Enzalutamide plus ADT improves rPFS in hormone-sensitive PCa

San Francisco-Enzalutamide (XTANDI) added to androgen deprivation therapy (ADT) significantly extended radiographic progression-free survival (rPFS) compared with ADT alone in a large international phase III study of men with metastatic hormone-sensitive prostate cancer (mHSPC).

In the ARCHES study, at a median follow-up of 14.4 months, median rPFS was not reached in the enzalutamide arm compared with 19.4 months in the placebo arm, corresponding to a 61% reduction in the risk of radiographic progression or death (HR=0.39; p<.0001), said Andrew J. Armstrong, MD, at the Genitourinary Cancers Symposium in San Francisco.

In an interim analysis of overall survival (OS), data are immature with 39 deaths in the enzalutamide arm and 45 in the placebo arm (HR 0.81; p=.3361), about one fourth of the number of events required for final analysis. The median OS had not been reached in either arm; some 93% of patients were still alive at the interim analysis.

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ARCHES was a double-blind trial of 1,150 patients with histologically verified mHSPC (both low- and high-volume disease) conducted across North America, Europe, and the Asia-Pacific region. Participants were randomized to enzalutamide, 160 mg daily, or placebo.

Patients who received recent treatment with docetaxel (Taxotere) but did not have disease progression were allowed into the trial, a departure from recently published studies in mHSPC in which men who received prior docetaxel were excluded, noted Dr. Armstrong, of Duke University, Durham, NC. Patients were allowed to receive ADT <3 months prior to entry unless they received prior docetaxel, in which case they could have had ADT for up to 6 months before study entry. The primary endpoint was rPFS.

At initial diagnosis, 70% in the enzalutamide arm and 63% in the placebo arm had distant metastasis, about two-thirds in each arm had high-volume disease, and two-thirds in each arm had a Gleason score >8. About 18% overall had received prior docetaxel. The median duration of prior ADT was 1.6 months.

Median duration of therapy was 12.8 months for enzalutamide plus ADT versus 11.6 months for placebo plus ADT. As of the data cutoff of Oct. 14, 2018, “Nearly 76% of patients remain on the study drug for enzalutamide and 58% remain on ADT alone,” Dr. Armstrong said.

The 12-month event-free rate estimate was 84.5% for enzalutamide plus ADT and 63.7% for placebo plus ADT.

Significant benefit on rPFS to enzalutamide was realized in clinically important subsets of patients stratified by low and high disease volume and prior docetaxel. A significant advantage to enzalutamide on rPFS was also observed across subgroups by age, geographic region, Gleason score, disease localization and pattern of spread, volume of disease, and receipt of prior docetaxel.

“This important, nearly 20% subset of patients, had a hazard ratio of 0.53 indicating a 47% improvement in the hazard of progression or death over time,” said Dr. Armstrong.

Next: Enzalutamide plus ADT reduced the risk of PSA progression by 81%Other findings included:

• Enzalutamide plus ADT reduced the risk of PSA progression by 81% (p<.0001). The median time to PSA progression was not reached in either group. The 12-month event-free rate estimate was 91.2% for enzalutamide plus ADT and 62.8% for placebo plus ADT.

• Of the patients with detectable PSA at baseline, enzalutamide plus ADT significantly increased the PSA undetectable rate compared with placebo/ADT (68.1% vs. 17.6% [difference of 50.5%]; p<.0001).

• The time to initiation of new antineoplastic therapy was also reduced in the enzalutamide/ADT arm versus placebo/ADT (HR 0.28; p<.0001).

• More than one-third (36.7%) of the enzalutamide arm and 23.1% of the placebo arm achieved a complete response (disappearance of all lesions on imaging). The overall response rates were 83.1% for enzalutamide and 63.7% for placebo (p<.0001).

• The rate of adverse events was similar in each arm, as was the proportion of patients who had to discontinue study due to adverse events (enzalutamide: 7.2%; placebo: 5.2%). The rate of grade >3 adverse events was also similar (24.3% vs. 25.6%, respectively).

• The addition of enzalutamide to ADT did not have a significant impact on time to deterioration of urinary symptoms (HR 0.88; p=.2162) or the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score compared with placebo. “While we did not show a difference in the impact on urinary symptoms or FACT-P scores, most of these patients during 14.4 months of follow-up maintained a high level of quality of life,” Dr. Armstrong said.

Following the unblinding at the end of double-blind treatment, all patients in the placebo group are being offered enzalutamide in an open-label extension protocol.

Also see: Findings question validity of large PCa trial

Invited discussant Ian D. Davis, MD, of Monash University and Eastern Health, Melbourne, Australia, said that the primary endpoint in ARCHES, rPFS, is probably clinically meaningful, given that rPFS was correlated with OS for enzalutamide in the PREVAIL study. Another positive indicator of benefit was the PSA undetectable rate (68.1%), which was much higher than that reported with abiraterone (ZYTIGA)/prednisone (47.6%) in LATITUDE and with docetaxel (32%) in CHAARTED.

“If you have an undetectable PSA (≤0.2) at 7 months after commencing the treatment, this is associated with much better outcomes,” he said.

Until the OS data are mature, ARCHES should probably not change practice, said Dr. Davis, although topline data recently released from the TITAN study demonstrated that apalutamide (ERLEADA) showed a significant benefit in both rPFS and OS as co-primary endpoints in patients with metastatic castration-sensitive prostate cancer.

Astellas Pharma Inc. and Medivation LLC funded the study. Dr. Armstrong has several disclosures related to Astellas Scientific and Medical Affairs Inc., Medivation, Pfizer, and other pharmaceutical companies; for full disclosures, click here.