Optimizing Androgen Signaling Blockade in High-Risk Prostate Cancer

New long-term data from 3 pivotal phase 3 trials, presented at the European Society for Medical Oncology (ESMO) Congress held in Berlin, Germany, provide important practice-changing updates to the standard of care for locally advanced prostate cancer and high-risk biochemically relapsed prostate cancer. The findings signal a decisive shift away from single-agent androgen deprivation therapy (ADT), underscoring the significant survival benefit of combined androgen blockade.

Collectively, the 3 trials, PRESTO (NCT03009981), EMBARK (NCT02319837), and ENZARAD (ANZUP 1303), explore intensification of androgen blockade in the specific clinical scenario of early biochemical recurrence or primary treatment for locally advanced disease.^1-3

PRESTO Trial

Men with biochemically recurrent prostate cancer after radical prostatectomy with a prostate-specific antigen (PSA) doubling time of less than 9 months are at increased risk for the development of subsequent distant metastases. The final results of the PRESTO trial suggest that ADT plus apalutamide (Erleada) may improve long-term clinically relevant outcomes for these patients. Findings were presented by Rahul Aggarwal, MD, during ESMO 2025.¹

A standard of care in the biochemically relapsed setting had previously been to provide intermittent single-agent ADT with finite treatment intervals of 9 to 12 months.⁴ Long-term end points evaluated in PRESTO included metastasis-free survival (MFS), time to castration-resistant prostate cancer, PSA progression-free survival (PSA-PFS) in the testosterone-recovered subset, and time to subsequent therapy.

“We observed a delay in MFS, particularly with the doublet of ADT plus apalutamide,” Aggarwal, the Thomas Perkins Distinguished Professor in Cancer Research and a professor of medicine at University California, San Francisco (UCSF) and associate director for clinical sciences at UCSF Helen Diller Family Comprehensive Cancer Center, said during an interview to discuss the PRESTO trial and other clinical implications with Targeted Therapies in Oncology.

The PRESTO study randomly assigned patients 1:1:1 to receive a luteinizing hormone–releasing hormone (LHRH) analog alone, an LHRH analog plus apalutamide, or an LHRH analog, apalutamide, abiraterone acetate (Zytiga), and prednisone for 12 months.

Comparing the doublet arm to the monotherapy arm, 35% of patients reported MFS events compared with 40% in the apalutamide-only arm (HR, 0.80; 95% CI, 0.56-1.13). There was a difference of 2.92 months of restricted mean survival over the first 48 months favoring the combination. With the addition of both apalutamide and abiraterone vs ADT alone, the HR was 0.92 (95% CI, 0.56-1.13), with a difference in restricted mean survival over the first 48 months of 2.41 months (95% CI, –0.20 to 4.62).¹

With 20% of patients developing castration-resistant prostate cancer combined in both arms, the HR of 0.58 (95% CI, 0.36-0.95; nominal P = .0283) favored apalutamide plus ADT. Comparing apalutamide, abiraterone, and ADT vs ADT alone, the HR was 0.55 (95% CI, 0.34-0.90; P = .0176).¹

“Adding abiraterone didn’t provide additional efficacy, only more toxicity, so we don’t recommend the triplet,” Aggarwal said. “It’s really the ADT plus apalutamide doublet that appears to benefit patients with high-risk, biochemically relapsed prostate cancer.”

The primary study objective was PSA-PFS, and secondary end points were MFS, time to castration resistance, PSA-PFS in the testosterone-recovered population, safety, and quality of life.

In the triplet arm, 53% of patients received subsequent therapy, and the median time to treatment was 52.8 months with the combination vs 35.7 months with ADT alone (HR, 0.64; 95% CI, 0.47-0.86; P = .0028).¹

In terms of safety, adverse events (AEs) were reported in 96% of the ADT arm, 100% of the ADT-plus-apalutamide arm, and 99% of the triplet arm. Grade 3 or 4 AEs were reported in 22%, 26%, and 41%, respectively, and AEs led to discontinuation in 0.6%, 1%, and 2%, respectively.¹

Aggarwal noted that the patient population was enrolled with rising PSA levels (PSA doubling time < 9 months) after prior radical prostatectomy, with the majority having undergone prior salvage radiation.

Imaging Standards

Aggarwal emphasized that an evolution in imaging standards occurred during the PRESTO trial. Patients had undergone conventional imaging, such as a CT scan or an abdomen or bone scan. But during the course of the trial, prostate-specific membrane antigen (PSMA) PET imaging became the standard. To reflect this change, the trial investigators adopted a composite end point that Aggarwal described as “a pragmatic definition of first metastasis detected by either PSMA PET or by conventional imaging.” These findings inform clinical practice in the PSMA PET era, setting the stage for subsequent trials.

“Next steps in research should focus on biomarkers. We need to [be able to] select those patients with higher-risk disease who derive the maximum benefit from combined hormone therapy,” Aggarwal said.

EMBARK Trial

Investigators for the EMBARK trial demonstrated that adding enzalutamide (Xtandi) to leuprolide acetate resulted in a 40.3% lower risk of death compared with leuprolide acetate alone in patients with high-risk, biochemically recurrent prostate cancer.^2,5

At 8 years follow-up, patients in the enzalutamide-plus-leuprolide arm had an overall survival (OS) rate of 78.9% vs 69.5% for the leuprolide-alone arm (HR, 0.597; 95% CI, 0.444-0.804; P = .0006). Further, investigators reported improvements with enzalutamide plus leuprolide in secondary end points, including time to first use of new antineoplastic therapy, time to symptomatic skeletal events, and PFS on first subsequent therapy.

“The trial included patients who had had prior prostatectomy as well as patients who had prior radiation,” Aggarwal said. "At entry, patients had a higher median PSA than patients in the PRESTO trial," he continued.⁵

The primary end point was MFS in the combination group vs the leuprolide-alone group, as assessed by blinded independent central review. A key secondary end point was MFS in the monotherapy group compared with the leuprolide-alone group.

Safety

Regarding safety, no new safety signals were observed relative to what was previously reported. A higher incidence of serious treatment-emergent AEs (TEAEs) related to the study drug was reported in the enzalutamide combination, but overall TEAEs were lower than 10% across the 3 arms (enzalutamide combination, 8.5%; leuprolide alone, 2.5%; and enzalutamide alone, 7.6%). Grade 3 or higher TEAEs were experienced by 19.3%, 9.5%, and 20.3% of patients, respectively.⁵

“I think community oncologists and clinicians who are prescribing these medicines are familiar with their adverse events,” Aggarwal said. “Both apalutamide and enzalutamide do carry added risk of adverse events compared with ADT alone. In my clinical practice, it’s all about good counseling and understanding what a patient’s baseline frailty or fall risk is, understanding their baseline cardiovascular risk and history, and then managing those risks [by employing] risk-reduction [strategies].

“The results of EMBARK solidified the discussion that combination hormone therapy, given for a finite interval, should be the standard of care for high-risk biochemical relapsed patients,” Aggarwal continued. “In particular, ADT plus enzalutamide extended OS compared with ADT alone, whereas enzalutamide monotherapy did not demonstrate that same long-term benefit.”

ENZARAD Trial

The phase 3 ENZARAD trial sought to determine whether 2 years of enzalutamide therapy improves MFS when added to 2 years of an LHRH agonist and high-dose radiation for patients with regionally advanced or locally advanced prostate cancer.³

“These were patients who were T3 to T4, had a high Gleason score, and were node positive. They were the highest risk for biochemical relapse and recurrence after primary radiation,” Aggarwal said.

A total of 802 patients were randomly assigned to receive enzalutamide, an LHRH agonist, and radiotherapy or a nonsteroidal antiandrogen, an LHRH agonist, and radiotherapy. The primary end point was MFS based on conventional imaging.

After a median follow-up of 8 years, patients in the treatment arm had a PFS rate of 67% vs 62% in the control arm (HR, 0.78; 95% CI, 0.61-0.99; P = .04). The OS rate for the treatment arm was 83% vs 80% in the control arm (HR, 0.87; 95% CI, 0.63-1.20; P = .40).³

Overall, in the intention-to-treat population, investigators reported no difference in MFS between the 2 treatment arms.³

“However, when you review the subgroup of patients who had lymph node involvement that was detected on baseline imaging, there did appear to be a benefit in MFS and OS in the treatment arm,” Aggarwal said.

Implications of the Findings

Nguyen PL et al³ reported that the implications for practice were 2-fold: Most contemporary patients with clinically localized or locally advanced prostate cancer receiving high-dose radiation and 2 years of ADT do not need enzalutamide; for patients with positive nodes on CT/MRI or other indications for pelvic radiation, the ENZARAD trial provides good evidence of a benefit for enzalutamide.³

Where do these findings fall in the context of other trials, such as the STAMPEDE trial (NCT00268476)?⁶

In the STAMPEDE trial, patients received ADT alone or ADT plus abiraterone acetate and prednisolone. Local radiotherapy was mandated for patients with node-negative, nonmetastatic disease and encouraged for those with positive nodes. For patients with nonmetastatic disease with no radiotherapy planned and for patients with metastatic disease, treatment continued until radiologic, clinical, or PSA progression; otherwise, treatment was to continue for 2 years or until any type of progression, whichever came first.⁶

Aggarwal emphasized the different populations in the 2 trials. The STAMPEDE trial enrolled patients who had high-risk localized disease to node-positive metastatic disease, whereas ENZORAD enrolled patients who had localized disease with a Gleason score of 8 to 10 and T3 to T4 disease.

“The safety profiles of abiraterone and enzalutamide are slightly different, and that could affect a clinician’s choice given safety, tolerability, and patient comorbidity,” Aggarwal said. “That could affect a decision to select one agent over another.”

Nonetheless, the findings from the ENZARAD trial supports consideration of adding enzalutamide, for patients with positive pelvic nodes on CT or MRI or other indications for pelvic field irradiation.³ Unlike the findings from EMBARK, which demonstrated generalizable OS benefit in the recurrent setting, the benefit of adding enzalutamide to high-dose radiotherapy and long-term ADT in unselected, high-risk patients with localized disease was negligible for MFS and OS.³

“I think all patients with clinically node-positive disease who are receiving primary radiation to the prostate and pelvis should receive combination hormone therapy with ADT plus an androgen receptor pathway inhibitor,” Aggarwal said. “These 2 studies together tell us that combination therapy makes sense.”

On the question of choosing enzalutamide over abiraterone, the data remain a little murky. “I don’t think we have definitive data to say that we should use enzalutamide over abiraterone,” Aggarwal said. “I think it comes down to a choice based on comorbidities, financial toxicity, and other factors. For abiraterone, you have to give prednisone along with it, and patients might prefer not to take it. In which case, you would go with enzalutamide. But I think it’s those pragmatic factors that drive the decision.”

Conclusion

These major trials presented during ESMO 2025 empower community oncologists with robust data to deliver optimal precision-guided care. The theme of intensifying androgen blockade in the presence of high-risk disease was emphasized, but the approach should be tailored to specific clinical scenarios.

REFERENCES

1. Aggarwal R, Heller G, Hillman DW, et al; Alliance AFT-19 Study Investigators. Final results from PRESTO: a phase 3 open-label study of combined androgen blockade in patients with high-risk biochemically relapsed prostate cancer (AFT-19). Presented at: ESMO Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA88.

2. Shore, ND, de Almeida Luz M, De Giorgi U, et al. Overall survival with enzalutamide in biochemically recurrent prostate cancer. Presented at: ESMO Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA87.

3. Nguyen PL, Sweeney CJ, Stockler MR, et al. Randomised phase 3 trial of androgen deprivation therapy (ADT) with radiation therapy with or without enzalutamide for high risk, clinically localised, and locally advanced prostate cancer: ENZARAD (ANZUP 1303). Presented at: ESMO Congress 2025; October 17-21, 2025; Berlin, Germany. Abstract LBA86.

4. NCCN. Clinical Practice Guidelines in Oncology. Prostate cancer, version 3.2026. Accessed November 21, 2025. https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf

5. Shore ND, de Almeida Luz M, De Giorgi U, et al. Improved survival with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. Published online October 19, 2025. doi:10.1056/NEJMoa2510310

6. James ND, de Bono JS, Spears MR, et al; STAMPEDE Investigators. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med. 2017;377(4):338-351. doi:10.1056/NEJMoa1702900