Multi-institutional trial explores new lifeline for advanced prostate patients

For men with advanced prostate cancer that no longer responds to standard hormone therapies, treatment options are limited – and time matters. 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 therapies. The study, published in Cancer Medicine, explored a novel strategy to overcome treatment resistance in advanced prostate cancer.

This is a very difficult-to-treat population. These are patients whose cancer has already become resistant to standard therapies, so there's 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 therapies

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.

Those treatments, namely the drugs abiraterone and enzalutamide, are standard therapies. They can be highly effective at first, but most patients eventually develop resistance, leaving limited options, often a transition to chemotherapy, which can carry significant side effects.

"We're always looking for new pathways to target," said Omer Kucuk, M.D., oncologist and the Correll Chair in Genitourinary Cancer at Winship Cancer Center of Emory University, which helped to lead patient enrollment and clinical efforts. "After androgen receptor therapies fail, there are limited precise options for individualized treatment."

Rather than replacing those standard therapies, the researchers tested whether an additional oral drug could allow them to work better, improve patient outcomes and extend the duration of response.

From MUSC discovery to clinical trial

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

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

"This was built 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 outcomes for patients."

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

"There are not 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 signals of effectiveness

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

About 15% of patients taking opaganib with abiraterone and 9% taking it with enzalutamide experienced disease control at 16 weeks, which was short of 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 drops in prostate-specific antigen (PSA) levels and periods of disease stabilization. These findings suggest the treatment may be slowing the disease and enabling patients to stay on the therapy longer.

"Even though it's a small percentage, those are real patients," Ogretmen emphasized. "We're talking about people who are benefiting from this treatment when others have not worked."

Beyond effectiveness, the drug's tolerability is another important part of the story. The combination treatment was generally manageable, with most side effects mild to moderate. Some patients did experience more serious side effects, but most improved when the drug dose was reduced or stopped.

A path toward precision medicine

According to the researchers, the findings represent an important step forward by uncovering a new biological pathway for targeting prostate cancer. A key next step will be identifying which patients are 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 refine the therapy for a smaller group of patients – a hallmark of precision medicine.

"We can look at which lipids change in patients who respond versus those who don't," Ogretmen said. "That may help us stratify patients and better match the treatment to the right person."

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

"It was a great collaboration between the two institutions," Kucuk said. "This is a very novel approach, and it was exciting to be part of bringing it into a clinical setting."

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

Looking ahead, the researchers are hopeful that refining this approach or developing next-generation drugs targeting the same pathway could expand treatment options, with growing optimism that these therapies could become part of future treatment strategies.