ARCHES and ENZAMET Trials Confirm Long-Term Xtandi Efficacy in Metastatic Hormone-Sensitive Prostate Cancer

Long-term data from the Phase III ARCHES trial (NCT02677896) and Phase III ENZAMET trial (NCT02446405) reinforce the durability of Xtandi (enzalutamide; Astellas and Pfizer) in improving survival outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC).^1-3

ARCHES trial data, to be presented at the upcoming American Society of Clinical Oncology (ASCO) Annual Meeting, show a sustained relative reduction in the risk of death with frontline Xtandi added to androgen deprivation therapy (ADT) compared to ADT monotherapy.

“Historically, the likelihood of survival at five years for men with [mHSPC] was low, but with advancements in initial treatment intensification like what we’ve seen with XTANDI, this is now becoming the standard,” ARCHES primary investigator Andrew J. Armstrong, MD, ScM, director of Research at the Center for Prostate & Urologic Cancers, Duke Cancer Institute, Durham, NC, said in a press release. “In our five-year follow up of the global ARCHES trial, two-thirds of men are now surviving five years, representing a 13% absolute and 30% relative improvement over standard hormonal therapy alone, with benefits in patients with high and low disease burden that are meaningful to our patients.”¹

• Xtandi is an androgen receptor signaling inhibitor that is a standard of care worldwide for mHSPC, metastatic castration-resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC), and non-mHSPC with high-risk biochemical recurrence.
• Xtandi has multiple approvals in prostate cancer, most recently in November 2023 for the treatment of nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis.
• To date, more than 300,000 men in the United States have been prescribed Xtandi, which has demonstrated improved overall survival (OS) in patients with mCRPC, nmCSPC, and metastatic castration-sensitive prostate cancer.⁴

Phase III ARCHES Trial Shows 5-Year Survival Gains With Xtandi in mHSPC

• The randomized, double-blind, placebo-controlled, multi-national ARCHES trial randomly assigned 1,150 patients with mHSPC to receive Xtandi 160 mg daily or placebo.
• Patients enrolled in the trial continued taking a luteinizing hormone-releasing hormone agonist or antagonist, or had a history of bilateral orchiectomy.
• The trial included individuals with both low- and high-volume disease, those newly diagnosed with mHSPC, and those previously administered definitive therapy who went on to develop metastatic disease. Investigators also enrolled patients with mHSPC recently treated with docetaxel but who did not experience disease progression.
• The trial’s primary endpoint was radiographic progression-free survival (rPFS), defined as time from randomization to first objective evidence of radiographic disease progression as assessed by central review, or death within 24 weeks of stopping treatment.
• Key secondary endpoints included OS at the time of the final analysis, as well as a post hoc five-year analysis to quantify long-term OS at a clinically meaningful follow-up date of five years.

Survival Benefits Observed Across High- and Low-Volume Disease Subgroups

• ARCHES trial data to be presented at ASCO will show that patients with high-volume disease achieved a 36-month improvement in median OS (HR: 0.70; 95% CI: 0.56-0.88).
• The data will show a consistent survival improvement in patients with low-volume disease (HR: 0.71; 95% CI, 0.49-1.05) and in both those previously treated with docetaxel (HR: 0.67; 95% CI, 0.43- 1.05) and those not previously treated with docetaxel (HR: 0.71; 95% CI, 0.57-0.88).

Safety Profile Remains Consistent Over Long-Term Xtandi Treatment

In terms of safety, treatment-emergent adverse events at the five-year follow-up date were consistent with prior findings and no new safety signals were reported.

“The survival benefits of intervention with Xtandi in advanced prostate cancer are well-recognized,” Shontelle Dodson, executive vice president, head of Medical Affairs, Astellas, said in the release. “The collective—and growing—body of data for Xtandi continues to reinforce its long-term efficacy and patient impact in prostate cancer, including in the metastatic setting, and shows that Xtandi is changing the trajectory of those living with the disease.”¹

ENZAMET Trial Confirms 8-Year Survival Advantage With Xtandi Plus ADT

At ASCO, investigators will also present eight-year data from the randomized Phase III ENZAMET trial.

• The trial compared Xtandi plus ADT to a conventional non-steroidal anti androgen (NSAA) plus ADT in 1,125 patients with newly diagnosed metastatic prostate cancer.
• OS served at the trial’s primary endpoint, with secondary endpoints that included prostate-specific antigen PFS time, clinical PFS time, and safety.³
• At a median follow-up of 98 months, median OS in the Xtandi cohort was 8.0 years compared to 5.8 years in the NSAA cohort (HR: 0.73; 95% CI, 0.63-0.86).
• At 96 months, OS was 50% in the Xtandi cohort compared to 40% in the NSAA cohort. PFS data also favored Xtandi over NSAA (HR: 0.49; 95% CI, 0.42-0.57).
• Among 622 patients who died in the trial, 468 deaths were associated with prostate cancer, with 207 in the Xtandi cohort compared to 261 in the NSAA cohort.
• A total of 154 deaths were attributed to other causes and occurred at a similar rate in both cohorts, with 78 in the Xtandi cohort compared to 76 in the NSAA cohort.
• Mean duration of treatment was 58 months in the Xtandi cohort compared to 36 months in the NSAA cohort. Thirty-three percent of patients remained on Xtandi, of whom 88% remained at the full dosing level of 160 mg.

Xtandi Continues to Define Standard of Care in Advanced Prostate Cancer

“Data from the eight-year follow-up of Xtandi are highly encouraging, as they show the [PFS] and [OS] benefits are sustained out to at least eight years,” ENZAMET follow-up primary investigator Christopher Sweeney, MBBS, DHS, FRACP, ANZUP Cancer Trials Group Limited, Sydney, Australia, said in the release. “These results further support the value of Xtandi as a treatment regimen for metastatic hormone-sensitive prostate cancer.”¹

References

1. Astellas and Pfizer’s XTANDI™ (enzalutamide) Shows Long-Term Overall Survival in Metastatic Hormone-Sensitive Prostate Cancer. News release. Pfizer. May 22, 2025. Accessed May 23, 2025. https://www.pfizer.com/news/press-release/press-release-detail/astellas-and-pfizers-xtanditm-enzalutamide-shows-long-term

2. A Study of Enzalutamide Plus Androgen Deprivation Therapy (ADT) Versus Placebo Plus ADT in Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC) (ARCHES). ClinicalTrials.gov. Updated December 12, 2024. Accessed May 23, 2025. https://clinicaltrials.gov/study/NCT02677896?term=NCT02677896

3. Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET). ClinicalTrials.gov. Updated February 6, 2025. Accessed May 23, 2025. https://www.clinicaltrials.gov/study/NCT02446405?cond=NCT02446405

4. Pfizer and Astellas’ XTANDI® Approved by U.S. FDA in Earlier Prostate Cancer Treatment Setting. Astellas Pharma Inc. News release. November 17, 2023. Accessed May 23, 2025. https://www.astellas.com/en/news/28626