Combination Therapy Shows Promise in High-Risk Prostate Cancer, Study Finds

A large international clinical trial has found that adding the drug apalutamide to standard hormone therapy before and after prostate cancer surgery significantly improved outcomes for men with high-risk disease, according to details published in The New England Journal of Medicine.

The study outlines a new treatment option for patients who face a substantial risk of relapse, said Ashley Ross, MD, PhD, professor of Urology and a co-author of the study.

“This does not replace other standard treatments,” Ross said. “What it does is open up an option for men with locally advanced or high-risk disease who are considering surgical treatment.”

That nuance is critical, he said, especially given the complexity of treating aggressive prostate cancer, which often requires a combination of approaches.

In the study, more than 2,100 patients with newly diagnosed high-risk localized or locally advanced prostate cancer were randomly assigned to either androgen-deprivation therapy (ADT) plus apalutamide or a placebo, to test whether the combination could improve surgical outcomes.

The patients enrolled in the trial had particularly aggressive cancers, and many showed signs that the cancer had already begun to spread locally and regionally, Ross said.

Traditionally, such patients might undergo surgery first and receive additional therapies later if the cancer showed signs of persistence or recurrence. The trial instead tested a “perioperative” strategy, administering therapy both before and after surgery.

The results showed that patients who received apalutamide in addition to ADT had significantly better outcomes than those receiving ADT alone.

Nearly 9 percent of patients in the apalutamide group achieved either a complete response or minimal residual disease at the time of surgery, compared with just 1 percent in the placebo group, according to the study.

“Even though only about 10 percent of patients reached minimal residual disease or complete response, that was tenfold higher than with ADT alone,” said Ross, a member of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “The drug itself is not going to do the full job, but it’s way better than ADT alone.”

The combination therapy also improved metastasis-free survival, a key measure of how long patients live without their cancer spreading. At five years, 78 percent of patients who received apalutamide remained free of metastasis, compared with 73 percent in the control group.

“That tells you that if you’re going to treat what is likely the systemic component of the disease, you should be using a combination regimen,” Ross said.

The benefits came with an increase in side effects. Nearly 40 percent of patients receiving apalutamide experienced adverse events, compared with 31 percent in the placebo group. Overall, however, Ross described the safety profile as manageable.

“The side effect profile was generally tolerable,” he said. “Most of the additional adverse events were related to rash, which is straightforward to manage in the majority of cases.”

The findings add a new potential pathway for treating high-risk prostate cancer, alongside existing options such as surgery alone or radiation combined with hormone therapy.

“It opens up a third standard-of-care option,” Ross said. “You can do surgery alone followed by additional radiation with or without hormonal therapy if needed, you can do radiation therapy with hormone therapy, or you can now do androgen-deprivation therapy plus an androgen receptor inhibitor for six months, then proceed to surgery.”

Still, he cautioned that it remains unclear which approach is best for individual patients.

“A lot of questions remain unanswered about which pathway is optimal,” he said.

The study team is continuing to analyze data, including from a PROTEUS (Perioperative Treatment with Erleada United with Surgery) sub-study comparing outcomes in patients who underwent initial surgery without systemic therapy.  An additional ongoing trial, ATLAS, evaluates apalutamide in combination ADT and radiation instead of surgery.

“This study answers some questions and provides a new option,” Ross said. “But there’s still more to learn.”

The study was funded by Johnson & Johnson.