Tag: Urothelial Cancer (Bladder-Ureters-Renal-Pelvis)

SUMMARY: The American Cancer Society estimates that 84,870 new cases of bladder cancer will be diagnosed in 2025 and 17,420 will die of the disease. Bladder cancer is the fourth most common cancer in men but is less common in women and the average age at the time of diagnosis is 73 years. Caucasians are more likely to be diagnosed with bladder cancer than African Americans or Hispanic Americans.

Persistent Unmet Need in BCG-Naïve High-Risk NMIBC

High-risk Non–Muscle-Invasive Bladder Cancer (NMIBC) remains a clinically challenging disease despite decades of experience with intravesical Bacillus Calmette-Guérin (BCG). Standard management consists of complete TransUrethral Resection of Bladder Tumor (TURBT) followed by BCG induction and maintenance, However, up to 40% of patients experience early recurrence or progression within two years. For those with high-risk recurrence, radical cystectomy is frequently recommended, an intervention associated with substantial morbidity and quality-of-life implications. These limitations have driven interest in immunotherapy-based strategies aimed at improving disease control earlier in the treatment course and potentially delaying or avoiding radical surgery.

Rationale for Combining PD-L1 Blockade with BCG

Durvalumab (IMFINZI®), a monoclonal antibody targeting Programmed Death-Ligand 1 (PD-L1), has demonstrated clinically meaningful benefit in bladder cancer, most notably in the perioperative setting for muscle-invasive disease. Biologic rationale for combining immune checkpoint inhibition with BCG includes immune priming within the bladder microenvironment and the observation that PD-L1 expression may increase with disease progression or BCG resistance. Introducing checkpoint blockade earlier, before immune escape is fully established, may therefore enhance the durability of response to BCG.

POTOMAC Trial Design and Patient Population

POTOMAC (NCT03528694) was a global, randomized, open-label Phase III trial evaluating whether adding Durvalumab to standard BCG therapy improves outcomes in patients with BCG-naïve, high-risk NMIBC. A total of 1,018 patients from more than 120 centers across 12 countries were randomized 1:1:1 following TURBT to one of three treatment arms:

• Durvalumab plus BCG induction and maintenance (N=339)
• Durvalumab plus BCG induction alone (N=339)
• BCG induction and maintenance alone (control– N=340)

Durvalumab was administered at 1,500 mg IV every four weeks for 13 cycles (one year), while intravesical BCG induction therapy was weekly for 6 weeks and maintenance therapy consisted of three doses at weekly intervals at 3, 6, 12, 18, and 24 months. Patients were stratified by Carcinoma in Situ (CIS) and higher-risk papillary disease. The Primary endpoint was investigator-assessed Disease-Free Survival (DFS) comparing Durvalumab plus BCG induction and maintenance versus BCG alone.

Durable Improvement in Disease-Free Survival

At a median follow-up of 60.7 months, POTOMAC met its primary endpoint. The addition of one year of Durvalumab to BCG induction and maintenance resulted in a 32% reduction in the risk of high-risk disease recurrence or death compared with BCG alone (HR=0.68; P=0.015). Disease-free survival curves separated early and remained consistently apart over time, underscoring both early and sustained benefit. The median DFS was not reached in either arm. Importantly, Durvalumab combined with BCG induction alone, without maintenance BCG, did not improve outcomes, reinforcing the central role of adequate BCG exposure in disease control.

Overall Survival and Long-Term Follow-Up

Although the study was not powered to detect Overall Survival differences, extended follow-up showed no evidence of harm associated with Durvalumab. Descriptive analyses suggested numerically favorable survival outcomes with the combination regimen, providing reassurance regarding long-term safety in this curative-intent population.

Safety Profile and Treatment Tolerability

The safety profile of Durvalumab plus BCG was consistent with the known toxicities of each agent. Grade 3 or 4 treatment-related adverse events occurred more frequently with combination therapy than with BCG alone, but these events were generally manageable. No treatment-related deaths were reported. Common adverse effects reflected expected urinary and immune-related events, supporting the feasibility of integrating systemic immunotherapy into NMIBC management.

Context within the Evolving NMIBC Landscape

POTOMAC represents one of the longest follow-up datasets evaluating immune checkpoint inhibition in NMIBC and adds to a growing body of evidence supporting this strategy. Together with prior positive trials exploring PD-1/PD-L1 inhibitors alongside BCG, the data suggest that immune checkpoint blockade can meaningfully augment standard therapy when combined with full-course BCG. Differences among trials highlight the importance of patient selection, adequate maintenance therapy, and sufficient duration of treatment exposure.

Clinical Implications for Practice

The POTOMAC findings reinforce several key principles for clinicians:

• Maintenance BCG remains essential and should not be replaced by systemic immunotherapy alone
• Early integration of immune checkpoint blockade can improve disease control in carefully selected high-risk patients
• Long-term follow-up matters, particularly in NMIBC where durable bladder preservation is a primary goal

Conclusion

For patients with BCG-naïve, high-risk NMIBC, the addition of one year of Durvalumab to standard BCG induction and maintenance delivers a statistically significant and clinically meaningful improvement in Disease-Free Survival with a manageable safety profile. POTOMAC raises the bar for first-line NMIBC therapy and positions combined systemic and intravesical immunotherapy as a compelling new option for this high-risk population.

Durvalumab in combination with BCG for BCG-naive, high-risk, non-muscle-invasive bladder cancer (POTOMAC): final analysis of a randomised, open-label, phase 3 trial. De Santis M, Redorta JP, Nishiyama H, et al. The Lancet. 2025;406:2221-2234.

SUMMARY: The American Cancer Society estimates that in the United States for 2025, about 84,870 new cases of bladder cancer will be diagnosed and approximately 17,420 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

Patients with urothelial carcinoma are currently treated in the first line setting with a Platinum based chemotherapy regimen, and a checkpoint Inhibitor (PD-1 or PD-L1 inhibitor) in the second line setting. However, approximately 50% of patients with advanced urothelial carcinoma are ineligible for Cisplatin-based chemotherapy due to toxicities, and responses are rarely durable. There is therefore a critical need for effective and tolerable first line treatment options in locally advanced or metastatic urothelial carcinoma.

Enfortumab vedotin-ejfv (PADCEV®) is a first-in-class Antibody-Drug Conjugate (ADC) that targets Nectin-4, a cell adhesion molecule highly expressed in urothelial cancers and other solid tumors. Nectin-4 has been implicated in tumor cell growth and proliferation. Following binding to Nectin-4 on the cell surface, Enfortumab vedotin becomes internalized and is processed by lysosomes, with the liberation of its cytotoxic payload, MonoMethyl Auristatin E (MMAE), which in turn disrupts microtubule assembly, leading to cell cycle arrest and apoptosis. Enfortumab vedotin resulted in significantly longer Overall Survival, Progression Free Survival, and a higher Overall Response Rate, than standard chemotherapy, in patients with locally advanced or metastatic urothelial carcinoma, who had previously received Platinum-based treatment and a PD-1 or PD-L1 inhibitor. Preclinical studies with Enfortumab vedotin have shown hallmarks of immune cell death potentially augmented by PD-1/PD-L1 inhibitors, and the rationale for this clinical trial was based on results from a previous cohort study.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response. Pembrolizumab is the first agent to improve Overall Survival over chemotherapy, in the second line setting, for patients with recurrent, advanced urothelial carcinoma, and a significant proportion of patients who respond, have very durable responses.

EV-302 is a landmark Phase III, global, open-label, randomized trial comparing the efficacy and safety of Enfortumab vedotin and Pembrolizumab with the efficacy and safety of platinum-based chemotherapy, in patients with previously untreated locally advanced or metastatic urothelial carcinoma. A total of 886 eligible patients were randomly assigned in a 1:1 ratio to receive 3-week cycles of Enfortumab vedotin 1.25 mg/kg IV on days 1 and 8 and Pembrolizumab 200 mg IV on day 1 of every 3-week cycle (N=442) or chemotherapy consisting of Gemcitabine and either Cisplatin or Carboplatin (N=444), determined on the basis of eligibility to receive Cisplatin, for a maximum of 6 cycles. The maximum number of Pembrolizumab cycles allowed was 35 and there was no maximum number of cycles set for Enfortumab vedotin. The treatment groups were well balanced. The median age was 69 yrs and randomization was stratified according to eligibility to receive Cisplatin (eligible or ineligible), PD-L1 expression status (High-CPS 10 or more versus Low-CPS less than 10), and liver metastases (present or absent). The co-Primary end points were Progression Free Survival (PFS) and Overall Survival (OS) as assessed by Blinded Independent Central Review (BICR). Secondary end points included Overall Response Rate (ORR) as assessed by BICR, Duration of Response, and Safety.

In the primary analysis of EV-302 (KEYNOTE-A39) study, the combination of Enfortumab vedotin plus Pembrolizumab group nearly doubled median PFS (12.5 months versus 6.3 months) and OS (31.5 months versus to 16.1 months), when compared to platinum-based chemotherapy, in patients with previously untreated locally advanced or metastatic urothelial carcinoma.

In this report, the researchers reported the outcomes of EV-302 study after 1 year of additional follow-up (about 2.5 years of median follow-up), and an exploratory analysis of patients with confirmed Complete Response.

The PFS benefit with Enfortumab vedotin plus Pembrolizumab was maintained with an additional year of follow-up (12.5 versus 6.3 months; HR=0.48; P<0.00001). The OS benefit was also maintained with Enfortumab vedotin plus Pembrolizumab with a 49% reduction in the risk of death, when compared to platinum-based chemotherapy (33.8 versus 15.9 months; HR=0.51; P<0.00001). The PFS and OS benefit was observed across prespecified subgroups, including the Cisplatin-eligible and ineligible patients.

The ORR in the Enfortumab vedotin plus Pembrolizumab group was 67.5% versus 44.2% in the chemotherapy group (P<0.0.001) and the median Duration of Response was 23.3 months versus 7.0 months, respectively. A Complete Response was observed in 30.4% of patients treated with Enfortumab vedotin plus Pembrolizumab versus 14.5% among patients treated with chemotherapy. The median duration of Complete Response was not reached for Enfortumab vedotin plus Pembrolizumab and 15.2 months for chemotherapy. The probability of maintaining a Complete Response at 2 years with Enfortumab vedotin plus Pembrolizumab was 74%. For patients with a confirmed Complete Response, the 2-year PFS and OS rates were 78% and 95% in the Enfortumab vedotin plus Pembrolizumab group, respectively, versus 54% and 86% in the chemotherapy group, respectively.

It was concluded that, these data with longer follow up suggests that treatment with Enfortumab vedotin plus Pembrolizumab resulted in significantly superior outcomes, compared to chemotherapy, in patients with untreated locally advanced or metastatic urothelial carcinoma, emerging as a potential new standard of care, irrespective of Cisplatin eligibility. The results from this study mark a significant paradigm shift in the management of locally advanced or metastatic urothelial carcinoma, offering new hope for patients and clinicians alike.

EV-302: Updated analysis from the phase 3 global study of enfortumab vedotin in combination with pembrolizumab (EV+P) vs chemotherapy (chemo) in previously untreated locally advanced or metastatic urothelial carcinoma (la/mUC). Powles T, Van Der Heijden M, Loriot Y, et al. 2025 ASCO Genitourinary Cancers Symposium. Abstract 664. Journal of Clinical Oncology. Volume 43, Number 5_suppl February 2025.

SUMMARY: The American Cancer Society estimates that in the United States for 2025, about 84,870 new cases of bladder cancer will be diagnosed and approximately 17,420 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. Bladder cancer accounts for 90% of urothelial cancers, and urothelial cancer can also be found in the renal pelvis, ureter and urethra. Approximately 12% of urothelial cancer cases at diagnosis are locally advanced or metastatic.

The standard treatment for Cisplatin-eligible patients with Muscle-Invasive Bladder Cancer (MIBC) is neoadjuvant chemotherapy followed by radical cystectomy. However, the high relapse rate and risk of death despite this treatment has prompted further research into optimizing outcomes. Perioperative immunotherapy, particularly with immune checkpoint inhibitors, has shown promise in improving these outcomes. Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions. By inhibiting checkpoint proteins and their ligands, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response. It has been noted that PD-L1 is widely expressed in tumor and immune cells of patients with Urothelial Carcinoma. This in turn helps cancer cells to evade detection from the immune system by binding to the PD-1 receptor on cytotoxic T lymphocytes.

Durvalumab (IMFINZI®) is a selective, high-affinity human IgG1 monoclonal antibody directed against PD-L1 and blocks the interaction of PD-L1 with PD-1 and CD80. A preceding single-group, Phase 2 trial indicated that perioperative Durvalumab, combined with neoadjuvant Gemcitabine plus Cisplatin chemotherapy followed by radical surgery, was both safe and effective. Building on these findings, the Phase 3 NIAGARA trial aimed to evaluate the efficacy and safety of perioperative Durvalumab combined with neoadjuvant chemotherapy (Gemcitabine plus Cisplatin), followed by radical cystectomy, compared with neoadjuvant chemotherapy alone followed by radical cystectomy, in Cisplatin-eligible MIBC patients.

The NIAGARA trial was an open-label, randomized, multicenter, Phase 3 study, enrolling 1,063 (N=1063) Cisplatin-eligible patients with Muscle Invasive Bladder Cancer (clinical stage cT2–T4aN0/1M0). Patients were randomized in a 1:1 ratio to receive one of two treatment regimens. The experimental arm (Durvalumab group) included neoadjuvant Durvalumab 1500 mg IV alongside Gemcitabine plus Cisplatin every 3 weeks for 4 cycles, followed by radical cystectomy and adjuvant Durvalumab monotherapy 1500 mg IV every 4 weeks for up to 8 cycles (N=533). The comparison arm consisted of neoadjuvant Gemcitabine plus Cisplatin followed by radical cystectomy alone, without the addition of Durvalumab (N=530). Patients were stratified by clinical tumor stage (cT2N0 vs more than cT2N0), renal function (CrCl 60 mL/min or more vs 40 or more to less than 60 mL/min), and PD-L1 status (high vs low/negative). The dual Primary endpoints of the trial were Event-Free Survival (EFS) and pathological Complete Response (pCR), with Overall Survival (OS) as a key Secondary endpoint, as well as Metastasis Free Survival and Disease-Specific Survival. Event-Free Survival was defined as the time from randomization until progression that precluded surgery, failure to undergo surgery, recurrence after cystectomy, or death from any cause.

In the pre-planned interim analysis, the results demonstrated a significant improvement in both EFS and OS in the Durvalumab group compared to the chemotherapy-alone group. At 24 months, the estimated EFS was 67.8% in the Durvalumab group, compared to 59.8% in the comparison group (HR=0.68; P<0.001). Furthermore, the estimated OS at 24 months was 82.2% in the Durvalumab group versus 75.2% in the comparison group (HR for death=0.75; P=0.01). A pathological Complete Response (pCR) as assessed by central pathology review was noted in 37.3% of the patients in the Durvalumab group and in 27.5% of those in the comparison group. Notably, the percentage of patients who underwent radical cystectomy was similar between the two groups, with 88% in the Durvalumab group and 83% in the comparison group, indicating that the addition of Durvalumab did not reduce surgical completion rates.

An exploratory post hoc analysis of EFS and OS in patients with pCR versus those without pCR was also performed in the intent-to-treat population. The researchers herein reported additional outcomes and exploratory analysis results from NIAGARA study.

Patients in the Durvalumab group had a 33% reduction in risk of developing distant metastases or death (HR=0.67; P<0.001), and 31% reduction in risk of death from bladder cancer (HR=0.69; P=0.008) versus patients in the comparator group. More patients in the Durvalumab group achieved a pCR at the time of surgery versus the comparator (37% versus 28%) and patients who achieved a pCR had better EFS and OS, compared to those who did not. Patients in the Durvalumab group derived greater EFS and OS benefit versus the comparator group in both pCR group (EFS HR=0.58; OS HR=0.72), reducing the risk of disease progression or death by 42% and the risk of death by 28%, as well as non-pCR group (EFS HR=0.77; OS HR=0.84), reducing the risk of disease progression or death by 23% and risk of death by 16%. The most common immune-related adverse events included hypothyroidism in 10% of patients treated with Durvalumab compared to 1% in the comparator group, and hyperthyroidism in 3% versus 0.8% respectively. All immune mediated adverse events resolved in 41% of affected patients in the Durvalumab group and 44% in the comparator group.

It was concluded that the addition of perioperative Durvalumab to neoadjuvant chemotherapy significantly improved EFS and OS in both pCR and non-pCR groups, compared to chemotherapy alone, without compromising the ability to perform radical cystectomy. Further, perioperative Durvalumab combined with neoadjuvant chemotherapy reduced the risk of developing metastases and death from bladder cancer. These results are practice-changing, marking a major advancement in the treatment of MIBC. The findings support the hypothesis that perioperative immune checkpoint inhibitors, by priming the immune system before surgery and targeting residual micrometastatic disease post-surgery, improve long-term clinical outcomes. Biomarkers like circulating tumor DNA (ctDNA) could be pivotal in guiding treatment decisions, as emerging data suggests that negative ctDNA status post-neoadjuvant therapy correlates with reduced relapse risk.

Additional efficacy and safety outcomes and an exploratory analysis of the impact of pathological complete response (pCR) on long-term outcomes from NIAGARA. Galsky M, Van Der Heijden M, Catto J, et al. J Clin Oncol 43, 2025 (suppl 5; abstr 659). DOI 10.1200/JCO.2025.43.5_suppl.659