KEYTRUDA® and Padcev® Combination Improves Survival and Response in Muscle-Invasive Bladder Cancer

08/12/2025 – 05:33 AM

First and only systemic therapy to improve survival when used before and after surgery for patients with MIBC who are ineligible for cisplatin-based chemotherapy

First ever positive Phase 3 study in this cisplatin-ineligible patient population, representing significant advancement in MIBC

RAHWAY, N.J. – Merck (MRK) is making waves this morning, announcing positive topline results from its Phase 3 KEYNOTE-905 trial, a.k.a. EV-303. The study focused on patients battling muscle-invasive bladder cancer (MIBC) who aren’t eligible for cisplatin-based chemotherapy, a common hurdle in treatment.

The trial’s design involved administering Merck’s KEYTRUDA (pembrolizumab) alongside Padcev (enfortumab vedotin-ejfv), an antibody-drug conjugate (ADC), both before and after patients underwent surgery (radical cystectomy). The results, according to Merck, showed a statistically significant and clinically meaningful improvement in event-free survival (EFS), the study’s primary endpoint. Moreover, the combination therapy also demonstrated improved overall survival (OS) and pathologic complete response (pCR) rate, key secondary endpoints, compared to patients who underwent surgery alone.

Dr. Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent (IKG) and Clinical Trial Unit Oncology Ghent and KEYNOTE-905 principal investigator, emphasized the significance of these findings. “Patients with muscle-invasive bladder cancer who are ineligible for cisplatin-based chemotherapy have faced a treatment standstill beyond surgery,” he explained. “The KEYNOTE-905 study marks the first time a systemic treatment approach has significantly extended survival compared to standard surgery in this population, highlighting the potential of this combination to fill a critical unmet need.”

Financially, this news could be a boon for Merck, Pfizer (previously Seagen), and Astellas, the collaborators behind this trial. The study builds on their existing success in locally advanced or metastatic urothelial cancer. While the trial continues to evaluate secondary endpoints, these initial results suggest a potential new standard of care for a challenging patient population.

Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, echoed this sentiment. “There is a real and pressing need for more effective options for patients with bladder cancer who are ineligible for cisplatin-based treatment,” she stated. “The compelling survival results observed in this study reinforce the potential of combining KEYTRUDA with an antibody-drug conjugate to help address a significant unmet need in this vulnerable population.”

From a safety perspective, the KEYTRUDA plus Padcev combination presented a safety profile consistent with the known individual profiles of each agent, and no new red flags were raised. The companies intend to present the data at an upcoming medical meeting and will be seeking regulatory approvals worldwide.

It’s worth noting that KEYTRUDA plus Padcev is already approved in the U.S., the European Union, Japan, and other countries for treating adult patients with locally advanced or metastatic urothelial cancer, as well as KEYTRUDA as a monotherapy in the U.S., EU, Japan and other countries for the treatment of certain patients with la/mUC or a type of non-muscle-invasive bladder cancer (NMIBC).

Looking ahead, Merck has a robust bladder cancer program, with five additional Phase 3 studies currently exploring KEYTRUDA across all stages of the disease. This includes trials KEYNOTE-866, KEYNOTE-992, KEYNOTE-B15 (also known as EV-304, in collaboration with Pfizer and Astellas), KEYNOTE-676 (evaluating KEYTRUDA in combination with Bacillus Calmette-Guerin (BCG) in patients with NMIBC), and KEYNOTE-123 (assessing KEYTRUDA as adjuvant treatment in patients with localized muscle-invasive urothelial carcinoma and locally advanced urothelial carcinoma).

KEYNOTE-905, also known as EV-303, is an open-label, randomized, multi-arm, controlled, Phase 3 trial (ClinicalTrials.gov, NCT03924895) evaluating perioperative KEYTRUDA, with or without Padcev, versus surgery alone in patients with MIBC who are either not eligible for or declined cisplatin-based chemotherapy. The trial enrolled 595 patients who were randomized to receive either:

• Arm A: Three cycles of preoperative KEYTRUDA, followed by surgery to remove the bladder (radical cystectomy), followed by 14 cycles of postoperative KEYTRUDA;

• Arm B: Surgery alone;

• Arm C: Three cycles of preoperative KEYTRUDA plus enfortumab vedotin, followed by surgery to remove the bladder (radical cystectomy), followed postoperatively by six cycles of KEYTRUDA plus enfortumab vedotin and then eight cycles of KEYTRUDA alone.

The primary objective of this trial was to compare EFS between arm C and arm B, defined as the time from randomization to the first occurrence of any of the following events: progression of disease that precludes radical cystectomy (RC) surgery or failure to undergo RC surgery in participants with residual disease, gross residual disease left behind at the time of surgery, local or distant recurrence as assessed by imaging and/or biopsy or death due to any cause. The key secondary objectives were to compare OS and difference in pCR rate between arm C and arm B, as well as EFS, OS and the difference in pCR rate between arm A and arm B. The study remains ongoing to test hypotheses between arm A and arm B.

About Bladder Cancer: Bladder cancer remains a significant global health concern, with over 614,000 diagnoses annually. Muscle-invasive bladder cancer, accounting for roughly 30% of cases, necessitates improved treatment strategies, particularly for those ineligible for cisplatin-based chemotherapy.

This early-stage focus for Keytruda is particularly salient: Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is studying KEYTRUDA in earlier disease states, with more than 25 ongoing registrational studies across multiple types of cancer.

KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD- L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.

Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 1,600 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.

Urothelial Cancer

KEYTRUDA, in combination with enfortumab vedotin, is indicated for the treatment of adult patients with locally advanced or metastatic urothelial cancer.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with locally advanced or metastatic urothelial carcinoma:

• who are not eligible for any platinum-containing chemotherapy, or

• who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

KEYTRUDA, as a single agent, is indicated for the treatment of patients with Bacillus Calmette-Guerin (BCG)-unresponsive, high-risk, non-muscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors who are ineligible for or have elected not to undergo cystectomy.

KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions.

Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments.

Additional factors that could cause results to differ materially from those described in the forward-looking statements can be found in the company’s Annual Report on Form 10-K for the year ended December 31, 2024 and the company’s other filings with the Securities and Exchange Commission (SEC).