Navigating the New Standard of Care: Patient Needs and the Pharmacist’s Critical Role in Perioperative MIBC Treatment

The recent FDA approval of enfortumab vedotin-ejfv (Padcev; Astellas Pharma Inc) in combination with pembrolizumab (Keytruda; Merck) as perioperative therapy for muscle-invasive bladder cancer (MIBC) marks a significant advancement in oncology.¹ This regimen is specifically approved for use as neoadjuvant therapy and as adjuvant treatment after radical cystectomy (RC) in patients who are ineligible for cisplatin-containing chemotherapy.¹

This combination has the potential to redefine the standard of care for a vulnerable patient population that previously had limited therapeutic avenues.¹ As this paradigm shift integrates into clinical practice, the pharmacist’s role in patient selection, safety monitoring, and optimizing care becomes critical.

The Unmet Need: Addressing the Cisplatin-Ineligible Patient

The standard approach for MIBC has historically been cisplatin-based neoadjuvant chemotherapy (NIAC) followed by RC.² However, a major limitation in MIBC management is that less than half of patients are fit for this cisplatin-based therapy.³ Many patients become cisplatin-ineligible due to significant comorbidities, such as impaired renal or cardiac function, or poor performance status.^2,3

Even for those who undergo standard therapy, the prognosis remains challenging, as approximately 50% of patients will relapse within 2 years despite surgery and systemic therapy.³ Adjuvant chemotherapy (AC) is often limited because patients who have had RC are more likely to be ineligible for cisplatin-based AC due to impaired renal function or poor performance status following the radical surgery.³

Furthermore, although RC remains the standard definitive treatment, it is a complex procedure associated with significant postoperative complications, morbidity, mortality, and deterioration of quality of life. The urgent need, therefore, is for improved localized disease management to reduce the risk of systemic recurrence, particularly for the cisplatin-ineligible group.³

The Evolving Treatment Landscape: Combination Efficacy and Novel Agents

The FDA approval of enfortumab vedotin plus pembrolizumab is grounded in compelling data from the phase 3 KEYNOTE-905/EV-303 trial.¹ This regimen demonstrated statistically significant and clinically meaningful improvements when compared to surgery alone in cisplatin-ineligible MIBC patients.²

The combination reduced the risk of recurrence, progression, or death by 60% and the risk of death by 50% compared to surgery alone.² Both event-free survival (EFS) and overall survival (OS) were also significantly improved. Median EFS was not reached versus 15.7 months (HR 0.40), and OR was not reached versus 41.7 months (HR 0.50).²

The pathological complete response rate was remarkably high at 57.1%, significantly surpassing the 8.6% observed with surgery alone.²

This groundbreaking treatment combination utilizes novel agents. Enfortumab vedotin is a first-in-class antibody-drug conjugate targeting Nectin-4, a protein highly expressed in bladder cancer, while pembrolizumab is an immune checkpoint inhibitor.¹

The broader treatment landscape for urothelial carcinoma is changing rapidly, introducing new therapeutic alternatives like immune checkpoint inhibitors, antibody-drug conjugates, and targeted agents. Ongoing phase 3 trials continue to explore the perioperative setting, including the KEYNOTE-B15/EV-304 trial comparing enfortumab vedotin plus pembrolizumab to cisplatin-based perioperative chemotherapy in cisplatin-eligible patients.^2,3

Another major area of development is the use of circulating tumor DNA (ctDNA) as a prognostic marker. Postsurgical ctDNA positivity is useful for identifying minimal residual disease and is associated with a higher probability of recurrence.² Trials are now assessing whether adjuvant therapy should be guided by ctDNA status, supporting personalized treatment approaches.^1,3 Treatment decisions for subsequent therapy after relapse may depend on the time to progression.²

Prioritizing the Pharmacist’s Role: Safety, Selection, and Management

The successful integration of perioperative enfortumab vedotin plus pembrolizumab into clinical practice hinges on the expertise and vigilance of the oncology pharmacist. The pharmacist plays a critical role in mitigating the higher toxicity profile of this highly effective combination, ensuring appropriate patient selection, and maintaining adherence throughout the complex perioperative course.

Expert Safety Monitoring and Adverse Event Management

Pharmacists must be keenly aware of the safety data, especially because grade 3 or higher treatment-emergent adverse events (AEs) occurred in 71.3% of the combination arm versus 45.9% in the control arm. Although the perioperative enfortumab vedotin plus pembrolizumab regimen did not negatively affect patients’ ability to undergo surgery, the pharmacist must proactively monitor for high-risk toxicities.^1,2

In particular, pharmacists must counsel patients extensively on and monitor for skin reactions, peripheral neuropathy, ocular disorders, and hyperglycemia. Patients with severe peripheral neuropathy or poorly controlled diabetes are likely not good candidates for this treatment, making pharmacist input into patient selection essential.²

There are also pembrolizumab-specific AEs to be mindful of. Monitoring for and managing potential immune-related adverse events, such as hypothyroidism and severe skin reactions, is necessary.

Optimizing Adherence and Completion of Adjuvant Therapy

The combination treatment spans neoadjuvant cycles, surgery, and adjuvant cycles.^1,2 Pharmacists are instrumental in coordinating medication access, ensuring patient adherence, and addressing treatment barriers across this continuum. In the EV-303 study, only 67% of patients who underwent cystectomy started adjuvant therapy.² The pharmacist can help mitigate clinical and practical barriers that lead to this drop-off rate, thereby maximizing the changes of completing the intended course of therapy.

Navigating Complex Data and Biomarkers

As treatment algorithms are constantly modified by ongoing trials involving combinations of immune checkpoint inhibitors, antibody-drug conjugates, and targeted agents,² pharmacists serve as vital information resources. They must utilize their clinical expertise to translate complex clinical data from ongoing trials into practical, patient-specific management strategies.

As ctDNA emerges as a key tool for guiding adjuvant therapy, the pharmacist will also be essential in helping the multidisciplinary team interpret these results and apply them to personalized treatment decisions for minimal residual disease.¹

Conclusion

The FDA approval of perioperative enfortumab vedotin plus pembrolizumab is a pivotal moment for patients with MIBC who are ineligible for cisplatin-based chemotherapy, offering a magnitude of clinical benefit not previously seen in this population.

Moving forward, the oncology pharmacist’s role is essential. They are critical navigators who must ensure appropriate and safe utilization of this new, highly active combination therapy. By prioritizing patient safety through rigorous AE monitoring and careful patient selection, and by actively engaging in interdisciplinary coordination to optimize adherence and integrate emerging biomarkers, pharmacists are central to improving outcomes in the evolving landscape of bladder cancer care.

REFERENCES
1. Antrim A. FDA approves enfortumab vedotin plus pembrolizumab for muscle-invasive bladder cancer. Pharmacy Times. November 24, 2025. Accessed December 2, 2025. https://www.pharmacytimes.com/view/fda-approves-enfortumab-vedotin-plus-pembrolizumab-for-muscle-invasive-bladder-cancer

2. Peri-operative enfortumab vedotin plus pembrolizumab prolongs survival in muscle-invasive bladder cancer. ESMO Daily Reporter. October 18, 2025. Accessed December 2, 2025. https://dailyreporter.esmo.org/esmo-congress-2025/genitourinary-cancers/peri-operative-enfortumab-vedotin-plus-pembrolizumab-prolongs-survival-in-muscle-invasive-bladder-cancer

3. Esteban-Villarrubia J, Torres-Jiménez J, Bueno-Bravo C, García-Mondaray R, Subiela JD, Gajate P. Current and future landscape of perioperative treatment for muscle-invasive bladder cancer. Cancers (Basel). 2023;15(3):566. doi:10.3390/cancers15030566