Longer-term follow-up results from an open-label extension of the Phase 3 ARCHES study (NCT02677896) show an overall survival (OS) benefits and reduction in the risk of death in men with metastatic hormone-sensitive prostate cancer (mHSPC) treated with the androgen receptor pathway inhibitor (ARPI) enzalutamide (Xtandi™; Astellas Pharma and Pfizer) plus androgen deprivation therapy (ADT) compared to placebo plus ADT.
Metastatic Hormone-Sensitive Prostate Cancer
Metastatic hormone-sensitive prostate cancer (mHSPC), also known as metastatic castration-sensitive prostate cancer, refers to prostate cancer that still responds to hormonal therapy and has spread outside of the prostate gland to other parts of the body, such as the lymph nodes, bones, lungs and liver. [2]
ARCHES study
The Phase 3 ARCHES study is a randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,150 patients with metastatic hormone-sensitive prostate cancer.
Patients in the ARCHES trial were randomized to receive enzalutamide 160 mg daily or placebo and continued on a luteinizing hormone-releasing hormone (LHRH) agonist or antagonist or had a history of bilateral orchiectomy.
The ARCHES trial included patients with both low- and high-volume disease and both newly diagnosed patients with mHSPC and patients who had prior definitive therapy and subsequently developed metastatic disease.
Survival Benefit
Five-year follow-up data from the Phase 3 ARCHES trial demonstrated that enzalutamide in combination with androgen deprivation therapy (ADT) reduces risk of death by 30%
After a median follow-up of 61.4 months, treatment with enzalutamide plus ADT was associated with a 66% probability of survival at five years compared to 53% probability of survival with placebo plus ADT
enzalutamide is the first and only androgen receptor inhibitor to demonstrate an overall survival benefit at five years in men with metastatic hormone-sensitive prostate cancer
These data, which show wide-ranging effect of treatment with enzalutamide plus ADT across various patient subgroups, notably those with high-volume disease, no prior docetaxel use, and synchronous disease, will be presented during an oral presentation (Abstract #5005) at the annual meeting of the American Society of Clinical Oncology (ASCO) scheduled to be held May 30 to June 3, 2025 in Chicago.
“Historically, the likelihood of survival at five years for men with metastatic hormone-sensitive prostate cancer was low, but with advancements in initial treatment intensification like what we’ve seen with enzalutamide, this is now becoming the standard,” said Andrew J. Armstrong, MD, ScM, Director of Research at the Center for Prostate & Urologic Cancers, Duke Cancer Institute, Durham, NC, and ARCHES primary investigator.
“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.”
In patients with high-volume disease (HR: 0.70; 95% CI: 0.56-0.88) a 36-month improvement in median Overall Survival (OS) was observed. Additional clinically relevant subgroups of patients were evaluated, showing consistently improved survival: low-volume disease (HR: 0.71; 95% CI, 0.49-1.05); patients who had previously received docetaxel therapy (HR: 0.67; 95% CI, 0.43- 1.05) and those who had not received prior docetaxel therapy (HR: 0.71; 95% CI, 0.57-0.88).
The incidence of treatment-emergent adverse events in the five-year follow-up is consistent with prior ARCHES analyses and no new safety signals were identified.
“The survival benefits of intervention with enzalutamide in advanced prostate cancer are well-recognized,” added Shontelle Dodson, Executive Vice President, Head of Medical Affairs, Astellas.
“The collective – and growing – body of data for enzalutamide continues to reinforce its long-term efficacy and patient impact in prostate cancer, including in the metastatic setting, and shows that enzalutamide is changing the trajectory of those living with the disease,” Dodson added.
These results of the five-year follow-up from the ARCHES study will be submitted for publication in a peer-reviewed journal in the near future.
“Until recently, patients with metastatic hormone-sensitive prostate cancer faced a poor prognosis, particularly in advanced stages, often due to treatment resistance,” noted Johanna Bendell, M.D., Oncology Chief Development Officer, Pfizer.
“As the only androgen receptor inhibitor demonstrating sustained five-year survival in this patient population, these data further reinforce enzalutamide combined with androgen deprivation therapy as the standard-of-care for treating this advanced disease,” Bendell noted.
ENZAMET-Study
In addition to five-year data from the follow-up ARCHES study, eight-year data from the ENZAMET study assessing outcomes of enzalutamide versus non-steroidal anti-androgen (NSAA) – both plus testosterone suppression with or without docetaxel – in mHSPC will also be presented during a poster session at ASCO (Monday, June 2, 9:00 a.m. US CT).
This independent, Phase 3 trial sponsored by the University of Sydney (NCT02446405), led by the Australian and New Zealand Urogenital and Prostate Cancer Trials Group Limited (ANZUP) with the NHMRC (National Health and Medical Research Council) Clinical Trials Centre at the University of Sydney, demonstrated a reduction in risk of death in men with mHSPC.
This study evaluates the potential of enzalutamide plus androgen deprivation therapy (ADT) versus a conventional non-steroidal anti androgen (NSAA) plus ADT in 1,125 men with mHSPC. The primary endpoint for the trial is overall survival (OS). Additional details about ENZAMET (NCT02446405) are available on www.clinicaltrials.gov. Astellas provided funding and support for the ENZAMET trial.
“Data from the eight-year follow-up of enzalutamide are highly encouraging, as they show the progression-free survival and overall survival benefits are sustained out to at least eight years,” said Christopher Sweeney, MBBS, DHS, FRACP, ANZUP Cancer Trials Group Limited, Sydney, Australia, and ENZAMET follow-up primary investigator.
“These results further support the value of enzalutamide as a treatment regimen for metastatic hormone-sensitive prostate cancer,” Sweeney concluded.
With a median follow-up of 98 months, patients with mHSPC were treated with enzalutamide plus testosterone suppression or NSAA plus testosterone suppression, each group with or without docetaxel. The median OS in the enzalutamide group was 8.0 years and 5.8 years in the NSAA group (HR: 0.73; 95% CI, 0.63-0.86). OS at 96 months was 50% with enzalutamide and 40% for NSAA; progression-free survival (PFS) also favored enzalutamide over NSAA (HR: 0.49; 95% CI, 0.42-0.57). Prostate cancer accounted for 468 of all 622 deaths and were less frequent among those assigned enzalutamide than NSAA (207 versus 261). Other causes accounted for a total of 154 deaths and were similarly frequent among those assigned enzalutamide versus NSAA (78 versus 76). Mean duration of treatment was longer for enzalutamide (58 months) than NSAA (36 months), with 33% remaining on enzalutamide and 88% of these patients remained at the full dose of 160 mg.
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Clinical trials
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 ID NCT02677896
Enzalutamide in First Line Androgen Deprivation Therapy for Metastatic Prostate Cancer (ENZAMET) – ClinicalTrials.gov ID NCT02446405
Highlights of prescribing information
Enzalutamide (Xtandi™; Astellas Pharma and Pfizer)[Prescribing Information]
Reference
[1] Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, Tagawa ST, Nordquist LT, Vaishampayan N, El-Haddad G, Park CH, Beer TM, Armour A, Pérez-Contreras WJ, DeSilvio M, Kpamegan E, Gericke G, Messmann RA, Morris MJ, Krause BJ; VISION Investigators. Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. N Engl J Med. 2021 Sep 16;385(12):1091-1103. doi: 10.1056/NEJMoa2107322. Epub 2021 Jun 23. PMID: 34161051; PMCID: PMC8446332.
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DOI
 show an overall survival (OS) benefits and reduction in the risk of death in men with metastatic hormone-sensitive prostate cancer (mHSPC) treated with the androgen receptor pathway inhibitor (ARPI) enzalutamide (Xtandi™; Astellas Pharma and Pfizer) plus androgen deprivation therapy (ADT) compared to placebo plus ADT.){kind=link}