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CHICAGO -- Two different direct androgen receptor inhibitors improved survival in randomized trials of men with metastatic castration-sensitive prostate cancer (mCSPC).

Patients treated with enzalutamide (Xtandi) and standard testosterone suppression had a 3-year overall survival (OS) of 80% compared with 72% among patients randomized to testosterone suppression and a nonsteroidal antiandrogen (NSAA, P=0.002). In the second study, treatment with apalutamide (Erleada) and standard hormonal therapy had a 24-month OS of 82% versus 74% with standard therapy (P=0.0053).

Both studies supported earlier use of androgen receptor inhibitors in prostate cancer treatment, as reported here at the American Society of Clinical Oncology (ASCO) annual meeting.

"Enzalutamide, added to testosterone suppression, represents an appropriate option for men with metastatic prostate cancer commencing testosterone suppression," said Christopher Sweeney, MD, of Dana-Farber Cancer Institute in Boston. "The benefit is clear in patients with low- and high-volume disease."

"For patients who are candidates for docetaxel when starting testosterone suppression, quality-of-life analyses and longer follow-up are needed to determine whether the delay in progression with concurrent enzalutamide results in a meaningful clinical benefit, and/or compounds castration-resistant prostate cancer therapy favorably, and augments survival between 3 years," Sweeney stated.

Results of the second study "support the addition of apalutamide to androgen deprivation therapy (ADT) for a broad range of patients with metastatic castration-sensitive prostate cancer, including those with high or low disease volume, prior docetaxel therapy, de novo metastatic disease or relapsed metastatic disease after initial diagnosis of localized disease, or prior treatment for localized disease," said Kim N. Chi, MD, of BC Cancer in Vancouver.

Both studies were published simultaneously in the .

Until 5 years ago, testosterone suppression, with or without NSAA, was the only available therapy for mCSPC. Since then, and (Zytiga), drugs with survival benefits in mCRPC, demonstrated a survival advantage for mCSPC. As reported earlier this year, enzalutamide plus hormonal therapy improved radiographic progression-free survival (rPFS) in mCSPC, but data for OS remained immature.

ENZAMET

Sweeney reported initial findings from the multinational phase III randomized , involving 1,125 men with mCSPC. Investigators at centers in Australia, New Zealand, England, Ireland, Canada, and the U.S. randomized patients to testosterone suppression plus a first-generation NSAA or enzalutamide. Patients in both treatment arms had the option to receive concurrent docetaxel.

The primary endpoint was OS, and the key secondary endpoint was PFS, defined as the time to a rise in PSA, clinical progression, or death.

The study population had a median age of 69, 45% received concurrent docetaxel, and 52% had high-volume metastatic disease. Sweeney said 71% of patients who received concurrent docetaxel had high-volume diseases as compared with 37% of patients who did not get docetaxel.

The 8% absolute difference in 36-month OS represented a 33% reduction in the hazard ratio in favor of enzalutamide (95% CI 0.52-0.86). Treatment with enzalutamide was associated with a 61% reduction in the PFS hazard (95% CI 0.33-0.47, P<0.001). Limiting the definition of PFS to time to clinical progression produced an HR of 0.40 (95% CI 0.33-0.49, P<0.001).

A subgroup analysis showed that enzalutamide significantly reduced the PFS hazard in patients who received concurrent docetaxel (HR 0.48, 95% CI 0.37-0.62) and those who did not (HR 0.34, 95% CI 0.26-0.44). Patients treated with docetaxel had a 10% reduction in the OS hazard, which did not reach statistical significance (95% CI 0.62-1.31), but the hazard was 47% lower with enzalutamide in the patients who did not receive docetaxel (95% CI 0.37-0.75).

Sweeney noted that more patients treated with enzalutamide and docetaxel received salvage therapies, which could have contributed to the lack of survival benefit in that subgroup.

TITAN

Chi reported initial findings from the multinational phase III , which involved 1,052 men with mCSPC. Eligible patients could have prior docetaxel treatment, and androgen deprivation therapy (ADT) enrollment criteria consisted of ≤6 months for mCSPC or ≤3 years for local disease. All patients received ADT and were randomized to apalutamide or placebo. The trial had coprimary endpoints of rPFS and OS.

The study population had a median age of 68-69, >60% had high disease volume, and 10%-11% had prior docetaxel treatment. Data analysis occurred after a median follow-up of 22-23 months for OS. Chi said 66% of the apalutamide group remained on treatment as compared with 46% of the ADT-placebo group.

The results showed that apalutamide was associated with a 33% reduction in the risk of death (95% CI 0.51-0.89), although median OS had yet to be reached in either treatment arm. Treatment with apalutamide led to a 20% absolute difference in rPFS at 24 months (68% vs 48%), representing a 52% reduction in the HR (95% CI 0.39-0.60, P<0.0001). The ADT-placebo group had a median rPFS of 22.1 months, whereas the median had yet to be reached in the apalutamide group.

Time to initiation of cytotoxic therapy increased significantly (P<0.0001) with apalutamide, and all other secondary endpoints favored the combination arm, said Chi.

Rates of adverse events (all grades, grade 3/4, and serious) were similar between treatment groups. Health-related quality of life did not differ significantly between the apalutamide and placebo groups.

The TITAN results added to evidence that combining ADT with chemotherapy or androgen-targeted therapy improves survival in mCSPC, said ASCO invited discussant Michael Carducci, MD, of Johns Hopkins Kimmel Cancer Center in Baltimore.

"Androgen deprivation therapy and apalutamide for hormone-sensitive prostate cancer improved survival, thus reinforcing the standard of ADT plus a single agent, whether it be docetaxel, abiraterone, enzalutamide, and now apalutamide," he said.

Carducci noted that the subgroup analysis showed certain groups did not appear to benefit as much or at all from apalutamide: patients with visceral disease, low disease volume, prior docetaxel therapy, and older patients (ages >75).

"This disease state -- metastatic hormone-sensitive prostate cancer -- is broadly heterogeneous, and the treatment benefit we offer with these drugs is not consistent in all the subsets," he said. "We really have to do a better job ... to get better predictors of which patients will respond to which drugs. We're still not sure which drug to use when."