Steve Freedland: Hi, I'm Steve Freedland, a urologist at Cedars-Sinai Medical Center in Los Angeles and the Durham VA Hospital in Durham, North Carolina. It is my pleasure today to present to you our manuscript entitled A Phase 3 Randomized Study of Enzalutamide Plus Leuprolide and Enzalutamide Monotherapy in High-Risk Nonmetastatic Hormone-Sensitive Prostate Cancer with Rising PSA After Local Therapy: EMBARK Study Design.

The clinical trial is funded by Pfizer and Astellas Pharma, the co-developers of enzalutamide. To disclose my conflict of interest... I'm a consultant to Astellas, Pfizer, Janssen, Bayer, Sanofi, Dendreon, Myovant, AstraZeneca, and Merck. Within 10 years after definitive therapy for prostate cancer, we know that a sizeable percentage of patients, up to 50% of those, will develop a biochemical recurrence. This is often the sign of micrometastatic disease and is a forbearer of, ultimately, metastatic disease and prostate cancer death. We know that those who have a short doubling time, less than nine months, are considered to have high risk for rapid disease progression and greater risk of prostate cancer-specific death.

We know that in those with metastatic castrate-sensitive disease, the treatment intensification with novel hormonal therapies, including enzalutamide, prolongs life, delays time to CRPC while maintaining quality of life. The question is whether similar results would be seen in non-metastatic high-risk prostate cancer. That was the objective of EMBARK: was to value the efficacy and safety of enzalutamide in combination with leuprolide acetate or monotherapy compared with leuprolide alone earlier in the disease course and specifically in those with high-risk non-metastatic HSPC.

EMBARK is an international randomized phase three study of enzalutamide plus leuprolide, enzalutamide monotherapy, or placebo plus leuprolide in men with high-risk non-metastatic prostate cancer after either radical prostatectomy or radiotherapy or both. High-risk patients are characterized as those having a PSA doubling time less than nine months and a screening PSA greater than one for those who under want prior radical prostatectomy with or without radiation, and greater than two nanograms per mil above the nadir for those who received primary radiation.

The target enrollment was 1050 patients. Inclusion criteria included multiple different factors, the most important being that prostate cancer treated by radical prostatectomy, radiation therapy, or both with curative intent, biochemical recurrence, PSA doubling time less than nine months, and with the PSA thresholds as previously mentioned. Patients also had to have a serum testosterone greater than 150 and an ECOG at zero or one.

Exclusion criteria included prior or present evidence of distant metastatic disease as seen on conventional imaging, including CT, MRI, or bone scans, as well as prior hormonal therapy, except as allowed as part of neoadjuvant and adjunct therapy as long as less than three years and greater than nine months before randomization. Additionally, prior use of novel hormonal therapies or chemotherapy were exclusion criteria, as well as prior investigational therapies.

Patients were then randomized one-to-one-to-one to enzalutamide plus leuprolide or placebo plus leuprolide in a double-blind fashion or enzalutamide monotherapy in an open-label. Patients were then stratified by screening PSA less than 10 versus greater than 10, PSA doubling time less than three months versus three to nine months, and prior hormonal therapy, yes-no. An important element of EMBARK was that study treatment was suspended once the PSA was less than 0.2 or if it was less than 0.2 at week 36 and then restarted when the PSA was greater than or equal to five for those without prior radical prostatectomy and greater than or equal a two with those who had received primary prostatectomy.

A key feature of the protocol is monitoring the PSA levels at week 36 and then suspending study drug at week 37 for those who had a very good PSA response, defined as less than 0.2, with the idea that intermittent hormonal therapy is non-inferior to continuous for overall survival in this disease space while trying to preserve quality of life for those who are having a very good response.

A central laboratory was used to quantify the on-treatment PSA levels. Imaging studies were conducted every six months with CT and MRI to detect soft tissue disease and whole body bone scans for bone metastasis. The primary outcome is metastasis-free survival, which is either development, metastasis, or death, between the double-blind arms, which is enzalutamide plus leuprolide versus placebo plus leuprolide.

Key secondary outcomes include MFS between enzalutamide monotherapy versus placebo plus leuprolide, time to PSA progression, time to first use of antineoplastic therapy, and overall survival for the double-blind arms.

Patient-reported outcomes will also be assessed and will be a key measure to ensure that quality of life is maintained. Periodic monitoring of safety is conducted by an independent external data monitoring committee. The study was initiated in December 2014, with a target enrollment achieved on June 2018. Study results are expected in the summer or early fall of 2022.

Concluding remarks: we expect that the results from EMBARK will change how patients with high-risk nmHSPC are managed. I'd like to thank my co-authors and everybody who's been involved in the EMBARK trial. It has been many years of long hard effort by a lot of people. I'm particularly thankful to all the patients who agreed to participate in this what, hopefully, will be an important practice-changing trial. Thank you for your attention.