Precision Strategies and Targeted Combinations in GU Oncology: Expert Insights From ESMO 2025

Precision medicine, biomarker-driven treatment selection, and next-generation targeted combinations took center stage in genitourinary (GU) oncology at the 2025 ESMO Congress, where investigators unveiled data expected to redefine sequencing strategies and expand the reach of immunotherapy and antibody-drug conjugates (ADCs) into earlier disease settings. At the meeting, OncLive® sat down with leading GU oncology experts to gather their perspectives on the most impactful presentations from the meeting. Insights were shared by:

• Andrea Necchi, MD, associate professor of oncology at Vita-Salute San Raffaele University in Milan, Italy, and director of Genitourinary Medical Oncology at IRCCS San Raffaele Hospital
• Andrew W. Hahn, MD, assistant professor in the Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center

Necchi highlighted the evolving role of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda), noting that data from the phase 4 KEYNOTE-905/EV-303 trial (NCT03924895) support the combination’s expansion into earlier, nonmetastatic and muscle-invasive settings, which may redefine sequencing strategies and influence treatment planning for patients previously exposed to ADC/immunotherapy combinations.1 He also pointed to findings from the phase 3 RC48-C016 trial (NCT05302284) evaluating disitamab vedotin (PF-08046051) in combination with toripalimab (Loqtorzi) in patients with HER2-positive advanced urothelial cancer, which showed a magnitude of benefit in progression-free survival (PFS) and overall survival (OS) vs chemotherapy, underscoring the growing complexity of patient selection and biomarker-driven differentiation among multiple ADC/immunotherapy regimens.2

Hahn discussed data from the phase 2 OPTIC-RCC (NCT05361720) and phase 1/2 KEYMAKER-U03 (NCT04626479) studies in metastatic renal cell carcinoma, which explored gene expression–guided treatment allocation and novel triplet strategies, establishing a foundation for precision-based therapy in the first-line setting. Freedland also emphasized the significance of data from the phase 3 PSMAddition trial (NCT04720157) evaluating the efficacy and safety of lutetium Lu 177 vipivotide tetraxetan (Pluvicto) in combination with standard of care vs standard of care alone in adult male patients with prostate-specific membrane antigen (PSMA)–positive metastatic hormone-sensitive prostate cancer (mHSPC), highlighting its potential to position PSMA-targeted therapy as a new standard in this setting and shape the future treatment landscape.

Missed the meeting in Berlin? Tune in to watch the video above to hear exclusive commentary from these experts, and read more of their insights below.

What do new data from KEYNOTE-905 reveal about the role of ADC-based combinations in muscle-invasive bladder cancer?

Abstract LBA2: Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: phase 3 KEYNOTE-905 study.

Findings from the phase 3 KEYNOTE-905 trial demonstrated that perioperative enfortumab vedotin plus pembrolizumab, combined with radical cystectomy and pelvic lymph node dissection (RC + PLND), significantly improved event-free survival (EFS), OS, and pathologic complete response (pCR) rates compared with RC + PLND alone in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for or declined cisplatin-based chemotherapy.1 Median EFS was not reached with the combination vs 15.7 months with the control, representing a 60% reduction in the risk of disease-related effects or death. Improvements in EFS and OS were consistent across all evaluated subgroups, including those defined by age, ECOG performance status, PD-L1 expression, and tumor stage.

Additionally, the safety profile was consistent with previously reported effects for each agent, and no new safety signals were identified. Collectively, these findings position the regimen as a potential new standard of care for cisplatin-ineligible patients with MIBC.

“The future of the enfortumab vedotin/pembrolizumab combination will shift our considerations, [since we have] never used it…earlier in [the disease course]. This will have a radical impact on the way we conceive sequential therapies, [the way] we treat patients with metastatic [disease], [and] the way we, in general, [approach treatment for patients] already exposed to [some form of] immune therapy or immunotherapy/ADC combination,” Necchi explained.

What do new data from RC48-C016 on disitamab vedotin plus toripalimab reveal about the role of HER2-targeted ADC/immunotherapy combinations in advanced urothelial carcinoma?

Abstract LBA 7: Disitamab vedotin plus toripalimab vs chemotherapy in first-line locally advanced or metastatic urothelial carcinoma with HER2-expression.

The phase 3 RC48-C016 trial demonstrated that the combination of disitamab vedotin and toripalimab significantly prolonged survival outcomes compared with standard chemotherapy in the first-line treatment of patients with HER2-expressing locally advanced or metastatic urothelial carcinoma.2

At a median follow-up of 18.2 months, median PFS assessed by blinded independent review committee was 13.1 months (95% CI, 11.1-16.7) in the disitamab vedotin plus toripalimab arm vs 6.5 months (95% CI, 5.7-7.4) with chemotherapy, corresponding to a 64% reduction in the risk of progression or death (HR, 0.36; 95% CI, 0.28-0.46; P < .0001). Twelve- and eighteen-month PFS rates with the combination were 54.5% and 38.4%, respectively, compared with 16.2% and 7.5% for chemotherapy.

Median OS was 31.5 months (95% CI, 21.7-not evaluable) for patients treated with disitamab vedotin plus toripalimab compared with 16.9 months (95% CI, 14.6-21.7) for those receiving chemotherapy, translating to a 46% reduction in the risk of death (HR, 0.54; 95% CI, 0.41-0.73; P < .0001). At 12, 18, and 24 months, OS rates were 79.5%, 64.6%, and 52.8% in the experimental arm, respectively, vs respective rates of 62.5%, 48.1%, and 39.4% in the control arm.

“[Moving forward,] we will struggle in identifying the patient population [who is] best suited for [an] anti–Nectin-2 strategy,as compared to [the] enfortumab vedotin/pembrolizumab strategy,” Necchi explained. “In the future, [patient selection] based on clinical or biomarker characteristics, and envisioning a sequence of therapy with multiple ADC/immunotherapy combinations [emerging as] standard therapies, will become very complicated and [represent] the next challenge for future clinical trials.”

What do findings from the phase 2 OPTIC-RCC trial reveal about the efficacy of cabozantinib and nivolumab in patients with cluster 1 or 2 metastatic clear cell renal cell carcinoma, based on RNA sequencing–derived biomarker classification?

LBA 2591O: Efficacy of Cabozantinib and Nivolumab in Cluster 1/2 Metastatic Clear Cell Renal Cell Carcinoma: Results from OPTIC RCC, a phase II trial of a novel RNAseq-based biomarker

“[OPTIC RCC]answered a really important and provocative question, which is: can we start using biomarkers to choose the right patient for the right first-line treatment?” Hahn said. “We have all these different options to choose from. We all make clinical inferences on who’s the best patient for which treatment regimen. The OPTIC-RCC study looked at gene expression, and [researchers observed] that patients who had high angiogenic scores seemed to benefit more from nivolumab [Opdivo] plus cabozantinib [Cabometyx]. [This strategy is] not ready for prime time—it’s not going into clinic next week, but it is something that we are all going to start thinking about moving forward [in the future].

What do results from substudy 03A of the KEYMAKER-U03 trial reveal about the efficacy and safety of first-line pembrolizumab-based triplet regimens in advanced clear cell renal cell carcinoma?

LBA 96: First-line Pembrolizumab-based Regimens for Advanced Clear Cell Renal Cell Carcinoma: KEYMAKER-U03 Substudy 03A

Substudy 3A of the KEYMAKER-U03 trial demonstrated encouraging efficacy outcomes with the triplet regimen of belzutifan (Welireg), pembrolizumab, and lenvatinib (Lenvima) in patients with advanced clear cell RCC.

At the time of analysis, objective response rates (ORRs) by blinded independent central review ranged from 42.5% to 80.6% across the evaluated treatment arms, with the belzutifan-containing triplet producing some of the most favorable response outcomes. Complete responses were observed in up to 12.5% of patients across arms, with median follow-up durations spanning approximately 16 to 39 months.

“[KEYMAKER-U03] showed that the combination of pembrolizumab plus [belzutifan] plus [lenvatinib] had good, encouraging antitumor activity, so it really just set us up for the phase 3 [LITESPARK-012 trial (NCT05012397)]. It provides an important concept for clinicians to consider moving forward.”

What do results from the phase 2 LenCabo trial (NCT05012371) reveal about the comparative efficacy of lenvatinib plus everolimus vs cabozantinib in metastatic clear cell renal cell carcinoma following PD-1 inhibitor progression?

LBA94 - LenCabo: A randomized phase II multicenter trial of lenvatinib plus everolimus vs cabozantinib in patients with metastatic clear cell RCC that progressed on PD-1 immune checkpoint inhibition

Data from LenCabo presented at the meeting releveled that the combination reduced the risk of disease progression or death by 49% vs cabozantinib (HR, 0.51; 95% CI, 0.29-0.89; P = .02).5 Median PFS, the primary end point, was 15.7 months with lenvatinib plus everolimus vs 10.2 months with cabozantinib. These findings position the regimen as a potentially effective option in the post–immunotherapy setting, where optimal sequencing strategies remain under investigation. Although adverse effects (AEs) were more frequent with lenvatinib plus everolimus, the difference did not reach statistical significance. Grade 3/4 AEs occurred in 67.5% of patients receiving the combination vs 50% of those treated with cabozantinib (odds ratio, 2.08; 95% CI, 0.86-5.02).

“[The] study is very relevant to the decisions being made in clinic today, particularly when a patient’s cancer is worsening on immunotherapy,” Hahn noted.

What do findings from the phase 3 PSMAddition trial reveal about the efficacy of combining lutetium Lu 177 vipivotide tetraxetan with androgen deprivation therapy and an androgen receptor pathway inhibitor in patients with PSMA-positive metastatic hormone-sensitive prostate cancer?

Abstract LBA6: Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition)

Adding lutetium Lu 177 vipivotide tetraxetan to an androgen receptor pathway inhibitor (ARPI) and androgen deprivation therapy (ADT) significantly improved radiographic PFS (rPFS) compared with ARPI plus ADT alone in patients with PSMA-positive mHSPC, according to findings from the phase 3 PSMAddition trial.6

Patients who received the lutetium-based combination achieved a median rPFS that was not reached (95% CI, not evaluable-not evaluable) compared with not reached (95% CI, 29.7-not evaluable) for those treated with ARPI and ADT alone, translating to a 28% reduction in the risk of disease progression or death (HR, 0.72; 95% CI, 0.58-0.90; P = .002).

“We saw pretty important findings, [and this was truly new data],” Hahn said.

References

1. Vulsteke C, Kaimakliotis HZ, Danchaivijitr P, et al. Perioperative enfortumab vedotin plus pembrolizumab in participants with muscle-invasive bladder cancer who are cisplatin-ineligible: phase 3 KEYNOTE-905 study. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA2.
2. Sheng X, Zeng G, Zhang C, et al. Disitamab vedotin plus toripalimab in HER2-expressing advanced urothelial cancer. N Engl J Med. Published online October 19, 2025. doi:10.1056/NEJMoa2511648
3. Efficacy of Cabozantinib and Nivolumab in Cluster 1/2 Metastatic Clear Cell Renal Cell Carcinoma: Results from OPTIC RCC, a phase II trial of a novel RNAseq-based biomarker. LBA 2591O.
4. Suarez Rodriguez C, Rojas CI, Shin SJ, et al. First-line pembrolizumab-based regimens for advanced clear cell renal cell carcinoma: KEYMAKER-U03 substudy 03A. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA96.
5. Hahn AW, Chahoud J, Skelton WP, et al. A multicenter randomized phase II trial of lenvatinib plus everolimus versus cabozantinib in patients with metastatic clear cell RCC that progressed on PD-1 immune checkpoint inhibition (LenCabo). Ann Oncol. 2025. Doi:10.1016/j.annonc.2025.10.009.
6. Tagawa ST, Sartor O, Piulats JM, et al. Phase III trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA6.