Eyeing Enzalutamide for Hormone-Sensitive Prostate Cancer

Men with advanced prostate tumors that respond to androgen-deprivation therapy (ADT) stand to benefit from additional treatment with the potent androgen-receptor inhibitor enzalutamide (Xtandi; Astellas/Pfizer), according to preliminary data from the phase III ARCHES study presented last month at the 2019 Genitourinary Cancers Symposium in San Francisco, CA.

The results confirm what a growing number of prostate cancer trials have shown: “There are greater treatment effects with early use of these drugs,” says Christopher Sweeney, MD, of Dana-Farber Cancer Institute in Boston, MA, who was not involved in the study. “That's been a bit of a paradigm shift.”

Enzalutamide is FDA-approved only for men with castration-resistant prostate cancer. Astellas and Pfizer launched the 1,150-patient ARCHES study with an eye to expanding the label to include metastatic hormone-sensitive prostate cancer (mHSPC).

At the symposium, trial investigator Andrew Armstrong, MD, of Duke University in Durham, NC, reported that those who received enzalutamide alongside ADT had a higher objective response rate compared with men given a placebo—83% versus 64%—and a 61% lower risk of disease progression or death, as measured by radiographic progression-free survival (rPFS).

Enzalutamide also delayed the need for additional therapies and increased the proportion of patients whose PSA reached undetectable levels. The drug's safety profile was comparable to that documented in previous trials involving patients with castration-resistant prostate cancer.

Currently, two other regimens are recommended to supplement ADT in men with mHSPC: chemotherapy with docetaxel, and a combination of prednisone plus the antiandrogen abiraterone acetate (Zytiga; Janssen). If enzalutamide is also approved for these patients, “it will provide another oral option,” says David Jarrard, MD, of the University of Wisconsin–Madison—one that could be especially beneficial for men with diabetes or liver dysfunction, who may not tolerate abiraterone's side effects.

The abiraterone–prednisone plus ADT combination earned FDA approval last year based on early data from the phase III LATITUDE trial, which demonstrated a significant benefit in rPFS, with a median of 33 months in the treatment arm and 15 months in the placebo group. Karim Fizazi, MD, PhD, of the Gustave Roussy Institute in Villejuif, France, reported the final results of that trial at the Genitourinary Cancers Symposium, showing that men who received the androgen biosynthesis inhibitor had a median survival of 4.4 years compared with 3 years for those taking a placebo.

Similar overall survival statistics are not yet available from the ARCHES trial. However, enzalutamide looks to prolong median rPFS by about the same amount as either abiraterone–prednisone or docetaxel, judging by the reported hazard ratios for disease progression or death.

That means it will likely boil down to patient and doctor preference when choosing between an antiandrogen drug or chemotherapy agent to pair with ADT for men with mHSPC. In the future, though, patients may opt to receive all three therapies at the same time—a strategy currently being tested in phase III trials involving ADT and docetaxel plus concurrent treatment with either abiraterone, enzalutamide, or an experimental androgen-receptor inhibitor called darolutamide (Bayer). Initial trial results are expected next year.

If the patients who respond to docetaxel are different than those who respond to antiandrogen therapy, or if the therapies work better in tandem, “we will hopefully see yet another great leap forward in the treatment of hormone-sensitive disease,” says Sweeney. “That's now the scientific question.” –Elie Dolgin