Oncology Decoded

In this episode of Oncology Decoded, hosts Manojkumar Bupathi, MD, MS, and Benjamin Garmezy, MD, discussed treatment for urothelial carcinoma following updates from the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting. With enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) now the frontline standard, the hosts focused on emerging biomarker-driven strategies that show efficacy after progression on first-line care.
Bupathi outlined the current algorithm, with platinum-based chemotherapy—typically gemcitabine plus carboplatin—representing the most common second-line option. Beyond chemotherapy, sacituzumab govitecan-hziy (Trodelvy) retained its NCCN category 2 recommendation despite losing its FDA accelerated approval in urothelial carcinoma after the confirmatory phase 3 TROPiCS-04 trial (NCT04527991) did not yield an overall survival benefit. For biomarker-selected patients, erdafitinib (Balversa) is available for FGFR3-altered disease, and fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) is FDA-approved for HER2 immunohistochemistry (IHC) 3+ solid tumors, including bladder cancer.
Garmezy, an investigator on the phase 1 NEXUS-01 trial (NCT06465069), discussed data on LY4052031, a nectin-4-directed antibody drug conjugate (ADC) carrying a topoisomerase payload, in patients previously treated with enfortumab vedotin, which also targets nectin-4 but delivers a different payload class. The trial showed response rates of 30% to 40% in that population, with some durable responses, suggesting resistance to enfortumab vedotin often reflects payload-specific resistance rather than loss of nectin-4 expression. Garmezy described the data as hypothesis-generating.
Regarding patients who progress on frontline enfortumab vedotin plus pembrolizumab, the hosts said they would prioritize a biomarker-directed option, such as erdafitinib for FGFR3 alterations or T-DXd for HER2 expression, when a trial is not available, while reserving chemotherapy for later lines. Given the lack of comparative data to help guide a choice between erdafitinib and T-DXd when a patient has both an FGFR3 alteration and HER2 expression, the hosts noted that selections come down to shared decision-making around toxicity profile and route of administration.
Bupathi and Garmezy are executive cochairs of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI). Additionally, Bupathi is the president and a medical oncologist with Rocky Mountain Cancer Centers, specializing in solid tumors and genitourinary cancers. Garmezy is the associate director of genitourinary research for SCRI and a medical oncologist at SCRI Oncology Partners, specializing in genitourinary cancers. 

References

Gilead provides update on US indication for Trodelvy in metastatic urothelial cancer. News release. Gilead Sciences, Inc. October 18, 2024. Accessed July 14, 2026. https://tinyurl.com/hyk3fhmf

FDA approves erdafitinib for locally advanced or metastatic urothelial carcinoma. News release. FDA. January 19, 2024. Accessed July 14, 2026. https://tinyurl.com/bddc5zz9

FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. News release. FDA. April 5, 2024. Accessed July 14, 2026. https://tinyurl.com/567c9akx

Iyer G, Gao X, Wei AZ, et al. Initial results from NEXUS-01, a phase 1 study of LY4052031, an antibody-drug conjugate targeting Nectin-4, in participants with advanced or metastatic urothelial carcinoma. J Clin Oncol. 2026;44(16 suppl):4508. doi:10.1200/JCO.2026.44.16_suppl.4508

In the newest episode of Oncology Decoded, hosts Manojkumar Bupathi, MD, MS; and Benjamin Garmezy, MD, discussed takeaways from the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting that may guide clinical practice. Following their initial conversation on the most critical presentations in prostate cancer, Bupathi and Garmezy spoke about additional presentations that may influence decision-making in the clinic for patients with bladder cancer and kidney cancer.
Bupathi and Garmezy are executive cochairs of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI). Additionally, Bupathi is president and medical oncologist with Rocky Mountain Cancer Centers, specializing in solid tumors and genitourinary cancers. Garmezy is the associate director of genitourinary research for SCRI and a medical oncologist at SCRI Oncology Partners, specializing in genitourinary cancers.
They discussed the following presentations:
EV-302

Long-term data from the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) showed that enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) demonstrated a sustained overall survival (OS) benefit compared with platinum-based chemotherapy in the first-line treatment of patients with locally advanced or metastatic urothelial carcinoma.
With a median follow-up of 42.8 months, the median OS was 33.6 months (95% CI, 26.6-39.8) in the enfortumab vedotin arm vs 15.9 months (95% CI, 13.6-18.3) in the chemotherapy arm (HR, 0.53; 95% CI, 0.45-0.63). Additionally, the objective response rate (ORR) was 67.5% vs 44.2% in each respective arm.
Overall, the long-term data reinforced enfortumab vedotin plus pembrolizumab as a frontline standard of care for patients with locally advanced or metastatic urothelial carcinoma.
RAMPART

In the phase 3 RAMPART trial (NCT03288532), combining durvalumab (Imfinzi) with tremelimumab-actl (Imjudo) showed a statistically significant improvement in disease-free survival (DFS) vs active monitoring among patients with resected primary renal cell carcinoma, although no significant improvement was observed with durvalumab monotherapy. According to the hosts, these findings may introduce some uncertainty surrounding the increased uptake of PD-L1 inhibitors in this patient population.
Data showed that durvalumab monotherapy reduced the risk of disease recurrence or death by 26%, although this improvement did not cross the prespecified threshold for statistical significance (HR, 0.74; 95% CI, 0.53-1.04; 1-sided P = .041). The 3-year DFS rates were 78% with durvalumab alone vs 72% with active monitoring.
References

Powles TB, van der Heijden MS, Bedke J, et al. Enfortumab vedotin plus pembrolizumab vs chemotherapy for previously untreated locally advanced or metastatic urothelial carcinoma: 3.5-year follow-up and response analyses from the phase 3 EV-302 study. J Clin Oncol. 2026;44(suppl 16):4507. doi:10.1200/JCO.2026.44.16_suppl.4507

Larkin JM, Powles T, Frangou E, et al. Durvalumab monotherapy versus active monitoring for resected primary renal cell carcinoma in RAMPART: an international, phase 3, randomized controlled trial. J Clin Oncol. 2026;44(suppl 17):LBA4511. doi:10.1200/JCO.2026.44.17_suppl.LBA4511

In the newest episode of Oncology Decoded, hosts Manojkumar Bupathi, MD, MS; and Benjamin Garmezy, MD, provided a recap of the most critical presentations and data to emerge from the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting. Specifically, they highlighted the late-breaking abstracts that may transform the standard of care for different prostate cancer populations.
Bupathi and Garmezy are executive cochairs of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI). Additionally, Bupathi is president and medical oncologist with Rocky Mountain Cancer Centers, specializing in solid tumors and genitourinary cancers. Garmezy is the associate director of genitourinary research for SCRI and a medical oncologist at SCRI Oncology Partners, specializing in genitourinary cancers.
Together, they dissected updated results from the following trials:
TALAPRO-3

In the phase 3 TALAPRO-3 trial (NCT04821622), combining talazoparib (Talzenna) with enzalutamide (Xtandi) significantly improved radiographic progression-free survival (rPFS) vs standard enzalutamide monotherapy among patients with metastatic castration-sensitive prostate cancer (CSPC) harboring homologous recombination repair (HRR) alterations. Based on investigator assessment, the median rPFS was not reached (NR; 95% CI, NR-NR) with the talazoparib combination vs 45.8 months (95% CI, 37.7-NR) with enzalutamide plus placebo (HR, 0.481; 95% CI, 0.357-0.647; P <.0001).
Overall, the data supported talazoparib plus enzalutamide as a potential treatment option for patients with HRR-altered metastatic CSPC and highlighted the importance of early molecular testing in prostate cancer.
PROTEUS

Findings from the phase 3 PROTEUS trial (NCT03767244) demonstrated a reduced risk of death or metastasis with apalutamide (Erleada) plus androgen deprivation therapy (ADT) vs placebo plus ADT among patients with high-risk localized or locally advanced prostate cancer. With a median follow-up of 61.7 months, 8.9% of patients in the apalutamide group experienced a pathological complete response (pCR) vs 1% of those who received placebo (OR, 10.17; 95% CI, 5.27-19.64; P <.001). The likelihood of metastasis-free survival at 5 years was 78.2% vs 73.5% in each respective arm (HR, 0.80; 95% CI, 0.67-0.96; P = .02).
According to the study investigators, results from PROTEUS may support apalutamide plus ADT and radical prostatectomy as a new standard of care for patient with high-risk localized or locally advanced disease.
References

Agarwal N, Matsubara N, Azad A, et al. TALAPRO-3: Talazoparib (TALA) + enzalutamide (ENZA) compared with placebo (PBO) + ENZA for the treatment of patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) harboring homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2026;44(suppl 17):LBA5007. doi:10.1200/JCO.2026.44.17_suppl.LBA5007

Taplin ME, Gleave M, Shore N, et al. Perioperative (neoadjuvant and adjuvant) apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT with radical prostatectomy (RP) in high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): final analysis of the PROTEUS phase 3 study. J Clin Oncol. 2026;44(suppl 17):LBA1. doi:10.1200/JCO.2026.44.17_suppl.LBA1

In the newest episode of Oncology Decoded, hosts Manojkumar Bupathi, MD, MS, and Benjamin Garmezy, MD, convened with their colleagues Suzanne B. Merrill, MD, FACS, and Mark D. Tyson, II, MD, MPH. They broke down the current treatment paradigm for those with non–muscle-invasive bladder cancer (NMIBC) by discussing how novel therapeutic modalities, patient selection criteria, and other practical considerations fit into effective clinical strategies. 
The discussion began with an overview of the effectiveness and limitations associated with Bacillus Calmette-Guérin (BCG), and how clinical trials like the phase 3 KEYNOTE-676 (NCT03711032) and phase 3 POTOMAC (NCT03528694) studies may support novel treatment regimens that incorporate checkpoint inhibitors. The group discussed how immunotherapy agents like pembrolizumab (Keytruda) may play important roles in the treatment of patients with NMIBC, especially in the event of BCG-unresponsive disease or BCG shortages. 
Additionally, the experts spoke about forming effective collaborations between urologists and medical oncologists to optimally care for patients. Specifically, Merrill emphasized a dedicated team approach to check symptoms, process referrals, and handle other tasks when treating patients who are receiving immune checkpoint inhibitors for their diseases. The conversation concluded with the group emphasizing the development of novel treatment delivery systems across the NMIBC space, which may improve outcomes and positively impact patients from a quality-of-life perspective.
Drs. Bupathi and Garmezy are executive cochairs of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI). Additionally, Dr. Bupathi is president and a medical oncologist with Rocky Mountain Cancer Centers, specializing in solid tumors and genitourinary cancers. Dr. Garmezy is the associate director of genitourinary research for SCRI and a medical oncologist at SCRI Oncology Partners, specializing in genitourinary cancers.
Merill is a board-certified urologic surgeon at Colorado Urology. Tyson is a urologic oncologist with a subspecialty interest in bladder cancer at Mayo Clinic in Arizona.

In the latest episode of Oncology Decoded, hosts Manojkumar Bupathi, MD, MS; and Benjamin Garmezy, MD, spoke about the clinical utility of enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) for those with muscle-invasive bladder cancer (MIBC) and similar patient populations. They highlighted the “transformational” potential of this therapeutic regimen in the context of findings from the phase 3 KEYNOTE-B15/EV-304 trial (NCT04700124) that investigators presented at the 2026 ASCO Genitourinary Cancers Symposium.

Although certain data from the EV-304 trial, including the improvements in pathologic complete responses (pCRs) with the enfortumab vedotin combination over gemcitabine/cisplatin, represent “historical gamechangers”, the hosts pointed towards some uncertainty related to outcomes for those with varying or mixed histologies. According to Bupathi, it may still make sense to administer chemotherapy with immunotherapy in some of these subgroups. 
The hosts also considered how many cycles of enfortumab vedotin plus pembrolizumab should be administered across the neoadjuvant and adjuvant settings, noting how markers like circulating tumor DNA may help inform treatment schedules. Additionally, they highlighted a need for additional research to clarify whether cystectomy could be spared for patients receiving this combination regimen while translating the benefits observed in trials like EV-304 to the real world.
The discussion also touched upon the treatment of those with metastatic disease, as the hosts considered how dosing cycles, consolidated radiotherapy, and cystectomy with nodal dissection fit into the treatment algorithm for these patients. Garmezy and Bupathi also discussed how the efficacy and safety of the enfortumab vedotin combination compared with gemcitabine plus nivolumab (Opdivo), noting how the EV-304 regimen may be simpler to administer and manage.
Bupathi and Garmezy are executive cochairs of the Genitourinary Cancer Research Executive Committee at Sarah Cannon Research Institute (SCRI). Additionally, Bupathi is president of and a medical oncologist with Rocky Mountain Cancer Centers, specializing in solid tumors and genitourinary cancers. Garmezy is the associate director of genitourinary research for SCRI and a medical oncologist at SCRI Oncology Partners, specializing in genitourinary cancers.
Reference

Galsky MD, Valderrama BP, Maruzzo M, 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. J Clin Oncol. 2026;44(suppl 7):LBA630. doi: 10.1200/JCO.2026.44.7_suppl.LBA630