Dr Sharma on the Role of Enfortumab Vedotin Plus Pembrolizumab in Bladder Cancer

“EV-302 read out [in 2023]... [Data from this study] led to the eventual full FDA approval of [treatment with enfortumab vedotin plus pembrolizumab] in patients with bladder cancer in the frontline [setting].”

Janaki Neela Sharma, MD, assistant professor, clinical medicine, Genitourinary Medical Oncology, University of Miami Health Systems, discusses how data from the randomized, open-label, phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856) 

enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda)

 in patients with advanced urothelial cancer, irrespective of cisplatin eligibility.

This study included a broad population of patients with previously untreated metastatic bladder cancer, comparing the combination therapy against the standard chemotherapy regimen of gemcitabine and cisplatin, Sharma begins. The 

findings from EV-302 ultimately supported the

full approval of enfortumab vedotin plus pembrolizumab

 for the first-line treatment of patients with locally advanced or metastatic urothelial cancer in December 2023, she reports.

The EV-302 trial demonstrated a significant overall survival (OS) benefit with the use of the combination therapy, Sharma continues. The median OS was 31.5 months (95% CI, 25.4-not reached) for patients treated with enfortumab vedotin plus pembrolizumab compared with 16.1 months (95% CI, 13.9-18.3) for patients who received standard-of-care chemotherapy (HR, 0.47; 95% CI, 0.38-0.58;

 < .001), she states. Importantly, the OS advantage was consistent across cisplatin-eligible and cisplatin-ineligible patients, as highlighted by a preplanned subgroup analysis, Sharma notes, adding that this uniform survival benefit underscores the broad applicability of the combination therapy, regardless of a patient’s ability to tolerate cisplatin.

The overall response rate (ORR) data further emphasized the effectiveness of enfortumab vedotin plus pembrolizumab, Sharma expands. Patients who received the combination achieved a confirmed ORR of 67.7% (95% CI, 63.1%-72.1%),significantly surpassing the 44.4% (95% CI, 39.7%-49.2%) ORR observed with standard chemotherapy, she says. These robust response rates, coupled with improved survival outcomes, establish enfortumab vedotin plus pembrolizumab as a highly effective frontline treatment option for patients with advanced urothelial cancer, offering new hope for improved treatment outcomes across diverse patient populations, Sharma concludes.

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Janaki Neela Sharma, MD, discusses how data from EV-302 further defined the role of frontline enfortumab vedotin plus pembrolizumab in bladder cancer.

Dr Sharma on the Impact of Frontline Treatment Advances in Advanced Bladder Cancer

"In the last 3 years, [we have seen] the development of new drugs, specifically combinations with immunotherapy, being brought into the first-line treatment of metastatic bladder cancer. These have completely changed the landscape of available options, as well as the treatment paradigm."

Janaki Neela Sharma, MD, assistant professor, clinical medicine, Genitourinary Medical Oncology, University of Miami Health Systems, discusses the implications of therapeutic advancements in the front line treatment of patients with advanced bladder cancer.

For decades, cisplatin and gemcitabine have been the standard chemotherapy for the treatment of patient with bladder cancer, Sharma begins. However, these agents often produced low response rates and had a short durability of effect. As a result, metastatic bladder cancer was historically challenging to manage effectively, with poor survival outcomes, Sharma explains. However, significant advancements in treatment options in the last 3 years, especially with immunotherapy combinations in the frontline metastatic setting, have transformed the management landscape, Sharma states.

Among these innovations is the development of the Nectin-4–targeted antibody-drug conjugate enfortumab vedotin-efjv (Padcev), which has redefined therapeutic approaches, Sharma notes. Patients can now be evaluated for these options with an emphasis on balancing efficacy with quality of life, given that individual patient comorbidities can impact their tolerance to different regimens, she says.

Although there is substantial experience with the toxicity profiles of traditional agents like gemcitabine and cisplatin, the adverse effects associated with enfortumab vedotin combined with pembrolizumab (Keytruda) may be unfamiliar to many practicing oncologists, Sharma notes. Yet, with experience and multidisciplinary support, these toxicities are manageable, underscoring the need for a collaborative approach to help patients benefit fully from these advanced treatments, Sharma concludes.

Janaki Neela Sharma, MD, discusses the implications of treatment advances in the front line for patients with advanced bladder cancer.

Dr Sharma on the CheckMate 901 Study in Advanced Urothelial Cancer

“Although you can’t compare between trials…we have seen a larger percentage of patients have a response to the enfortumab vedotin and pembrolizumab combination, which is why I think it is in the forefront of most providers’ treatment armamentariums.”

Janaki Neela Sharma, MD, assistant professor, clinical medicine, Genitourinary Medical Oncology, University of Miami Health Systems, 

discusses key data from the phase 3 CheckMate 901 study (NCT03036098)

 and where nivolumab (Opdivo) plus chemotherapy fits into the frontline treatment setting for advanced urothelial cancer.

Notably, data from this clinical trial supported 

the March 2024 FDA approval of frontline nivolumab plus cisplatin and gemcitabine

 for the frontline treatment of adult patients with unresectable or metastatic urothelial carcinoma. This trial showed that the combination significantly improved overall survival (OS) and progression-free survival vs cisplatin/gemcitabine alone. CheckMate 901 included randomization to receive either nivolumab or placebo alongside chemotherapy, followed by maintenance with nivolumab or placebo, Sharma begins. The trial evaluated whether adding nivolumab could enhance outcomes compared with standard chemotherapy.

The trial demonstrated a median OS of 21.7 months (95% CI, 18.6-26.4) with nivolumab plus chemotherapy, an improvement over the control arm’s median OS of 18.9 months (95% CI, 14.7-22.4); these findings align with historical data showing median OS lengths of approximately 18 to 20 months with traditional chemotherapy in this setting, she reports. This survival benefit of nivolumab highlights the potential of using nivolumab combined with chemotherapy as a viable frontline treatment option, Sharma says.

In terms of response rates, nivolumab plus chemotherapy achieved an overall response rate (ORR) of 57.6% (95% CI, 51.8%-63.2%), reflecting solid efficacy, she continues. However, when compared indirectly with the enfortumab vedotin-ejfv (Padcev) plus pembrolizumab (Keytruda) combination studied in the phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856), which generated an ORR of 67.7% (95% CI, 63.1%-72.1%) in patients with untreated locally advanced or metastatic urothelial cancer, nivolumab plus chemotherapy appeared to elicit less robust responses, Sharma emphasizes. Although cross-trial comparisons should be interpreted cautiously, these data indicatethat enfortumab vedotin plus pembrolizumab may offer superior response rates vs nivolumab plus chemotherapy, positioning the former as a preferred frontline treatment in many cases, she concludes.

Janaki Neela Sharma, MD, discusses CheckMate 901, and where nivolumab plus chemotherapy fits into the advanced urothelial cancer treatment paradigm.

Dr Sharma on Key Trials Within the Urothelial Cancer Therapeutic Paradigm

Janaki Neela Sharma, MD, assistant professor, clinical medicine, Genitourinary Medical Oncology, University of Miami Health Systems, discusses which trials have shifted the therapeutic paradigm for patients with urothelial cancer, specifically highlighting novel agents that have made a splash in this arena.

The phase 3 JAVELIN Bladder 100 trial (NCT02603432), an investigation with initial results published in 2020, enrolled patients with metastatic bladder cancer who had received first-line chemotherapy, Sharma begins. Following standard chemotherapy—typically cisplatin and gemcitabine at the time—patients were randomly assigned to receive either maintenance immunotherapy with avelumab (Bavencio) or best supportive care, which involved observation alone, she explains. The trial’s primary end point was overall survival (OS), and findings demonstrated a significant OS advantage with the use of immunotherapy following chemotherapy, Sharma reports. These results established a new standard of care in which immunotherapy serves as maintenance therapy after upfront chemotherapy for metastatic bladder cancer, she emphasized.

Subsequent notable advancements in bladder cancer management were limited until 2023, when the results of the phase 2 EV-103/KEYNOTE-869 trial (NCT03288545) of enfortumab vedotin-ejfv (Padcev) were reported, she continues. This dose-escalation and -expansion trial included multiple study arms, but a key focus was on patients with frontline metastatic bladder cancer who were ineligible for cisplatin, Sharma states, noting that the data revealed impressive progression-free survival and OS benefits vs chemotherapy in this patient subgroup.

The median OS in patients treated with frontline enfortumab vedotin plus pembrolizumab (Keytruda) reached 26.1 months, representing approximately a 30% improvement compared with traditional chemotherapy OS outcomes, she expands. Among cisplatin-ineligible patients, the most remarkable outcome was the observed overall response rate (ORR), which was 73.3%—substantially higher than the historical ORR of approximately 30% to 40% associated with conventional chemotherapy, Sharma emphasizes. These findings underscore enfortumab vedotin’s potential as a new therapeutic option with superior efficacy in the management of metastatic bladder cancer, she concludes.

Janaki Neela Sharma, MD, discusses which trials have shifted the therapeutic paradigm for patients with urothelial cancer.

Dr Sharma on the Clinical Utility of Enfortumab Vedotin Plus Pembrolizumab in Bladder Cancer

Janaki Neela Sharma, MD, assistant professor, clinical medicine, Genitourinary Medical Oncology, University of Miami Health Systems, discusses the clinical significance of the FDA approval of enfortumab vedotin-ejfv (Padcev) in combination with pembrolizumab (Keytruda) for patients with locally advanced or metastatic urothelial cancer.

this combination for the treatment of patients in this population

based on findings from the randomized, open-label, phase 3 EV-302/KEYNOTE-A39 trial (NCT04223856). During the original presentation of the trial data, the findings received a standing ovation because of the high response rates, durable responses, and overall survival benefits, which were impressive, especially for bladder cancer, where such results are rare, Sharma begins. Initially, enfortumab vedotin plus pembrolizumab 

 for patients ineligible for cisplatin, creating a unique scenario where cisplatin-ineligible patients were eligible to receive this effective treatment but cisplatin-eligible patients were not, she states. This accelerated approval was a significant first step, offering remarkable outcomes for patients who otherwise had limited treatment options, Sharma reports.

With expanded approval now covering all patients with metastatic disease, regardless of cisplatin eligibility, enfortumab vedotin plus pembrolizumab has become a favored first-line regimen due to its manageable adverse effect profile, she continues, noting that this, however, raises questions regarding optimal sequencing for second-line treatments and beyond. Specifically, response rates with traditional chemotherapy, such as cisplatin and gemcitabine, following enfortumab vedotin plus pembrolizumab, remain unclear, Sharma emphasizes.

Sharma states that another key issue is whether the combination of enfortumab vedotin and pembrolizumab as first-line therapy is superior to 

the nivolumab (Opdivo) plus cisplatin and gemcitabine combination

. Although preliminary data with the enfortumab vedotin and pembrolizumab combination are promising, showing better outcomes compared with nivolumab plus cisplatin and gemcitabine, there is still a need for direct, head-to-head comparisons to definitively establish superiority of one regimen over the other, Sharma says. Until such data are available, evidence-based practitioners may remain cautious, awaiting robust comparative data to confirm these findings and optimize treatment pathways for metastatic bladder cancer, she concludes.

Janaki Neela Sharma, MD, discusses the FDA approval of enfortumab vedotin plus pembrolizumab for patients with locally advanced/metastatic bladder cancer.

Dr Sharma on Questions Regarding the Optimal Use of Triplet Therapies in HSPC

Janaki Neela Sharma, MD, assistant professor, genitourinary oncology, Sylvester Comprehensive Cancer Center, University of Miami Health System, discusses data on the use of triplet therapies in patients with hormone-sensitive prostate cancer (HSPC), highlighting unanswered questions regarding triplet vs doublet treatment options for patients whose disease is not considered high risk.

The phase 3 PEACE-1 (NCT01957436) and ARASENS (NCT02799602) trials demonstrated the survival benefit associated with adding an androgen receptor pathway inhibitor (ARPI) to standard-of-care (SOC) therapy vs SOC alone for patients with prostate cancer, Sharma says. PEACE-1 evaluated treatment with SOC (n = 296; defined as androgen deprivation therapy [ADT] alone or in combination with docetaxel) vs SOC plus radiotherapy (n = 291) vs SOC plus abiraterone acetate (Zytiga; n = 292) vs SOC plus radiotherapy and abiraterone (n = 291) in patients with metastatic castration-resistant prostate cancer.

In the overall population, at a median follow-up of 3.5 years (IQR, 2.8-4.6), the median radiographic progression-free survival was longer among patients who received abiraterone (n = 583) than those who did not receive abiraterone (n = 589; HR, 0.54; 99.9% CI, 0.41-0.71; 

 < .0001). At a median follow-up of 4.4 years (IQR, 3.5-5.4), the median overall survival (OS) was longer among patients treated with abiraterone vs those not treated with abiraterone (HR, 0.75; 95.1% CI, 0.59-0.95; 

The ARASENS trial randomly assigned patients with metastatic HSPC to receive either darolutamide (Nubeqa; n = 651) or placebo (n = 655), both in combination with docetaxel and ADT. The addition of darolutamide to docetaxel and ADT reduced the risk of death by 32.5% vs placebo (HR, 0.68; 95% CI, 0.57-0.80; 

 < .001). The 4-year OS rates in the darolutamide and placebo arms were 62.7% (95% CI, 58.7%-66.7%) and 50.4% (95% CI, 46.3%-54.6%), respectively.

Although both PEACE-1 and ARASENS met their primary end points, these trials were not designed to determine whether docetaxel plus an ARPI is superior to an ARPI alone in patients with HSPC, Sharma explains. Therefore, the optimal treatment for patients with HSPC who do not have high-risk disease remains unclear, Sharma emphasizes. Ongoing and planned studies are investigating which patients with HSPC should receive a triplet regimen and which will receive a doublet regimen, Sharma concludes.

Janaki Neela Sharma, MD, discusses data with triplet therapies in patients with hormone-sensitive prostate cancer.