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PEACE-3 KEYNOTE-B15 RETAIN LITESPARK-011

EORTC 1333/PEACE-3: final overall survival results of enzalutamide with or without radium-223 in metastatic castration-resistant prostate cancer

 

While androgen receptor pathway inhibitors (ARPIs) such as enzalutamide have improved survival in metastatic castration-resistant prostate cancer (mCRPC), outcomes remain limited, particularly in patients with symptomatic bone metastases. Radium-223, an alpha-emitting radiopharmaceutical, has previously demonstrated an overall survival (OS) benefit in men with bone-only mCRPC, but concerns regarding fracture risk and optimal combination strategies have tempered its broader integration. A clear unmet need has been to determine whether combining radium-223 with contemporary AR-targeted therapy can safely and meaningfully extend survival.1,2

 

The Phase III PEACE-3 trial (NCT02194842) evaluated enzalutamide with or without radium-223 in men with asymptomatic or mildly symptomatic mCRPC and bone metastases, without visceral disease. In this international study, 466 patients were randomized 1:1 to receive enzalutamide alone or enzalutamide plus six cycles of radium-223. The primary endpoint was radiographic progression-free survival (rPFS), with overall survival as a key secondary endpoint.3

Previous updates have initially confirmed that the key endpoint was met,4 and the final analysis presented at ASCO GU 2026 confirmed a significant improvement in OS with the combination approach. Median OS was 38.2 months in the combination arm versus 32.6 months in the enzalutamide arm (95% CI: 0.60–0.95). OS benefit was reported in most predefined subgroups, with the exception of patients over 75 years old. No new safety signals were reported.3

PEACE-3 provides definitive evidence supporting the integration of radium-223 with enzalutamide in selected patients with bone-dominant mCRPC. These results are practice-changing, establishing a new standard for appropriately selected men and underscoring the importance of bone-protective strategies when combining systemic and radiopharmaceutical therapies.

KEYNOTE-B15: neoadjuvant and adjuvant enfortumab vedotin plus pembrolizumab in cisplatin-eligible muscle-invasive bladder cancer

 

Patients with muscle-invasive bladder cancer (MIBC) face a substantial risk of recurrence and death despite radical cystectomy and cisplatin-based neoadjuvant chemotherapy. While perioperative chemotherapy modestly improves survival, many patients are either ineligible for cisplatin or experience disease relapse due to micrometastatic spread.5 Antibody–drug conjugates (ADCs) such as enfortumab vedotin have shown impressive activity in metastatic disease, and their role in the curative-intent perioperative setting has shown promise in several clinical trials.6

The Phase III KEYNOTE-B15/EV-304 trial (NCT04700124) evaluated perioperative enfortumab vedotin plus pembrolizumab compared with standard cisplatin-based chemotherapy in patients with previously untreated, cisplatin-eligible MIBC. In this global study, patients were randomized 1:1 to receive neoadjuvant enfortumab vedotin plus pembrolizumab followed by surgery and adjuvant pembrolizumab, or standard neoadjuvant chemotherapy followed by surgery. The primary endpoint was event-free survival (EFS) and key secondary endpoints included pathological complete response (pCR) and overall survival (OS).7

At the median follow up of 33.6 months, the combination met its primary endpoint; median EFS was not reached in the investigational arm and was 48.5 months in the chemotherapy arm, and at 24 months, EFS was 79.4% in patients receiving perioperative enfortumab vedotin plus pembrolizumab and 66.2% in the chemotherapy arm (95% CI: 0.41–0.70). Whilst median OS was not reached in both groups, OS at 24 months was 86.9% and 81.3% in

 

the investigational and chemotherapy arms respectively (95% CI: 0.48–0.89). The pCR rate was also markedly higher in the experimental arm at 55.8% versus 32.5% (95% CI: 16.7–29.8). The safety profile was consistent with known toxicities of both agents, including peripheral neuropathy, rash, and immune-related adverse events; treatment-related discontinuation rates were acceptable, and surgery was not meaningfully delayed.7

These findings position enfortumab vedotin plus pembrolizumab as a potential new perioperative standard for eligible patients with MIBC. By demonstrating superior pathological responses and improved event-free survival over cisplatin-based chemotherapy, KEYNOTE-B15 signals a paradigm shift toward integrating ADCs and immunotherapy earlier  in the disease course, with the goal of increasing cure rates in high-risk bladder cancer.

ctDNA-guided response-adapted bladder preservation in muscle invasive bladder cancer (MIBC): Integrated analysis of the RETAIN trials

 

Whilst radical cystectomy is a standard treatment for MIBC, a proportion of patients achieve a complete response after chemotherapy, raising the possibility that some individuals could safely avoid surgery. The key challenge has been identifying reliable biomarkers that can distinguish patients who have truly eradicated disease from those who still harbor residual cancer. Circulating tumor DNA (ctDNA) has emerged as a promising tool to detect minimal residual disease, but its clinical utility in guiding bladder preservation strategies has remained uncertain.8,9

New findings from an integrated analysis of the Phase II RETAIN trials (NCT04506554), explored whether ctDNA could help identify

 

patients who may safely omit cystectomy following neoadjuvant therapy. In these studies, patients with MIBC received neoadjuvant accelerated methotrexate, vinblastine, doxorubicin, and cisplatin (AMVAC) and patients in RETAIN-2 additionally received nivolumab. Patients with favorable biomarkers and evidence of response could enter an active surveillance strategy instead of immediate surgery. In the RETAIN-2 trial, the primary endpoint was 2-yr metastasis-free survival (MFS) in the intent to treat (ITT) population.10

With 29.2 months of follow-up, the projected 2-year MFS reached 79.8% (95% CI, 70–90%) in the ITT cohort and 80% (95% CI, 64–100%) in those managed with active surveillance. Results demonstrated that ctDNA status was strongly associated with clinical outcomes. Patients who were ctDNA-negative after neoadjuvant therapy had a low risk of recurrence and could be safely monitored without immediate cystectomy, whereas those with detectable ctDNA had a substantially higher likelihood of disease relapse.10

These findigs provide important proof-of-concept evidence that ctDNA may help guide bladder-sparing approaches in selected patients with MIBC, allowing some patients to avoid radical surgery without compromising oncologic outcomes. Larger prospective trials will be needed to confirm these results and refine patient selection, but the data represent a meaningful step toward precision-guided bladder preservation.

LITESPARK-011: belzutifan and lenvatinib versus cabozantinib in post-PD-(L)1 advanced renal cell carcinoma

 

Advanced renal cell carcinoma (RCC) remains difficult to treat once patients progress after immune checkpoint inhibitor–based regimens. Although combinations of PD-(L)1 inhibitors with VEGF-targeted therapies have improved first-line outcomes, many patients ultimately develop resistance and require additional effective options.11 Therapies targeting the hypoxia-inducible factor (HIF) pathway have emerged as a promising strategy in advanced RCC, and the optimal use of HIF-2α inhibitors in combination with established targeted agents such as VEGF inhibitors has remained an important clinical question.12

The Phase III LITESPARK-011 trial (NCT04586231) evaluated the combination of belzutifan, a selective HIF-2α inhibitor, with lenvatinib in patients with advanced ccRCC who had previously received immune checkpoint inhibitor therapy. In this global, randomized study, 747 patients were assigned 1:1 to receive belzutifan plus lenvatinib or the standard targeted therapy of cabozantinib. The dual primary endpoints were progression-free survival (PFS) and overall survival (OS), and secondary endpoints were duration of response (DOR), objective response rate (ORR), and safety.13

At the second interim analysis, median PFS was 14.8 and 10.7 months in the combination and cabozantinib arms respectively (95% CI: 0.59–0.84), demonstrating a significant improvement in patients receiving belzutifan and lenvatinib. OS findings did not

 

reach statistical significance, but favored the combination. The safety profile was consistent with the known effects of the individual agents, including anemia and hypoxia associated with HIF-2α inhibition and hypertension, fatigue, and diarrhea linked to VEGF-targeted therapy.13

LITESPARK-011 represents an important advance in the post–immunotherapy treatment landscape for advanced RCC. These findings position belzutifan plus lenvatinib as a potential new standard option for patients with previously treated advanced RCC, expanding the arsenal of targeted therapies and offering renewed hope for improved long-term disease control.

References

  1. Stanbury S. Emerging Evidence-Based Treatment Strategies in Metastatic Castration-Resistant Prostate Cancer. EMJ Oncology. 2025 Dec 2;
  2. Connell B, Hwang C, Folefac E, Lawlor C, Koethe B, Mathew P. Dose-Dense Docetaxel and Radium-223 in Bone-Dominant Metastatic Castration-Resistant Prostate Cancer. Clinical Genitourinary Cancer. 2025 Aug;23(4):102368.
  3. Gallardo E, Tombal BF, Choudhury A, Saad F, Soares A, Loriot Y, et al. Final overall survival results from the EORTC 1333/PEACE-3 trial: Enzalutamide with or without radium-223 in metastatic castration-resistant prostate cancer. Journal of Clinical Oncology. 2026 Mar 1;44(7_suppl):15–5.
  4. Tombal B, Choudhury A, Saad F, Gallardo E, Soares A, Loriot Y, et al. Enzalutamide plus radium-223 in metastatic castration-resistant prostate cancer: Results of the EORTC 1333/peace-3 trial. Annals of Oncology. 2025 Sept;36(9):1058–67.
  5. Squires P, Cook EE, Song Y, Wang C-Y, Zhang A, Seshasayee SM, et al. Treatment patterns, disease recurrence, and overall survival in patients with muscle-invasive bladder cancer after radical cystectomy: A population-level claims-based analysis. Clinical Genitourinary Cancer. 2026 Feb;24(1):102466
  6. Fahey CC, Clark-Garvey S, Porten S, Kamat AM, Flaig TW, Taylor JA, et al. Mechanistic Insights and Future Directions for Enfortumab Vedotin in Urothelial Carcinoma: Highlights from the 10th Annual Leo & Anne Albert Institute for Bladder Cancer Care and Research Symposium. Current Oncology. 2025 May 14;32(5):278.
  7. Galsky MD, Valderrama BP, Maruzzo M, Font Pous A, Ciuleanu TE, Chatzkel JA, et al. Neoadjuvant and adjuvant enfortumab vedotin (EV) plus pembrolizumab (pembro) for participants with muscle-invasive bladder cancer (MIBC) who are eligible for cisplatin: Randomized, open-label, phase 3 KEYNOTE-B15 study. Journal of Clinical Oncology. 2026 Mar 1;44(7_suppl).
  8. Fujiwara M, Tanaka H, Kobayashi M, Nakamura Y, Fan B, Ishikawa Y, et al. Neoadjuvant Chemoradiotherapy Followed by Radical Cystectomy for Muscle-Invasive Bladder Cancer: Analysis of Efficacy and Safety in 119 Patients. Clinical Genitourinary Cancer. 2024 Apr;22(2):193-200.e1.
  9. Konstantinos Kapriniotis, Lazaros Tzelves, Lazarou L, Mitsogianni M, Iraklis Mitsogiannis. Circulating Tumour DNA and Its Prognostic Role in Management of Muscle Invasive Bladder Cancer: A Narrative Review of the Literature. Biomedicines. 2024 Apr 21;12(4):921–1.
  10. Ghatalia P, Ross EA, Zibelman MR, Anari F, Abbosh P, Herberts C, et al. Circulating tumor DNA (ctDNA) to guide response-adapted bladder preservation in muscle invasive bladder cancer (MIBC): Integrated analysis of the RETAIN trials. Journal of Clinical Oncology. 2026 Mar 1;44(7_suppl).
  11. Yang Y, Mori SV, Li M, Hinkley M, Parikh AB, Collier KA, et al. Salvage nivolumab and ipilimumab after prior anti‐PD‐1/PD‐L1 therapy in metastatic renal cell carcinoma: A meta‐ Cancer Medicine [Internet]. 2022 Feb 9 [cited 2026 Mar 12];11(7):1669–77
  12. Wu X, Lazris D, Wong R, Tykodi SS. Belzutifan for the treatment of renal cell carcinoma. Therapeutic Advances in Medical Oncology. 2025 Jan;17. doi:10.1177/17588359251317846
  13. Motzer RJ, Park SH, McDermott RS, Porta C, Heng DYC, Burotto M, et al. Belzutifan (bel) plus lenvatinib (lenva) versus cabozantinib (cabo) for advanced renal cell carcinoma (RCC) after anti–PD-(L)1 therapy: Open-label phase 3 LITESPARK-011 study. Journal of Clinical Oncology. 2026 Mar;44(7_suppl).
The content of VJOncology is intended for healthcare professionals