Multi-institutional trial explores new lifeline for advanced prostate patients

For men with advanced prostate cancer that no longer responds to standard hormone treatments, treatment options are limited – and time is of the essence. As the disease progresses, the window for effective, less intensive treatments begins to close.

A multi-institutional clinical trial led by researchers at the Medical University of South Carolina (MUSC) and Emory University tested whether an experimental drug could extend the effectiveness of existing treatments. The study, published in Cancer Medicineexplored a new strategy to overcome treatment resistance in advanced prostate cancer.

This is a very difficult population to treat. These are patients whose cancer has already become resistant to standard treatments, so there is a clear need for new options.”

Besim Ogretmen, PhD, Study Co-Author and Associate Director, Basic Science, Hollings Cancer Center, Medical University of South Carolina

Trying to extend the life of existing treatments

The study focused on men with metastatic castration-resistant prostate cancer – an aggressive form of the disease that has spread and no longer responds to hormone-blocking treatments.

These treatments, namely the drugs abiraterone and enzalutamide, are standard treatments. They can be very effective at first, but most patients eventually develop resistance, leaving limited options, often a switch to chemotherapy, which can have significant side effects.

“We’re always looking for new pathways to target,” said Omer Kucuk, MD, oncologist and Correll Chair in Genitourinary Cancer. at Emory University’s Winship Cancer Center, which helped guide patient enrollment and clinical efforts; “After androgen receptor therapies fail, there are limited precise options for individualized therapy.”

Rather than replace these standard treatments, the researchers looked at whether an additional oral drug might allow them to work better, improve patient outcomes and prolong the duration of response.

From MUSC discovery to clinical trial

The experimental drug at the center of the study – opaganib – has its roots in MUSC.

A first-in-class treatment, opaganib was developed based on fundamental research led by Charles Smith, Ph.D., and proceeded through years of laboratory and early-stage work at MUSC. That included an early-phase clinical trial conducted at Hollings, which was then turned in this work into a mid-phase clinical trial led by Hollings oncologist Michael Lilly, MD, now professor emeritus, who helped move the drug from early discovery to patient treatment.

“This was based on years of preclinical and early clinical studies,” Ogretmen said. “The goal was to take what we learned in our labs and see if we could improve patient outcomes.”

Importantly, opaganib works differently from standard treatments. Instead of targeting hormones, it blocks a pathway involved in sphingolipid metabolism—a process cells use to manage lipids, or fats, that affect cell survival. Researchers are increasingly focusing on this pathway because disturbances in fat metabolism may help cancer grow and become resistant to treatment.

“There aren’t many drugs in the clinic that target this pathway,” Kucuk said. “That makes it very exciting and very different from the treatments we currently use.”

Early signs of effectiveness

In this Phase 2 trial, 66 patients received opganib in combination with either abiraterone or enzalutamide after their cancer had already progressed.

About 15% of patients who received opaganib with abiraterone and 9% who received it with enzalutamide had disease control at 16 weeks, which was less than the study’s primary goal. However, a closer look revealed a more nuanced picture.

A subset of patients showed clear biological signs of response, including declines in prostate-specific antigen (PSA) levels and periods of disease stabilization. These findings suggest that the treatment may slow the disease and allow patients to stay on treatment longer.

“Even though it’s a small percentage, these are real patients,” Ogretmen stressed. “We’re talking about people benefiting from this treatment when others haven’t worked.”

Beyond efficacy, drug tolerability is another important part of the story. Combination therapy was generally manageable, with most adverse events mild to moderate. Some patients experienced more severe side effects, but most improved when the dose of the drug was reduced or stopped.

A path to precision medicine

According to the researchers, the findings represent an important step forward in uncovering a new biological pathway to target prostate cancer. A key next step will be to identify the patients most likely to benefit from the drug combination.

Using blood samples collected from participants, the researchers now plan to look for biomarkers, or measurable signals in the blood, that could predict response. This approach could improve treatment for a smaller group of patients—a hallmark of precision medicine.

“We can see which lipids change in responders versus non-responders,” Ogretmen said. “This can help us stratify patients and better match treatment to the right person.”

The study, which was supported in part by a program grant from the National Cancer Institute (NCI) to Ogretmen and team, also underscores the power of collaboration, bringing together teams from MUSC and Emory to move a discovery from the lab to clinical trials.

“It was a great collaboration between the two institutions,” Kucuk said. “This is a very novel approach and it was exciting to be involved in bringing it into a clinical setting.”

“This kind of work depends on strong collaborations between academic researchers, clinicians and industry partners,” added Ogretmen. “That’s how we bring new treatments to patients who otherwise don’t have effective treatments.”

Looking ahead, researchers hope that improving this approach or developing next-generation drugs targeting the same pathway could expand treatment options, with growing optimism that these treatments could become part of future therapeutic strategies.