ESMO 2025: Discussant – EMBARK and PRESTO Trials

(UroToday.com) The 2025 European Society for Medical Oncology (ESMO) Annual Congress was host to a prostate, penile, and testicular cancers proffered paper session. Derya Tilki, MD, discussed the overall survival (OS) results from EMBARK, a randomized phase III trial of enzalutamide or placebo plus leuprolide acetate and enzalutamide monotherapy in high-risk biochemically recurrent prostate cancer, and the final results from PRESTO, a phase III trial of combined androgen blockade in patients with high-risk biochemically relapsed prostate cancer.

EMBARK is a phase III trial that included patients with a PSA ≥1 ng/ml after radical prostatectomy or ≥2 ng/ml above nadir after primary external beam radiotherapy (EBRT), with a PSA doubling time (PSADT) of ≤9 months. Patients had no evidence of metastasis on conventional imaging, and baseline testosterone was ≥150 ng/dL. Hormone therapy ≥9 months prior to enrolment was permitted. Patients underwent stratified randomization to one of three arms:

• Enzalutamide 160 mg (standard dose) + leuprolide acetate (blinded arm)
• Placebo + leuprolide acetate (blinded)
• Enzalutamide monotherapy (unblinded)

PSA was assessed at 36 weeks, and if patients had:

• PSA<0.2   Treatment was suspended at week 37, and PSA was monitored with treatment reinitiated if PSA rose again
• PSA>0.2  Treatment was continued 

The final OS analysis demonstrated that enzalutamide combination therapy was associated with a 40.3% lower rate of overall deaths, compared with leuprolide alone (8-year OS: 79% versus 69.5%; HR: 0.60, 95% CI: 0.44–0.80, p=0.0006):

In the comparison of enzalutamide monotherapy to leuprolide alone, the risk of death was 17% lower with enzalutamide monotherapy; however, this did not reach statistical significance (HR: 0.83, 95% CI: 0.63–1.10, p=0.19).
PRESTO is a randomized phase III, open-label trial in patients with biochemically relapsed prostate cancer and PSA doubling time ≤ 9 months, without distant metastases on conventional imaging (NCT03009981). Patients were randomized 1:1:1 to receive a finite 52-week treatment course with ADT, ADT + apalutamide, or ADT + apalutamide + abiraterone acetate plus prednisone, stratified by PSA doubling time (< 3 vs 3–9 months). 
For the outcome of metastasis-free survival:

• ADT + apalutamide vs. ADT: HR=0.80, 95% CI: 0.56–1.13
  • Difference in restricted mean survival over the first 48 months between ADT + apalutamide vs. ADT was 2.92 months (95% CI: 0.45–5.39)

• ADT + apalutamide + abiraterone vs. ADT: HR=0.92, 95% CI: 0.56–1.13
  • Difference in restricted mean survival over the first 48 months between ADT + apalutamide vs. ADT was 2.41 months (95% CI: -0.20–4.62) 

PSA-PFS in the testosterone recovered subset:

• ADT + apalutamide vs. ADT: HR=0.72, 95% CI: 0.55–0.93, p=0.03
  • 78% of patients recovered their testosterone levels

• ADT + apalutamide + abiraterone vs. ADT: HR=0.67, 95% CI: 0.50–0.90, p=0.008
  • 68% of patients recovered their testosterone levels

Notable differences between the two trials were as follows:

• EMBARK allowed for the inclusion of patients who had received radiotherapy, in addition to radical prostatectomy, whereas PRESTO included only post-radical prostatectomy patients
• EMBARK included an ARPI (enzalutamide) monotherapy arm, whereas PRESTO did not
• EMBARK incorporated a ‘treatment holiday’ period in PSA responders by week 37, whereas treatment in PRESTO was for a fixed duration of 52 weeks
• The primary endpoint in EMBARK was metastasis-free survival (MFS) by conventional imaging, whereas MFS was a secondary endpoint in PRESTO (conventional or next-generation imaging)

Furthermore, the PSA cut-off at study entry in the EMBARK trial was higher (≥1 ng/ml post-radical prostatectomy versus >0.5 ng/ml in PRESTO). Both trials included patients with a PSA doubling time of ≤9 months. These differences in the eligibility criteria were reflected in the baseline patient characteristics of each study. 

Dr. Tilki noted that had the patients in PRESTO and EMBARK undergone a PSMA PET/CT, then it is estimated that ~80% would have had PET-detected metastases.¹

Why is this significant? Dr. Tilki noted that the utilization of PSMA PET in this patient population leads to management changes in more than half of patients with biochemical recurrence.²

There are ongoing studies that are incorporating PSMA PET into their study design. ARASTEP (NCT05794906) will evaluate whether darolutamide, when added to ADT, improves radiologic progression-free survival by PSMA PET/CT versus placebo + ADT in patients with biochemically recurrent prostate cancer following primary therapy and PSMA PET/CT-positive lesions.

In addition to ARPI intensification in the BCR setting, additional treatment modalities evaluated have included metastasis-directed therapy (MDT), both to delay use of hormone therapy and in conjunction with systemic therapy. She highlighted a recent paper from her group that evaluated PSMA-radioguided surgery in an EMBARK-like cohort of patients with oligorecurrent hormone-sensitive prostate cancer. At study inclusion (n=111), the median PSA was 2 ng/ml and the median PSA doubling time was 4 months. A complete biochemical response (PSA ≤0.2) was observed in 48% of men. In this group of responders, the two-year BCR-free and treatment-free survivals were 50% and 65%, respectively.⁴ 

She highlighted the EXTEND trial, which evaluated the addition of MDT to intermittent hormone therapy. This was a phase II trial that included men with oligometastatic prostate cancer (≤5 metastases) and were randomized 1:1 to MDT, consisting of definitive radiation therapy to all sites of disease and intermittent hormone therapy (combined therapy arm; n = 43) or to hormone therapy only (n = 44). A planned break in hormone therapy occurred 6 months after enrollment, after which hormone therapy was withheld until progression. At a median follow-up of 22 months, progression-free survival (PFS) was improved in the combined therapy arm (HR: 0.25, p<0.001. Eugonadal PFS was also improved with MDT compared with hormone therapy only (HR: 0.32, p=0.03).⁵ An updated report from this trial has also recently demonstrated that the addition of MDT improves radiographic progression-free survival (rPFS).⁶ Notably, only a small proportion of patients in either arm used an ARPI as part of their hormonal therapy regimen.

Dr. Tilki concluded with the following take-home messages from her discussant of PRESTO and EMBARK:

• EMBARK demonstrates both MFS and OS benefits for doublet therapy versus ADT alone (but no OS benefit for enzalutamide monotherapy), establishing enzalutamide plus ADT as a standard of care in high-risk biochemically recurrent prostate cancer
• Enzalutamide monotherapy remains a treatment option after weighing the risks and benefits in the context of shared decision-making
• Intensification when moved earlier in high-risk disease prolongs survival
  • PRESTO provides supportive data for class effect in this regard (doublet better than singlet), but triplet not better than doublet
• The interpretation of PRESTO is limited by being underpowered for estimating the impact on longer-term endpoints and by the lack of intermittent scheduling
• Whether further intensification of treatment, potentially with additional PSMA PET metastasis-directed therapy, can lead to increased efficacy and longer treatment-free intervals requires prospective evaluation
• Concepts that are worthy of further prospective randomized evaluation
  • ARPI doublet +/- MDT vs MDT monotherapy vs ARPI monotherapy + MDT
  • Biomarker-selected combination therapies
  • Cycle length: intermittent versus prolonged first cycle

Presented by: Derya Tilki, MD, Professor of Urology, Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Written by: Rashid K. Sayyid, MD, MSc, Assistant Professor, Urologic Oncologist, Department of Urology at The University of Arizona and Banner University Medical Center – Tucson, AZ, @rksayyid on X during the 2025 European Society for Medical Oncology (ESMO) Annual Congress, Berlin, Germany, October 17–21, 2025

Related content: EMBARK Trial Reports Overall Survival Benefit for Enzalutamide with ADT in High-Risk Non-Metastatic Prostate Cancer - Stephen Freedland

1. Holzgreve A, Armstrong WR, Clark KJ, et al. PSMA-PET/CT findings in patients with high-risk biochemically recurrent prostate cancer with no metastatic disease by conventional imaging. JAMA Netw Open. 2025; 8(1): e2452971.
2. Fendler WP, Calais J, Eiber M, et al. Impact of ⁶⁸Ga-PSMA-11 PET on management of recurrent prostate cancer. J Nucl Med. 2020; 61(12):1793–1800.
3. Morgans AK, Niazi T, Shore N, et al. Darolutamide plus androgen-deprivation therapy (ADT) in patients with high-risk biochemical recurrence (BCR) of prostate cancer: a phase 3, randomized, double-blind, placebo-controlled study (ARASTEP). J Clin Oncol. 2025;43(suppl 17):TPS5131.
4. Falkenbach F, Lischewski F, Knipper S, et al. Prostate-specific membrane antigen-radioguided surgery in an EMBARK-like cohort of patients with oligorecurrent hormone-sensitive prostate cancer: delay in systemic treatment. Eur Urol Oncol. 2025; [epub ahead of print].
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