ESMO 2025 Updates in Prostate Cancer: Advances in Radioligand, Genomic, and AR-Targeted Therapies
The 2025 European Society for Medical Oncology (ESMO) Congress featured key updates in prostate cancer, showcasing advances in radioligand and genomically targeted therapies for metastatic castration-sensitive prostate cancer (mCSPC), as well as androgen receptor pathway inhibitors for locally advanced and biochemical relapse disease. Four studies stood out for their practice-informing and forward-looking insights.
1. PSMAAddition: Survival and Response Rates Boosted With 177Lu-PSMA-617
PSMAAddition is the first randomized phase 3 trial evaluating radioligand therapy for patients with metastatic hormone-sensitive prostate cancer (mHSPC). Patients with untreated or minimally treated mHSPC were randomized 1:1 to Lu-PSMA-617 plus androgen deprivation therapy (ADT) and androgen receptor pathway inhibitor (ARPI) or ADT plus ARPI. Lu-PSMA-617 was administered at 7.4 GBq ±10% for 6 cycles every 6 weeks, and crossover was allowed upon blinded independent review confirmed progressive disease.
At ESMO 2025, PSMAAddition demonstrated that Lu-PSMA-617 combined with ADT and ARPI led to a significant improvement in radiographic progression-free survival (rPFS; NR vs NR; HR 0.72, 0.58–0.90; P = .002) relative to ADT plus ARPI. Subgroup analysis demonstrated rPFS benefit regardless of tumor volume, age, and timing of the cancer (denovo, recurrent). Key secondary endpoints favored the Lu-PSMA-617 arm, including complete response (CR; 57.1% vs 42.3%), time to prostate-specific antigen (PSA) progression (HR 0.42, 0.30-0.59), and time to metastatic castration-resistant prostate cancer (mCRPC) (HR 0.70; 0.58-0.84). The interim overall survival (OS) analysis did not demonstrate a significant OS benefit (NR vs NR; HR 0.84, 0.63–1.13; P = 0.125).
The Lu-PSMA-617 arm was associated with higher toxicities including any grade 3 or higher (50.7% vs 43%), grade 3 or higher cytopenias (14.4% vs 5%), and secondary malignancies (4.3% vs 2.5%). Health-related quality of life (HRQOL) outcomes were similar between treatment arms including Brief Pain Inventory-Short Form pain intensity (HR 1.02, 0.87-1.18) and Functional Assessment of Cancer Therapy-Prostate Total Score (HR 1.14, 0.98-1.33).
In summary, the addition of Lu-PSMA-617 to ADT plus ARPI demonstrated a statistically significant improvement in rPFS, CR, and times to PSA progression/CRPC. However, the Lu-PSMA-617 arm was associated with higher toxicity and has not demonstrated an improvement in OS or HRQOL outcomes relative to ADT plus abiraterone.
Lu-PSMA-617 combined with ADT and ARPI is poised to become a treatment option for mCSPC. However, it will require multidisciplinary collaboration with nuclear medicine to optimally select patients for this regimen.
2. CAPItello-281: Key Findings
CAPItello-281 is the first randomized phase 3 trial to evaluate the role of AKT inhibition in patients with PTEN-deficient mCSPC, defined as 90% or greater loss of cytoplasmic staining by immunohistochemistry. More than 6200 patients were screened, and 1012 patients were randomized 1:1 to capivasertib plus ADT and abiraterone or placebo plus ADT and abiraterone.
The trial demonstrated that capivasertib/ADT/biraterone led to a significant improvement in median rPFS (33.2 months vs 25.7 months; HR 0.81, 0.66–0.98; P = .034) relative to ADT plus abiraterone. Key secondary endpoints favored the capivasertib arm, including symptomatic skeletal event-free survival, time to castration resistance, and time to PSA progression. Subgroup analysis of PTEN-deficient groups (≥90%, ≥95%, ≥99%, and 100%) showed greater response enrichment in the capivasertib arm. The interim OS analysis conducted at 26% maturity did not demonstrate a significant OS benefit (HR, 0.90, 0.71–1.15; P = .401).
Moreover, the capivasertib arm was associated with higher toxicities including any grade 3 or higher adverse events (AEs; 67% vs 40.4%), any serious AEs (42.5% vs 26%), and any grade diarrhea, rash, and hyperglycemia.
The results of CAPItello-281 underscore the importance of genomic testing for patients with mCSPC and highlights the poor prognosis associated with PTEN deficiency. While capivasertib combined with ADT and abiraterone may become a treatment option for these patients, clinicians must be careful during treatment selection.
3. EMBARK: OS Data Revealed at ESMO 2025
The phase 3 EMBARK study evaluated the role of enzalutamide in patients with high-risk biochemical recurrence (BCR) of prostate cancer. Eligible patients had a PSA doubling time of 9 months or less and no evidence of metastasis on bone scan or CT/MRI.
Over 1000 patients were randomized 1:1:1 to enzalutamide plus leuprolide, placebo plus leuprolide, or enzalutamide alone. Patients whose PSA dropped below 0.2 ng/mL at week 36 suspended treatment and reinitiated at a predetermined PSA threshold. The primary analysis, published In October 2023, showed that enzalutamide plus leuprolide significantly improved metastasis-free survival compared with placebo plus leuprolide. Based on the results, the FDA approved enzalutamide in November 2023, for non-metastatic castration-sensitive prostate cancer with BCR.
At the 2025 ESMO Congress, investigators presented the final OS, updated endpoints, and long-term safety data. At a median follow-up of 94 months, enzalutamide plus leuprolide significantly improved OS with 8-year rates of 78.9% versus 69.5% (HR, 0.59, 0.44-0.80; P = 0.0006) relative to placebo plus leuprolide. Enzalutamide monotherapy was associated with numerically higher 8-year OS rates 73.1% versus 69.5% (HR, 0.83, 0.63-1.09; P = 0.1867) relative to placebo plus leuprolide. Key secondary endpoints, including time to new antineoplastic therapy, time to symptomatic skeletal event, and PFS2, favored the enzalutamide-containing arms. However, bothenzalutamide combination and monotherapy were associated with higher rates of grade 3 or higher toxicity compared with leuprolide alone (87% vs 89.3% vs 80.3%, respectively).
EMBARK confirmed that enzalutamide plus leuprolide not only improves metastasis-free survival (MFS) but also demonstrates a significant OS benefit compared with leuprolide alone for patients with high-risk BCR by conventional imaging. With advances in PSMA PET imaging revealing small-volume disease and improved metastasis-directed radiotherapy options, future management of biochemical recurrence will require a personalized approach—integrating genomic data, PSA kinetics, and imaging—to guide shared decision-making on the use of enzalutamide plus leuprolide.
4. ENZARAD: ADT ± Enzalutamide With Radiation in High-Risk Localized Prostate Cancer
ENZARAD, a phase 3 randomized trial, evaluated enzalutamide plus a luteinizing hormone-releasing hormone agonist with high-dose radiation in patients with high-risk, clinically localized or locally advanced prostate cancer. At a median follow-up of 8 years, the combination demonstrated no improvement in MFS (HR, 0.88, 0.67-1.15; P = 0.34) or OS (HR, 0.87, 0.63-1.20; P = 0.40). Prostate cancer-specific survival was high in both treatment arms at 96%–97%. Subgroup analysis favored the combination in patients with regional lymph node involvement, pelvic field radiation, and very high-risk features.
In summary, most patients with clinically localized or locally advanced prostate cancer receiving ADT plus high-dose radiation do not need enzalutamide. For patients with lymph node metastasis or other indications for pelvic radiation, enzalutamide may provide benefit.