Trial Data Show Significant EFS and OS in Patients with Muscle-Invasive Bladder Cancer

Data from the phase 3 clinical trial EV-303 (NCT03924895)¹ show that perioperative pembrolizumab (Keytruda), plus radical cystectomy (RC), plus pelvic lymph node dissection (PLND), and perioperative enfortumab vedotin (Padcev) in combination with pembrolizumab plus RC+PLND, significantly improved event-free survival (EFS) and overall survival (OS) when used before and after surgery in patients with muscle-invasive bladder cancer (MIBC), who are ineligible for or decline cisplatin-based chemotherapy.²

The full trial results were announced at the 2025 European Society for Medical Oncology (ESMO) Congress on October 18 in Berlin, Germany.

The trial, also referred to as KEYNOTE-905, met its primary end point of EFS, resulting in a 60% reduction in the risk of tumor recurrence, progression, or death of patients treated with neoadjuvant and adjuvant combination treatments compared to surgery alone, which is the standard –of care (HR, 0.40; 95% CI, 0.28-0.57; P <.0001).²

The secondary end point was overall survival (OS), which showed a 50% reduction in the risk of death for neoadjuvant and adjuvant combination treatment compared to surgery alone (HR, 0.50; 95% CI, 0.33-0.74; P <.0002).²

In an interview with Targeted Oncology, Christof Vulsteke, MD, PhD, head of Integrated Cancer Center Ghent, Clinical Trial Unit Oncology Ghent, and EV-303 principal investigator, further explained the findings and methodology of the phase 3 clinical trial EV-303.

Targeted Oncology: What was the rationale or unmet needs that prompted this line of research?

Christof Vulsteke, MD, PhD: Two years ago, also at ESMO, we presented groundbreaking results of perioperative pembrolizumab in a metastatic setting. There, we saw a doubling of the [OS] and of the progressive-free survival. We saw 30% achieving a complete response, and 75% of these patients are still in complete response up to 2 years [later]. I didn’t bring these drugs in an earlier setting. That's what we did by adding a third arm, because the trial originally started as a 2-arm trial. Based on these promising results in a metastatic setting, we added the third arm, and what we presented was the old patients, concordantly randomized to the perioperative pembrolizumab vs the control arm. Patients received 3 cycles in a pre-op setting of perioperative pembrolizumab, and then 6 cycles of enfortumab vedotin and 40 cycles of pembrolizumab in the post-op setting. All the patients are not amenable for new elemental therapy. We chose the patient population with the proper agnostic factors that normally you only operate on.

What was the study's design and methodology?

Patients could be included if they have metastatic bladder cancer, clinical stage T2 to T4. There was a predominant histology. We modified it to admit for peripheral neuropathy. Patients were randomized. In stage 2 of the trial, only randomized, EVP vs control, and the statistical testing strategy changed on that basis. All of the alpha was initially allocated to test the compression of EVP vs control, centrally assessed [EFS], and when that was a hit, we could pass all the alpha to the OS and pathologic complete response (pCR) testing. Only when all those null hypothes[es] were rejected, we could further test the period monotherapy vs the control.

What were the findings of the study?

The topline results of the study for [EFS] were a strong hit as a primary end point. There was an early and sustained separation of the curves in favor of pembrolizumab, and this was translated in a significant hazard ratio [HR] of 0.4, so that's quite striking. And to give it the percentages, at 2 years, 39% of [the] control arm were pre-events. When you look at the intervention arm, this was 75%, so a huge difference between intervention arm and control arm.

When you look at overall survival, it was also a hit––the first trial [to] ever me[e]t [OS] benefit in this population, with a HR of 0.5 in favor of the pembrolizumab, and [at] 2 years, 63% alive in the control arm and 80% in the intervention arm. Also a hit for the pCR endpoint. It was the highest ever reported in the phase 3 trial, 57.1% pCR.

What are the major implications or takeaways that you think oncologists should know based on this study?

I think that we should be aware that in this patient population, we normally say there are no options, only surgery, and now we have a very, very, very good option. We should offer the option to the patient only when available, of course, but when available, I think we should offer this patient this because if we only operate on them, they do very, very poor[ly].

What are the next steps in this line of research?

I really hope that this trial paves the way [for] next-gen trials, and that we can leave the surgery away that has a lot of complications in this patient population. I think the next gen[eration] of trials should focus on blood preserving strategies. I think we entered a new era of bladder cancer. I hope we can cure more and more patients and leave their own bladder in their own body. That would be a great future.

REFERENCES:

1. Perioperative Pembrolizumab (MK-3475) Plus Cystectomy or Perioperative Pembrolizumab Plus Enfortumab Vedotin Plus Cystectomy Versus Cystectomy Alone in Participants Who Are Cisplatin-ineligible or Decline Cisplatin With Muscle-invasive Bladder Cancer (MK-3475-905/​KEYNOTE-905/​EV-303). ClinicalTrials.gov. Updated August 28, 2025. Accessed October 20, 2025. https://clinicaltrials.gov/study/NCT03924895

2.PADCEV Plus KEYTRUDA, Given Before and After Surgery, Cuts the Risk of Recurrence, Progression or Death by 60% and the Risk of Death by 50% for Certain Patients with Bladder Cancer. News Release. Astellas Pharma Inc. October 18, 2025. Accessed October 20, 2025. https://tinyurl.com/5e3yjh9s