The ESMO26 conference delivered practice changing, practice informing as well as multiple emerging treatments and strategies to treat genitourinary malignancies.
Practice-changing data
The VOLGA Phase III trial demonstrated improved event free survival (EFS, HR 0.51) as overall survival (OS, HR 0.58) for three cycles of neoadjuvant Enfortumab Vedotin (EV) + durvalumab plus adjuvant durvalumab in the setting of radical cystectomy for cisplatin-ineligible muscle-invasive bladder cancer (MIBC). These data arrive with the backdrop of EV + pembrolizumab approved regardless of cisplatin-eligibility. The corresponding HRs for EFS and OS in the similar but slightly lower-risk EV303 cisplatin-ineligible trial population were 0.40 and 0.50, respectively. While it is reassuring that the omission of adjuvant EV in VOLGA (unlike the EV + pembrolizumab trials) did still lead to improved outcomes in the VOLGA trial, no trial has compared the inclusion versus omission of adjuvant EV when employing the EV + PD1/L1 strategy.
Previously, the STAMPEDE trial demonstrated improved outcomes for the addition of abiraterone plus prednisone for two years with three years of androgen deprivation therapy (ADT) for localized high-risk or high-risk PSA recurrent prostate cancer. In contrast, the ENZARAD Trial did not demonstrate improved outcomes for the addition of enzalutamide to radiation plus ADT in a somewhat lower risk population, although a subgroup with lymph node positive stage at baseline appeared to benefit. At ESMO26, the DASL-HiCaP Phase III trial compared the value of adding 2 years of darolutamide to radiation plus 2 years of ADT for very high risk localized prostate cancer or high-risk PSA recurrence post radical prostatectomy. The metastasis-free survival (MFS) by routine CT and bone scan imaging improved significantly with the addition of darolutamide (HR 0.42).
Practice-informing/affirming data
Gemcitabine-cisplatin (GC)-durvalumab is approved as perioperative therapy for cisplatin-eligible MIBC based on the NIAGARA trial. At ESMO26, two trials, Energize and KEYNOTE866, combining GC with nivolumab or pembrolizumab, did not demonstrate improved outcomes. Thus, given that two of the three phase III trials have been negative for improved outcomes with the GC-PD1/L1 approach, this should be considered a non-preferred option given the robust and consistent benefit observed with EV-PD1/L1 regimens.
The PROTEUS Phase III trial previously showed that 6 months of neoadjuvant plus adjuvant ADT with apalutamide improved MFS versus ADT alone (HR 0.80) in the setting of radical prostatectomy for high risk localized prostate cancer. At ESMO26, the PROTEUS substudy was reported, which compared radical prostatectomy alone versus radical prostatectomy with 6 months of neoadjuvant and adjuvant ADT plus apalutamide. The substudy reinforced the value of perioperative ADT plus apalutamide with improved RFS defined as PSA recurrence or PSMA-PET+ recurrence (HR 0.38) and MFS (HR 0.49). Intriguingly, another translational research study of patients enrolled in STAMPEDE suggested that the decipher RNA score could be used to intensify therapy with the addition of abiraterone to ADT plus radiation for high-risk localized disease. Previously, Capitello-281 demonstrated improved radiographic progression-free survival (rPFS) with the addition of capivasertib (AKT inhibitor) to abiraterone plus prednisone plus ADT for metastatic castration sensitive prostate cancer (HR 0.81) and PTEN-deficiency (90% loss on IHC of tumor). At ESMO26, this trial reported an update showing improved OS also (HR 0.82), with even greater loss of PTEN (e.g. ≥95% loss) showing even more robust improvements (HR ~0.75). Previously, the TALAPRO-3 trial demonstrated improved rPFS (HR 0.48) and a trend for improved OS (HR 0.77) for the addition of talazoparib to ADT plus enzalutamide for metastatic castration sensitive prostate cancer. Now, an analysis from TALAPRO-3 demonstrated similar mild decrements from baseline of global patient-reported outcomes but higher decrement of appetite loss for the talazoparib versus conventional arm.
The final analysis of the Phase III LITESPARK-011 trial demonstrated that the improved outcomes with belzutifan plus lenvatinib, which led to U.S. FDA approval, compared with cabozantinib were maintained in patients with advanced ccRCC following anti–PD-(L)1 therapy. Median PFS was 14.8 months with belzutifan plus lenvatinib versus 10.8 months with cabozantinib (HR 0.74). Objective response rates were 53.1% versus 40.2%, and median duration of response was 22.0 versus 11.9 months. The phase III LITESPARK-012 showed that combining either belzutifan or the anti-CTLA-4 antibody quavonlimab to pembrolizumab + lenvatinib did not improve efficacy in patients with previously untreated advanced clear cell renal cell carcinoma (ccRCC). Thus, more novel strategies may be necessary to provide increments over the currently used IO-IO and VEGF-IO doublets.
The PE-PE randomized Phase II trial showed that perioperative pembrolizumab (1 cycle approximately 3 weeks before metastasis directed therapy [MDT], followed by surgery and/or stereotactic ablative radiotherapy (SABR) and then adjuvantly every 6 weeks for 8 cycles) increases the recurrence free survival (RFS) in patients with oligometastatic ccRCC eligible for definitive therapy (surgery or SABR) within 5 years from previous nephrectomy or metastasectomy. Notably, oligometastatic disease was defined as up to 3 metastatic lesions, with no more than 2 bone lesions, with each lesion measuring ≤3 cm, and the sum of lesion diameters ≤5 cm. In the setting of papillary RCC, the S2200 (PAPMET2) randomized Phase II trial was reported, which unfortunately closed prematurely due to slow accrual, but demonstrated improved outcomes with cabozantinib + atezolizumab versus cabozantinib as first-line treatment: the median PFS was 25 versus 10 months (HR 0.46).
Emerging treatments
Improved outcomes with the combination of adjuvant Intismeran autogene (V940/mRNA‑4157), a personalized mRNA neoantigen immunotherapy + pembrolizumab in high‑risk resected melanoma in the Phase 3 INTerpath‑001 trial bode well for similar efforts that are ongoing in multiple other malignancies including ccRCC and MIBC. The first-line triplet strategy of sacituzumab govitecan (SG) combined with EV + PD1 inhibition (zimberelimab) demonstrated promising activity as first-line therapy in metastatic urothelial carcinoma.
An ongoing Phase I trial, DADIO, is also evaluating SG in combination with EV-P. JNJ-6143, an AR-BRD4 RIPTAC (Regulated Induced Proximity Targeting Chimeras), which disrupts the function of an essential protein BRD4 (which promotes the expression of several oncogenes via transcriptional and epigenetic regulation) in AR expressing cells by cytosolic sequestration, demonstrated promising activity in a phase I trial of heavily pretreated metastatic castration resistant (androgen pathway modulation resistant) prostate cancer patients regardless of high-risk somatic PTEN, RB1 and P53 mutations. In the setting of heavily pretreated patients with advanced ccRCC, a T-cell engager binding ENPP3 and CD3, XMAB809, demonstrated promising activity, while ivonescimab, the PD1-VEGF bispecific agent, demonstrated promising activity as first-line therapy for favorable-risk ccRCC.
Conclusion
Thus, ESMO2026 successfully delivered multiple advances in the field of GU malignancies. Transformative advances will come with better knowledge of tumor biology and discovery of biomarkers to enable precision medicine. Accrual to clinical trials should be considered a preferred standard of care to expedite advances.
Dr. Sonpavde has received grants from Bayer, Sumitomo Pharma, and Blue Earth Diagnostics. He has received consulting fees or honorarium from EMD Serono, BMS, Merck, Astellas, Janssen, Pfizer, Gilead, Eli Lilly, Loxo Oncology, Aktis, Daiichi-Sankyo, GSK, Abbott, Ellipses, Lucence, and Coiled Therapeutics. He has received support for travel to meetings from BMS and Merck. He has received payment for lectures from Natera, Exelixis, Janssen, Astellas, Bayer, Aveo, Pfizer, Merck, and Astrazeneca. Dr. Sonpavde's spouse is or has been employed by Myriad, Exact Sciences, and Abbott.
