing if the triplet adds additional benefit beyond the 2 or the combination.

Reference

O'mally D. Therapeutic Approaches to Front Line Ovarian Cancer. Presented at Great Debates & Updates: Women's Oncology; April 27, 2022. Virtual.