Advancing Treatment in Platinum-Resistant Ovarian Cancer: Clinical Impact of the ROSELLA Trial

In this interview, Robert L. Coleman, MD, discusses the pivotal findings from the phase 3 ROSELLA trial of relacorilant plus nab-paclitaxel in patients with platinum-resistant ovarian cancer. The ROSELLA trial recently reported that the combination met its overall survival (OS) primary endpoint, demonstrating a 35 % reduction in the risk of death compared with nab-paclitaxel alone, while also achieving improved progression-free survival (PFS) without increased safety burden—findings that support regulatory submissions under review by the US Food and Drug Administration (FDA).

Key Clinical Summary:

• The phase 3 ROSELLA trial demonstrated that relacorilant plus nab-paclitaxel achieved a 35% reduction in the risk of death and improved PFS in patients with platinum-resistant ovarian cancer, meeting both primary endpoints.
• The combination was studied without biomarker selection, supporting broad applicability across this treatment population.
• If approved, this regimen may influence treatment sequencing alongside other recently validated phase 3 options in this setting.

Robert L. Coleman, MD: My name is Dr Rob Coleman. I'm a gynecologic oncologist practicing with Texas Oncology, and I have been a gynecologic oncologist since 1993. I served as chief scientific officer for US Oncology Research after retiring from the University of Texas MD Anderson Cancer Center. I also served as Chief Medical Officer for Vanium Group, where I currently am.

This area is one of my primary research areas, and I continue to be quite active in that. Investigations that I’m involved with traffic their way through US Oncology and the Gynecologic Oncology Group (GOG) Partners, which is a part of the GOG Foundation where I serve as a vice president.

Can you give some background about your study and what prompted you to undertake it?

Dr Coleman: Platinum-resistant ovarian cancer is an area where very little progress has been made for several years. It's also an area where we've done quite a bit of drug discovery, and most of the current compounds that we're using in earlier lines of therapy and as maintenance therapy have had a proving ground in this particular space.

One of these drugs, which was evaluated more than 15 years ago, was nab-paclitaxel. One of the primary drivers for the development of nab-paclitaxel was that it was an opportunity to deliver the active compound, namely paclitaxel, in a way that would potentially eliminate the issues that come with a carrier vehicle for native paclitaxel, which is cremaphor. So, the drug was developed in a way that we could deliver it without the use of a cremaphor solvent, and because of which, we were then able to reduce the need for steroid use.

And that was a primary motivator for developing a combination with nab-paclitaxel, such as relacorilant, which allowed us to deliver a highly effective chemotherapeutic agent—namely weekly paclitaxel in the platinum-resistant setting—and not have to worry about diminishing its potential efficacy by co-administering steroids. This allowed us to deliver another compound, relacorilant, which has specific activity on some of the processes that are related to the apoptotic cell death that's induced by a molecule like paclitaxel. So, we brought together an active agent, a strategy that could eliminate the use of steroids, and a targeting mechanism for the glucocorticoid pathway, which potentially could increase its efficacy.

ROSELLA demonstrated a ~35% reduction in the risk of death with relacorilant plus nab-paclitaxel. How clinically meaningful is this OS benefit in the context of existing options, and how might it influence treatment sequencing in current clinical pathways?

Dr Coleman: OS has been an important regulatory and clinically relevant endpoint for our patients with this disease. It is a very difficult endpoint to affect change largely because patients with this disease will frequently have multiple different lines of treatment that potentially could confound benefits that are seen at an earlier time point, such as PFS.

The ROSELLA trial was set up to evaluate not only the impact of the next immediate endpoint—PFS—but also the OS metric, which has been elusive over the many years that we have evaluated new drugs. The last compound that made its way into an OS efficacy endpoint was mirvetuximab, the antibody drug conjugate that targets the fluid receptor alpha—and that was the first. We have had an opportunity to affect the natural history of this disease by evaluating novel compounds in the space, such as in the ROSELLA trial.

At the patient level, a lot of the statistics that we talk about are at the population-based level. In other words, what is the effect in the total population? But when you're sitting in front of a patient, you are actually talking about the data that would be applied to the individual. And so, all we can provide at the patient level is how we can impact the risk of the next event. In this case, there was a 35% reduction in the probability that death would occur while on treatment and following treatment. Communicating this provides the patient with an opportunity to understand what their risks are and how those risks can be modulated by the use of the compound.

With respect to PFS, what this meant was that we could reduce the probability for progression by about 30%. This is important to a patient because we don't know what's going to happen to them in the next month, next week, or next day. All we can say is that if they're on the treatment—relative to patients that are not on this treatment—they have a 30% improvement in the potential for that event to happen. As it relates to OS, we have a 35% reduction in that probability. So, these are important metrics and they've been very difficult to achieve. This applies to our clinical domain as we think about the regimens that could influence those particular metrics, progression, and survivorship.

Since this is the first report of OS, which is mature for this combination, we'll hear from the FDA hopefully in the next 6 months as to how this will be approved and applied to our patient population. Hopefully we'll receive a regular approval so that we can adopt this into our normal treatment strategies. The way that it will be adopted will be somewhat nuanced because of how the compounds are going to be available to us, namely mirvetuximab soravtansine, which is an antibody drug conjugate. It is currently primarily used on patients whose tumors have a high expression of full receptor alpha.  

The KEYNOTE-B96 trial looked at the combination of weekly paclitaxel and pembrolizumab plus or minus bevacizumab, which also appears to achieve both of these endpoints. So, how we're going to incorporate this into our treatment algorithm will be somewhat newer for patient characteristics, prior treatment lines, and anticipated toxicities for the individual regimens.

The trial met both primary endpoints without biomarker selection. From a practical standpoint, how important is this for real-world adoption, and does it simplify decision-making compared with other targeted or biomarker-driven strategies?

Dr Coleman: Those treating this disease will do comprehensive evaluation for biomarker expression. We do this because it provides not only prognostic information for some of our biomarkers, but also potentially predictive opportunities for specific agents. This potentially segments the population in a way that could isolate a potential patient from a therapy that could provide them with some benefit. That is what we see with biomarker-directed therapies. Sometimes the biomarkers are not necessarily in the range where the approval is or ineffective below that trigger point. We're seeing this already with some of the agents that we have available to us.

Many of us are pleased to have a non-biomarker restricted opportunity. It will still play into the overall nuances of treatment that I mentioned previously, where we will look at a host of factors. These include: the presence or absence of a biomarker, the previous lines of therapy, the tolerance of those previous lines, and the number of potential regimens that patients have been exposed to and what the types of regimens. The art of medicine here will be largely focused on these individual patient characteristics.

Eliminating one descriptor without needing to have a biomarker is favorable so that we know that we have a robust effect across the potential expression levels of the targeted therapy, for example. We're used to doing this because most of the chemotherapy we administer today in this disease setting are not restricted or not further annotated by a biomarker. That helps us broaden our capabilities along the treatment paradigm.

How can the results of the ROSELLA trial shape future clinical pathways and standards of care for platinum-resistant ovarian cancer?

Dr Coleman: The clinical pathways and standards of care for patients with this disease in this setting and this morphology of platinum resistance are influenced by what we have approved. Our level of standardization for treatment is going to be predicated on effective therapies that are annotated or supported by formal phase 3 studies.

We now have 3 formal phase 3 trials, but we hope that in addition to mirvetuximab, the 2 most recent trials will lead to a label that will apply to this patient population, which will find their way to the highest level of evidence that would support clinical pathways. However, many of the regimens that we're studying now that have not been formally evaluated by phase 3 studies are still available to us. We use them in nuanced ways as we approach the patient population. It is comforting to have a therapeutic strategy that is supported by formal analytical phase 3 studies, such as the ROSELLA trial, which will then bring the confidence of this combination into the treatment landscape.