TREATMENT FIR PROSTATE CANCER

Enzalutamide (Xtandi, Astellas) has already demonstrated a benefit in men with metastatic and nonmetastatic castration-resistant prostate cancer (CRPC), but its efficacy when combined with androgen deprivation therapy (ADT) has until now been unclear.

Results from the phase 3 ARCHES trial show that enzalutamide added onto ADT in men with metastatic hormone-sensitive prostate cancer (mHSPC) improved outcomes as compared with ADT alone.

The addition of enzalutamide to ADT significantly extended radiographic progression-free survival (rPFS), and that was observed across all prespecified endpoints, explained lead author Andrew Armstrong, MD, professor of Medicine, Surgery, Pharmacology and Cancer Biology, and director of research in the Duke Cancer Institute's Center for Prostate and Urologic Cancers, Durham, NC.

"The risk of radiographic progression or death was reduced by 61% vs ADT alone," said Armstrong. "The significant benefit in rPFS was seen across all prespecified subgroups, including low- and high-disease volume and with or without prior docetaxel therapy."

There was also significant improvement in other endpoints, including time to prostate-specific antigen (PSA) progression, reduction in the risk of starting a new antineoplastic therapy, and objective response rate, as compared to ADT alone.

Armstrong presented the results here at the Genitourinary Cancers Symposium (GUCS) 2019.

Commenting on the study, Bobby Liaw, MD, clinical director of genitourinary oncology at Mount Sinai Health System in New York City, put the new results into context.

In recent years, he said, "clinical trials have demonstrated the clinical benefits of the addition of docetaxel or abiraterone, which had both previously been reserved for the mCRPC setting, to standard-of-care ADT for the treatment of mHSPC."

"The phase 3 ARCHES study continues this trend by showcasing that the combination of enzalutamide plus ADT demonstrates a significantly improved radiographic progression-free survival benefit as compared to ADT alone," Liaw said, adding that secondary endpoints also heavily favored the addition of enzalutamide. 

"As more highly active therapeutic agents continue to find their way into the mHSPC space, optimal drug selection and sequencing will be a growing issue," noted Liaw, who was not involved with the current research. He cautioned, however, that there is no definitive study data available yet to provide clear guidance. 

"Additional follow up of the ARCHES study cohort may start to shed some light on this clinical question, as 18% of enrolled patients had received prior docetaxel as part of their mHSPC management," he added.

an D. Davis, MBBS, PhD, FRACP, FAChPM, Monash University Eastern Health Clinical School, Australia, who served as discussant for the study at the meeting, pointed out that overall survival data is not yet available, and that  it is yet unknown if the treatment is cost effective.

Hence, he suggested that "cautiously, this should probably not yet change practice."

Davis added that, in general, the field "continues to evolve rapidly and some of these studies have given us clues to different cancer biologies."

"Possibly, we may also have to think in terms of new diagnostics and how they may redefine conventional classifications and treatments," Davis said. "Effects on practice depend on local healthcare systems and funding models, and high bars should be set for new treatments."

Study Details 

The ARCHES trial included patients with both low- and high-volume disease and with and without prior docetaxel therapy..

A total of 1150 men were randomized to receive either ADT plus enzalutamide 160 mg/day (n = 574) or ADT plus placebo (n = 576). The patients were stratified by disease volume and prior docetaxel therapy.

At the time of data cut-off (October 14, 2018), 769 patients remained on treatment — 437 (76%) for enzalutamide and ADT and 332 (56%) for ADT alone. The median follow up time was 14.4 months, and at data cutoff, there were 262 events of radiographic progression (77 in the combination group and 185 for the ADT alone group). There were also 25 deaths without radiographic progression.

The median time to rPFS event was not reached in the combination group and 19.4 months in the ADT alone group (hazard ratio [HR], 0.39; P < .0001).

Significant improvements in rPFS were also observed in all prespecified subgroups, including disease volume, pattern of disease localization at baseline, geographic region, and prior docetaxel use (HRs 0.24 - 0.53).

Combination enzalutamide plus ADT was also superior to ADT alone when looking at the secondary endpoints. The risk of PSA progression was reduced (HR, 0.19; P < .0001) and the median time to castration resistance was not reached in the combination therapy group vs 13.9 months for ADT alone (HR, 0.28; P < .0001).

The risk of starting a new antineoplastic therapy was reduced by 72% in the combination group (HR, 0.28; P < .0001) compared to ADT alone. Undetectable PSA and objective response rates were also higher (68.1% vs 17.6%; P < .0001 and 83.1% vs 63.7%; P < .0001, respectively). Treatment with enzalutamide plus ADT did not significantly reduce the risk of deterioration in urinary symptoms compared to ADT alone.

"Analysis of quality of life is still ongoing and will be presented at upcoming meetings," said Armstrong. "These men were generally asymptomatic and had a very high quality of life."

Overall survival data are also immature right now, he explained. "There have been 84 deaths and the hazard ratio favors enzalutamide. The final overall survival analysis will be conducted after there are 342 deaths."

Armstrong noted that adverse events were generally consistent with those reported in other enzalutamide clinical trials. Grade 3 or 4 adverse events were reported in 23.6% who received enzalutamide vs 24.7% for ADT alone, and the most common events reported in the combination group included hot flashes, fatigue, arthralgia, hypertension, nausea, musculoskeletal pain, diarrhea, asthenia, and dizziness.

"Following unblinding at the end of the double-blind treatment period and a statistically significant positive outcome from the primary endpoint analysis, eligible patients are being offered the opportunity to be treated with enzalutamide and ADT in a prespecified open-label extension," Armstrong concluded.

The study was funded by Astellas Pharma Inc. and Medivation LLC, a Pfizer Company, the codevelopers of enzalutamide. Armstrong has disclosed relationships with Dendreon; Janssen Oncology; Sanofi, Astellas Scientific and Medical Affairs Inc; AstraZeneca; Bayer; Clovis Oncology; Janssen Biotech; Medivation; Pfizer; Bayer; Active Biotech (Inst); Astellas Pharma; Bristol-Myers Squibb (Inst); Gilead Sciences (Inst); Novartis (Inst); Pfizer (Inst); Roche/Genentech (Inst); and has patents, royalties, and other intellectual property from  Circulating tumor cell novel capture technology (Inst). The other study coauthors have disclosed no relevant financial relationships. Davis has disclosed multiple relationships with industry. Liaw is part of an investigator-initiated clinical trial for prostate cancer that is sponsored by Bayer and Sanofi.

Genitourinary Cancers Symposium (GUCS) 2019: Abstract 687. Presented February 14, 2019.