Drug Combo Therapy Lowers Death Risk by Over 40%

• A drug combination already used in advanced prostate cancer now appears to significantly extend survival when given earlier.
• In males whose cancer returned after surgery or radiation, pairing enzalutamide with leuprolide cut the risk of death by more than 40% compared to standard therapy.
• Doctors and patients must weigh early treatment benefits against side effects and potential overtreatment.

A new drug combination may benefit men whose prostate cancer has returned after primary surgery or radiation therapy.

Pairing enzalutamide, an androgen receptor blocker, with the hormone therapy drug leuprolide significantly improved overall survival in patients with locally advanced prostate cancer.

Although the combination is already approved by the Food and Drug Administration (FDA) for metastatic disease, researchers wanted to know whether using it earlier in the course of the illness could also extend survival.

The phase 3 EMBARK trial previously showed that the drug combination delayed the development of metastatic disease. But whether that benefit translated into longer survival remained unclear — until now.

In a new analysis published on October 19 in the New England Journal of Medicine and presented at the European Society for Medical Oncology (ESMO) Congress, researchers reported that the combination reduced the risk of death by more than 40%.

“Many patients when they’re diagnosed with prostate cancer will choose to undergo surgery or radiation with the hope that that cures the cancer. Unfortunately, in about a third of those patients the cancer will come back,” said senior study author Stephen Freedland, MD, a urologist at Cedars-Sinai Medical Center in Los Angeles.

In these patients, treatment options are limited. However, the drug combination of enzalutamide and leuprolide appears to offer some hope.

“We’ve already shown that we’re delaying progression. and that’s great. But are we actually making patients live longer? The answer is unequivocally, yes,” Freedland told Healthline.

The EMBARK trial, which was funded by Pfizer Astellas Pharma, included more than 1,000 patients across 244 sites in 17 countries. All patients had high risk biochemically recurrent prostate cancer, indicated by a PSA doubling time of nine months or less.

High levels of PSA may indicate the presence of cancer before other symptoms appear. Patients whose PSA levels climb rapidly following primary treatment of their cancer are considered high risk of metastasis and ultimately death.

“The shorter it takes for your PSA to double, the more likely that it is just a matter of time before the cancer shows up in the bones,” said Edmund Folefac, MD, a medical oncologist and associate professor at The Ohio State University Comprehensive Cancer Center. Folefac wasn’t affiliated with the research.

Trial participants were randomly assigned to one of three groups: leuprolide alone, enzalutamide alone, or a combination of both drugs.

After eight years of follow-up the overall survival rate of patients taking the combination therapy was 78.9% compared to 69.5% among those taking leuprolide alone, which translates to a 40% lower risk of death.

The survival rate of patients taking enzalutamide alone didn’t differ significantly from those taking leuprolide.

The study reflects a broader shift in prostate cancer care toward treating aggressively earlier in the disease course, rather than waiting for metastasis to be confirmed on imaging such as CT scan.

“We started this therapy with people who have had very little hope, and we are gradually walking ourselves backward and continuing to see that this drug is benefiting patients,” Folefac told Healthline. “In other words, you are using more effective tools earlier and earlier.”

However, such strategies must be weighed against the potential risks of overtreatment and drug side effects.

The most common side effects of patients taking the combination therapy were hot flashes and fatigue. Other symptoms, including gynecomastia and nipple pain were also reported. Bone fractures and falls were more common among those in the combination group than in the other groups.

“Ultimately, we are striving to balance the benefits of treatment with the known harms of therapy,” said Kristen R. Scarpato, MD, an associate professor of urology at Vanderbilt University Medical Center. Scarpato wasn’t involved in the research.

“Physicians should always be aware of the potential for over treatment in prostate cancer whether a patient has localized or advanced disease. While androgen receptor pathway inhibitors are generally well tolerated, there are important side effects that may limit their use and clinicians should be cautious when prescribing these medications,” she told Healthline.

The results of the EMBARK trial are promising, but there are some limitations as well. Notably, the trial did not utilize a form of imaging technology known as PSMA PET scans, which were not part of standard practice at the time.

PSMA PET scans are able to more accurately detect signs of metastatic cancer that may not be picked up by other forms of imaging technology.

The implication of this limitation is that some participants may in fact have had undetected metastatic cancer, making them a more traditional candidate for the combined drug therapy.

“Whether this is the group that is driving the benefit, we don’t yet know,” Folefac said.

Despite this remaining question, Freedland offers an optimistic vision of prostate cancer care and advances in treatment.

“We’re really revolutionizing the management of prostate cancer convincingly over and over. We’re showing that earlier is better. You have to pick the right patients because if you go early enough, not everyone’s going to die of their cancer,” Freedland said.