Bladder cancer research is continuously advancing, from new developments to best standards of care. Explore the links and research highlights below to stay informed and learn more about the latest advancements in the field.
Bladder Cancer Research & Studies
Efficacy and Safety of Disitamab Vedotin in Patients With Human Epidermal Growth Factor Receptor 2–Positive Locally Advanced or Metastatic Urothelial Carcinoma: A Combined Analysis of Two Phase II Clinical Trials
Bladder cancer patients with overexpression of a protein called human epidermal growth factor receptor 2 (HER2) typically demonstrate tumour progression and poor disease prognosis. Disitamab vedotin (DV) is a HER2-targetting therapeutic agent that has the potential to prolong survival in HER2-positive patients with advanced, chemotherapy-refractory urothelial carcinoma, which has a 5-year survival rate of only 5%. In an analysis of two phase II clinical trials involving 107 patients with locally advanced or metastatic cancer that had progressed after chemotherapy, DV was found to have a confirmed objective response rate (ORR) of 50.5%, a median progression-free survival (PFS) of 5.9 months, and a median overall survival (OS) of 14.2 months. Moreover, treatment-related adverse events (TRAEs) were manageable, with only 54.2% of patients experiencing adverse events of severity grade ≥3. Thus, DV therapy presents a promising novel treatment option for patients with advanced urothelial cancer who progressed on standard therapies.
Patient-Reported Outcomes in Patients With Advanced Urothelial Cancer Who Are Ineligible for Cisplatin and Treated With First-Line Enfortumab Vedotin Alone or With Pembrolizumab
Locally advanced/metastatic urothelial cancer (la/mUC) is an aggressive and incurable disease that has a high symptom burden and negatively impacts patients’ quality of life (QOL) and day-to-day functioning. The standard first-line treatment for patients with la/mUC is cisplatin-based chemotherapy, but 50% of patients are ineligible, and there is thus a need for alternative first-line treatment options for these patients. Enfortumab vedotin (EV) is a therapeutic agent that targets and kills tumour cells while leaving healthy cells intact, while pembrolizumab (P) is an immunotherapeutic drug that stimulates the immune system to fight off the cancer. In a recent clinical trial comparing the efficacy of EV + P combination therapy in 65 patients with EV monotherapy in 63 patients, researchers found that EV + P maintained patient-reported QOL outcomes through 24 weeks, and even improved emotional functioning, pain, and insomnia scores; similarly, EV alone maintained QOL outcomes through 24 weeks, with improvements seen in pain, insomnia, and constipation scores. These promising results support the use of EV + P as a first-line treatment option for la/mUC patients, in particular for those who are cisplatin-ineligible.
Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3
Patients with advanced or metastatic urothelial carcinoma who progress after receiving first-line platinum-based chemotherapy have a markedly poor prognosis and thus require effective second-line treatments. Two such treatments are pembrolizumab, an immunotherapeutic drug that stimulates the immune system to fight off the cancer, and sacituzumab govitecan (SG), a drug that targets tumour cells with elevated expression of trophoblast cell surface antigen-2 (Trop-2), which is a protein that promotes cell growth and proliferation. In a recent phase II clinical trial involving 41 patients with metastatic urothelial carcinoma who had progressed after receiving platinum-based chemotherapy, researchers investigated the efficacy of combining SG with pembrolizumab. The study found that the combination therapy yielded an objective response rate (ORR) of 41%, which is significantly higher than pembrolizumab monotherapy (at approximately 21%), as well as a median progression-free survival and overall survival of 5.3 and 12.7 months, respectively. The high response rate combined with the manageable toxicity profile presents a promising new treatment option for patients with metastatic urothelial carcinoma who progress after platinum-based chemotherapy.
Recently Announced at ESMO Congress: Breakthrough Medication Combination Shows Extended Survival in Advanced Bladder Cancer Patients (Nov 2023)
Exciting advancements in bladder cancer treatment are on the horizon as a new combination of cancer medications demonstrates promising results. Recently presented at the European Society for Medical Oncology Congress in Madrid, the research highlights the efficacy of Enfortumab Vedotin and Pembrolizumab (Pembro), administered via IV infusions. The combination significantly reduced the risk of disease progression or death by 55% in previously untreated patients with advanced bladder cancer, leading to a remarkable median overall survival of 31.5 months compared to 16.1 months with standard chemotherapy. These findings mark a significant stride in the ongoing efforts to enhance the treatment landscape for advanced bladder cancer.
Enfortumab Vedotin With or Without Pembrolizumab in Cisplatin-Ineligible Patients With Previously Untreated Locally Advanced or Metastatic Urothelial Cancer (Oct 2023)
Cisplatin-based chemotherapy is the standard first-line treatment for patients with locally advanced or metastatic urothelial cancer (la/mUC). Unfortunately, around half of all patients are ineligible for this therapy because of one or more comorbidities (e.g., impaired renal function), and thus there is a need for other efficacious and tolerable first-line treatments. One therapeutic strategy that has gained attention is to combine an antibody-drug conjugate such as Enfortumab Vedotin (EV) with an anti-PD-1 antibody such as pembrolizumab (Pembro); these drugs, individually, have shown moderate effectiveness as second-line treatments in improving overall survival (OS) in patients with la/mUC, but preclinical data suggests that when used in combination, their antitumour activity can be enhanced, thereby significantly improving their efficacy as a first-line treatment. In a recent clinical trial comparing EV + Pembro combination therapy vs. EV monotherapy in terms of response and safety profiles in la/mUC patients, researchers found that the confirmed objective response rate (cORR) was 64.5% for 76 patients treated with EV + Pembro, and 45.2% for 72 patients treated with EV monotherapy. Furthermore, 65.4% of patients who responded to the combination therapy, and 56.3% of monotherapy-responsive patients, maintained a response at 12 months. Adverse events/reactions in the EV + Pembro group were slightly increased, but still manageable, compared to the EV monotherapy group, and no new safety signals/concerns were observed. Altogether, these results are encouraging for continuing investigations into improving the efficacy and safety of EV and Pembro combination therapy as an alternative first-line treatment for muscle-invasive bladder cancer.
Reference: O’Donnell, P. H., Milowsky, M. I., Petrylak, D. P., Hoimes, C. J., Flaig, T. W., Mar, N., … & Rosenberg, J. E. (2023). Enfortumab vedotin with or without pembrolizumab in cisplatin-ineligible patients with previously untreated locally advanced or metastatic urothelial cancer. Journal of Clinical Oncology, 41(25), 4107-4117.
Perioperative Chemoimmunotherapy With Durvalumab for Muscle-Invasive Urothelial Carcinoma: Primary Analysis of the Single-Arm Phase II Trial SAKK 06/17 (Sept 2023)
Cisplatin-based neoadjuvant chemotherapy before local treatment (i.e., resection or radical cystectomy) is the standard of care for patients with localized muscle-invasive urothelial carcinoma (MIUC) of the bladder. However, even with the addition of adjuvant nivolumab (an immune checkpoint inhibitor, or ICI), outcomes for patients are still far from optimal, with 25%-50% experiencing relapse and eventual death from their disease. Several clinical trials have been done to examine whether perioperative chemoimmunotherapy with another ICI, durvalumab, can improve outcomes for patients with MIUC. In a recent study of 57 MIUC patients, researchers found that the combination of neoadjuvant durvalumab with chemotherapy, followed by adjuvant durvalumab alone, achieved significantly high rates of event-free survival (EFS; i.e., time after treatment until progression, recurrence, metastases, or death occurs) and overall survival (OS) after 2 years. EFS and OS rates at 2 years were 76% and 85%, respectively, thus pointing toward a promising future for the treatment of MIUC with chemoimmunotherapy.
Reference: Cathomas, R., Rothschild, S. I., Hayoz, S., Bubendorf, L., Özdemir, B. C., Kiss, B., … & Petrausch, U. (2023). Perioperative Chemoimmunotherapy With Durvalumab for Muscle-Invasive Urothelial Carcinoma: Primary Analysis of the Single-Arm Phase II Trial SAKK 06/17. Journal of clinical oncology, JCO-23.
Poly (ADP-ribose) Polymerase Inhibition in Advanced Urothelial Carcinoma (Aug 2023)
Genomic mutations in DNA damage repair (DDR) pathways are seen in a substantial proportion of patients with urothelial carcinoma, especially those with muscle-invasive or advanced disease. Poly (ADP-ribose) polymerase (PARP) is a family of proteins that play a crucial role in DDR, and recent investigations have found that pharmacologic inhibition of PARP can disrupt DDR in tumour cells, thereby killing these cells. Researchers are currently exploring the possibility of PARP inhibition as a promising therapeutic strategy for treating urothelial carcinoma, although issues such as genetic biomarker identification for patient selection and acquired resistance to treatment need to be overcome before optimal treatment efficacy can be achieved.
Reference: Tripathi, A., & Lerner, S. P. (2023). Poly (ADP-ribose) Polymerase Inhibition in Advanced Urothelial Carcinoma. JCO Precision Oncology, 7, e2300293.
Obesity and Complication Risk From Radical Cystectomy: Identifying a Body Mass Index Threshold
Obesity is one of the main risk factors for complications arising during radical cystectomy surgery. A recent analysis of almost 600 bladder cancer patients, divided according to Body Mass Index (BMI), found that patients who were overweight (BMI of 25 to 30 kg/m2) or obese (BMI of 30 kg/m2 or higher) were at increased risk of surgical complications compared to patients with a healthy BMI (18.5 to 25 kg/m2). Importantly, there was a steady increase in predicted complication risk for patients above a BMI of 34 kg/m2, suggesting a threshold at which preoperative measures such as weight loss regimens could be beneficial for reducing the likelihood of obesity-related complications.
Reference: McLoughlin, L. C., Kassouf, W., Breau, R. H., Fairey, A., Agnihotram V, R., Salimi, A., … & Kulkarni, G. S. (2023). Obesity and Complication Risk From Radical Cystectomy: Identifying a Body Mass Index Threshold. The Journal of Urology, 209(1), 111-120.
The Androgen Receptor in Bladder Cancer
Bladder cancer is known to have a marked difference in incidence rates between men and women, with men having a fourfold greater lifetime risk of developing the disease. Emerging evidence suggests that the role of the androgen receptor (AR; the receptor which mediates the effects of sex hormones such as testosterone) in the development and progression of bladder cancer is an important factor in explaining this observed difference. Therapies that target AR activity and signaling present a promising focus for novel therapeutic interventions for both men and women.
Nature Article: Chen, J., Huang, CP., Quan, C. et al. The androgen receptor in bladder cancer. Nat Rev Urol (2023). https://www.nature.com/articles/s41585-023-00761-y
Radical Cystectomy Versus Trimodality Therapy for Muscle-invasive Bladder Cancer: A Multi-institutional Propensity Score Matched and Weighted Analysis
This multi-institutional study provides the best evidence to date showing similar oncological outcomes between radical cystectomy and trimodality therapy for select patients with muscle-invasive bladder cancer. These results support that trimodality therapy, in the setting of multidisciplinary shared decision making, should be offered to all suitable candidates with muscle-invasive bladder cancer and not only to patients with significant comorbidities for whom surgery is not an option.
The Lancelot Article: Prof Alexandre R Zlotta, MD, Leslie K Ballas, MD, Andrzej Niemierko, PhD, Katherine Lajkosz, MSc, Cynthia Kuk, MSc, Gus Miranda, BS, et al. https://www.thelancet.com/journals/lanonc/article/PIIS1470-2045(23)00170-5/abstract
