NEW INDICATION FOR ENZALUTAMIDE?

Already approved for the treatment of metastatic castration-resistant prostate cancer, enzalutamide (Xtandi, Pfizer/Astellas) may soon join apalutamide (Erleada, Janssen) for treating earlier prostate cancer in men with nonmetastatic, castration-resistant prostate cancer (nmCRPC) whose prostate-specific antigen (PSA) level is rising despite their having a low level of testosterone.

The new use in earlier prostate cancer is based on data from the PROSPER study (NCT02003924), which showed a 71% reduced risk for metastasis or death. The study is scheduled to be published June 28 in the New England Journal of Medicine.

The PROSPER study authors conclude, "Enzalutamide treatment resulted in a significant delay in the development of metastases, in the time to first use of a subsequent antineoplastic therapy, and in time to PSA progression, with no difference in quality of life."

In an invited commentary, Matthew R. Smith, MD, PhD, of the Massachusetts General Hospital Cancer Center in Boston, concludes that the recent US Food and Drug Administration (FDA) approval of apalutamide for nonmetastatic prostate cancer "and the anticipated approval of enzalutamide in the same context represent important steps forward for men with rising PSA levels during androgen-deprivation therapy."

Apalutamide was the first drug to be approved for the treatment of nmCRPC. It was approved earlier this year on the basis of data from the SPARTAN study, which showed a 72% reduced risk for metastasis or death.

New Primary Endpoint

Both the SPARTAN and PROSPER trials used a new primary endpoint — metastatic-free survival. Previous approvals of drugs for prostate cancer have been based on the endpoint of overall survival.

Metastasis-free survival "is a brand-new primary endpoint in prostate cancer clinical trials, and one has to ask why this endpoint can now be used," Anthony D'Amico, MD, PhD, chief of genitourinary radiation oncology at the Brigham and Women's Hospital and the Dana-Farber Cancer Institute, Boston, commented to Medscape Medical News.

He noted that in prostate cancer, metastasis is nearly always associated with pain and suffering and therefore a diminished quality of life. In addition, the use of additional therapies is common. Metastasis often leads to death from prostate cancer, and so metastasis is a clinically relevant endpoint, he commented.

He also pointed out that "the study populations in both PROSPER and SPARTAN had short PSA doubling times (<10 4="" a="" about="" and="" cancer="" competing="" death="" following="" from="" herald="" is="" known="" less="" making="" median="" metastasis="" months="" of="" p="" prostate="" quicker="" relevant.="" risks="" to="" which="">

However, further follow-up of these studies is needed to confirm that the metastatic-free survival benefit will translate into an overall survival benefit, he added.

Results from the PROSPER Study 

PROSPER was a randomized, double-blind phase 3 study that was conducted in men with nmCRPC whose PSA doubling time was 10 months or less (median, 3.7 months) and who were continuing to receive androgen-deprivation therapy. The patients were randomly assigned to receive either enzalutamide 160 mg daily (n = 933) or matching placebo (n = 468).

The investigators, led by Maha Hussain, MD, of Northwestern University Feinberg School of Medicine, Chicago, Illinois, and Cora N. Stenberg, MD, from the Department of Medical Oncology at San Camillo Forlanini Hospital, Rome, Italy, report that the median duration of enzalutamide therapy was 18.4 months, and the median duration during which patients received placebo was 11.1 months.

At data cutoff, 810 men were receiving enzalutamide (634 patients in the enzalutamide group; 176 patients crossed over from the placebo group).

The primary endpoint of metastatic-free survival was determined with radiographic imaging performed every 16 weeks until radiographic progression was confirmed by central review.

The median metastatic-free survival was 36.6 months for the enzalutamide group (median follow-up, 18.5 months) and 14.7 months for the placebo group (median follow-up, 15.1 months). With a hazard ratio of 0.29, men with nmCRPC were at a 71% reduced risk for metastasis or death (P < .001).

Of the 219 patients in the enzalutamide group with the primary endpoint event, 187 (85%) experienced radiographic progression. Of 228 patients in the placebo group with the primary endpoint event, 224 (98%) experienced radiographic progression. Fifteen percent of patients in the enzalutamide group and 2% of patients in the placebo group died without radiographic progression.

For the secondary endpoints, median time between discontinuation of therapy and subsequent antineoplastic therapy was 25 days in the enzalutamide and 18 days in the placebo group.

Fifteen percent of patients in the enzalutamide group and 48% of patients in the placebo group discontinued therapy and received subsequent antineoplastic therapy; abiraterone was the therapy of choice in approximately one third of these patients.

At the first interim survival analysis, 11% and 13% of patients in the enzalutamide and placebo group, respectively, had died; median survival was not reached in either group.

Adverse events occurred in more patients who received enzalutamide than in those who received placebo (87% vs 77%). The incidence of serious adverse events was also higher with enzalutamide (24% vs 18% for placebo). Fatigue was the most common adverse event reported for enzalutamide (33% vs 14% for placebo).

No events of posterior reversible encephalopathy syndrome were reported during the study; however, five patients who received enzalutamide were later found to have "noninfectious encephalopathy or delirium." Three patients who received enzalutamide also had convulsions that were serious and that were considered to be drug related.

Cardiac events were also reported for patients in the enzalutamide group: cardiac death was reported in nine patients; myocardial infarction, in six patients; and cardiac failure, cardiorespiratory arrest, and ventricular arrhythmia in one patient each.

The investigators also noted that there was no decrease in quality of life associated with enzalutamide.

Benefit in Specific Patient Populations

In the editorial, Smith noted the potential harm associated with apalutamide and enzalutamide — fatigue, falls, and fractures. In addition, both drugs are associated with a small risk for seizures. "The benefit-risk ratio for either drug is not well characterized in patients with longer PSA doubling times," Smith notes.

D'Amico also shared his thoughts, which were mirrored in the editorial, on the imaging used in these studies. Both D'Amico and Smith noted that PROSPER and SPARTAN used standard imaging (bone scan and CT), which can delay detection of metastasis. "Today there are sophisticated imaging techniques [eg, positron-emission tomography (PET) with choline or fluciclovine] which are more sensitive for detecting metastasis," he said.

The newer imaging techniques would have detected metastases sooner, Smith and D'Amico point out. "[The] SPARTAN and PROSPER trials provide important new information about the appropriate treatment of patients with that novel category of disease (negative on conventional imaging yet positive on new imaging techniques)," Smith writes in the editorial.

Early vs Late Therapy

According to Smith, a key clinical decision is whether to provide additional therapy to men with nmCRPC who are already receiving androgen-deprivation therapy and in whom a rising PSA level is the only manifestation of early disease. He notes that SPARTAN and PROSPER were not designed to evaluate sequential treatment formally, but that the majority of patients in the placebo groups went on to receive subsequent therapy for metastatic disease.

D'Amico indicated that the market for these drugs may not increase if men are diagnosed with metastasis soon after their PSA level rises on conventional androgen-deprivation therapy if PET scanning is widely adopted and used for patients with low PSA levels (~0.5 ng/mL) before a PSA doubling time can be calculated. If that happens, patients would most likely receive androgen-deprivation therapy that may include abiraterone if three or fewer metastatic lesions are detected. If more than four metastatic lesions are detected, androgen-deprivation therapy may be used along with docetaxel.

The study was funded by Pfizer and Astellas. The published article contains a full listing of the authors' relevant financial relationships.

N Engl J Med. 2018;378:2465-2474.