Improved Survival with Enzalutamide in Biochemically Recurrent Prostate Cancer

Author(s): Neal D. Shore, M.D.¹; Murilo de Almeida Luz, M.D.²; Ugo De Giorgi, M.D., Ph.D.³; Martin Gleave, M.D.⁴; Geoffrey T. Gotto, M.D., M.P.H.⁵; Christopher M. Pieczonka, M.D.⁶; Gabriel P. Haas, M.D.⁷; Choung-Soo Kim, M.D.⁸; Miguel Ramirez-Backhaus, M.D.⁹; Antti Rannikko, M.D., Ph.D.^10,11; Matko Kalac, M.D., Ph.D.¹²; Swetha Sridharan, M.B., B.S.¹³; Matt Rosales, Ph.D.⁷; Yiyun Tang, Ph.D.¹⁴; Ronald F. Tutrone, Jr., M.D.¹⁵; Balaji Venugopal, M.B., B.S., M.D.^16,17; Arnauld Villers, M.D., Ph.D.¹⁸; Henry H. Woo, M.B., B.S., D.Med.Sc.^19,20; Fong Wang, M.D., Ph.D.¹⁴; Stephen J. Freedland, M.D.^21,22;

Source: DOI: 10.1056/NEJMoa2510310

Dr. Maen Hussein's Thoughts

Overall survival was 78.9% in the combination group compared with 69.5% in the leuprolide-alone group (HR 0.60). Enzalutamide monotherapy resulted in an overall survival of 73.1%, which was not statistically significant. We were already aware of the progression-free survival benefit; now we have overall survival data. This case was also presented in the MOC questions, where the correct answer was to add enzalutamide for a patient with a rising PSA on an LHRH agonist without imaging evidence of disease.

BACKGROUND

In the phase 3 EMBARK trial, enzalutamide plus leuprolide and enzalutamide monotherapy were associated with longer metastasis-free survival than leuprolide alone among patients with biochemically recurrent prostate cancer. The final analysis of overall survival has not been reported.

METHODS

We randomly assigned patients with prostate cancer who had high-risk biochemical recurrence in a 1:1:1 ratio to receive enzalutamide plus leuprolide (the combination group), leuprolide alone (the leuprolide-alone group), or enzalutamide monotherapy (the monotherapy group). The primary end point was metastasis-free survival, assessed in the combination group as compared with the leuprolide-alone group. Overall survival was an alpha-controlled, key secondary end point. Updated results for prespecified secondary end points, including the time to first use of new antineoplastic therapy and the time to the first symptomatic skeletal event, were summarized descriptively, as was progression-free survival with the first subsequent therapy, an exploratory end point. Research Summary Enzalutamide in Biochemically Recurrent Prostate Cancer

RESULTS

The 8-year overall survival was 78.9% (95% confidence interval [CI], 73.9 to 83.1) in the combination group and 69.5% (95% CI, 64.0 to 74.3) in the leuprolide-alone group; the hazard ratio for death was 0.60 (95% CI, 0.44 to 0.80; P

CONCLUSIONS

Overall survival was significantly longer with the combination of enzalutamide and leuprolide than with leuprolide alone among patients with prostate cancer with high-risk biochemical recurrence. Enzalutamide monotherapy was not superior to leuprolide alone in the analysis of overall survival. (Funded by Pfizer and Astellas Pharma; EMBARK ClinicalTrials.gov number, NCT02319837.)

Author Affiliations

¹START Carolinas, Myrtle Beach, SC; ²Division of Urologic Oncology, Erasto Gaertner Hospital, Curitiba, Brazil; ³Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori Dino Amadori, Meldola, Italy; ⁴Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada; ⁵Southern Alberta Institute of Urology, University of Calgary, Calgary, Canada; ⁶Clinical Research, U.S. Urology Partners and Associated Medical Professionals of New York, Syracuse; ⁷Oncology Global Development, Astellas Pharma, Northbrook, IL; ⁸Department of Urology, Ewha Womans University Mokdong Hospital, Seoul, South Korea; ⁹Servicio de Urología, Fundación Instituto Valenciano de Oncología, Valencia, Spain; ¹⁰Department of Urology and Research Program in Systems Oncology, University of Helsinki, Helsinki; ¹¹Helsinki University Hospital, Helsinki; ¹²Oncology Division, Pfizer, New York; ¹³Department of Radiation Oncology, Calvary Mater Newcastle, Waratah, NSW, Australia; ¹⁴Oncology Division, Pfizer, South San Francisco, CA; ¹⁵Chesapeake Urology Research Associates, Towson, MD; ¹⁶Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, United Kingdom; ¹⁷University of Glasgow, Glasgow, United Kingdom; ¹⁸Department of Urology, University of Lille, Claude Huriez Hospital, Centre Hospitalier Universitaire Lille, Lille, France; ¹⁹Department of Urology, Blacktown and Mount Druitt Hospitals, Blacktown, NSW, Australia; ²⁰Department of Uro-Oncology, Chris O’Brien Lifehouse, Camperdown, NSW, Australia; ²¹Department of Urology, Samuel Oschin Comprehensive Cancer Institute, Cedars–Sinai Medical Center, Los Angeles; ²²Durham Veterans Affairs Administration Medical Center, Durham, NC

Radiographic Progression With and Without Prostate-Specific Antigen Rise in Patients With Advanced Prostate Cancer Treated With Enzalutamide

An important post-hoc analysis from ARCHES and PROSPER that quantifies something we've suspected clinically, roughly 1 in 4 enzalutamide-treated patients who progress radiographically have no prostate-specific antigen (PSA) rise, and the majority won't meet PCWG2/3 PSA progression criteria. Liver metastases were 5-fold more common at radiographic progression on enzalutamide versus control, suggesting lineage plasticity and AR-independent clones are the culprit. Bottom line for practice: don't wait for PSA to rise before imaging your metastatic hormone-sensitive prostate cancer (mHSPC) and nonmetastatic castration-resistant prostate cancer (nmCRPC) patients on ARPIs, periodic cross-sectional imaging, especially in the first two years, is warranted regardless of PSA trend.

Alliance A222001: Oxybutynin Versus Placebo for the Treatment of Hot Flashes in Patients Receiving Androgen-Deprivation Therapy for Prostate Cancer

Solid pragmatic phase II showing oxybutynin 2.5mg and 5mg BID (twice a day) both beat placebo for hot flash reduction in men on androgen-deprivation therapy (ADT), with no serious toxicities beyond expected dry mouth. Given that venlafaxine failed in this population and megestrol/medroxyprogesterone carry real concerns, this gives us an evidence-based option we can feel good about reaching for, especially in patients who also have urinary symptoms. Neurokinin B (NKB) antagonists are coming but not yet studied here, so oxybutynin fills a real gap now.

PARP and Androgen-Signaling Inhibition plus ADT in Metastatic Prostate Cancer

Moving PARP inhibition earlier into the hormone-sensitive androgen pathway modulation–sensitive (APMS) setting, this trial shows talazoparib plus enzalutamide cuts the risk of progression or death in half (HR 0.48) in HRR-altered metastatic prostate cancer, with an impressive 3-year progression-free survival (PFS) of 77% versus 56%. The benefit extends beyond BRCA1/2 to ATM and CDK12 as well, which is clinically meaningful given that two-thirds of this population was non-BRCA.

Metformin Active Surveillance Trial in Low-Risk Prostate Cancer

Metformin did not significantly reduce the risk of disease progression compared with active surveillance in patients with low-risk prostate cancer.

177Lu-Prostate-Specific Membrane Antigen Neoadjuvant to Stereotactic Ablative Radiotherapy for Oligorecurrent Prostate Cancer (LUNAR): An Open-Label, Randomized, Controlled, Phase II Study

For our radiation oncology colleagues, the addition of PSMA-directed therapy prior to stereotactic body radiation therapy (SBRT) improved progression-free survival (PFS) in patients with oligometastatic prostate cancer. Two cycles of PSMA-directed therapy were administered before SBRT.