Bladder cancer treatment is advancing rapidly with novel therapies and biomarkers, according to presentations at the European Society for Medical Oncology (ESMO) 2024. Key studies highlighted include the SunRISe-1 trial of TAR-200, the AMBASSADOR trial update on pembrolizumab, and the VOLGA trial exploring ctDNA clearance. These developments signal a move towards personalized treatment strategies to improve patient outcomes across different stages of bladder cancer.
TAR-200 Monotherapy in Non-Muscle-Invasive Bladder Cancer
The SunRISe-1 trial (LBA85) investigated TAR-200, a novel gemcitabine intravesical system, in patients with BCG-unresponsive non-muscle-invasive bladder cancer (NMIBC), particularly carcinoma in situ (CIS). TAR-200 is designed to deliver sustained therapeutic levels of gemcitabine over an extended period, with the device replaced every three weeks. The expanded Cohort 2, a monotherapy arm, included 85 patients.
The primary endpoint was the complete response (CR) rate, which reached an impressive 83.5%. The 12-month CR rate was 57.4%, with a 65.7% duration of response at a median follow-up of 9.2 months. The treatment was well-tolerated, with a serious treatment-related adverse event rate of only 5.9%.
Maria De Santis noted that while several drugs are available for BCG-unresponsive NMIBC, none have been approved in Europe, where gemcitabine-docetaxel instillation remains a common practice. TAR-200 monotherapy shows promising results, with a 12-month CR rate comparable to gemcitabine-docetaxel but potentially higher than pembrolizumab or nadofaragene firadenovec.
Adjuvant Pembrolizumab in Muscle-Invasive Urothelial Carcinoma
The AMBASSADOR study evaluated adjuvant pembrolizumab in patients with high-risk muscle-invasive urothelial carcinoma. Updated results with a doubled follow-up of 44.8 months confirmed the benefits of pembrolizumab, with a hazard ratio of 0.73 for disease-free survival (DFS). These results remain statistically significant, though overall survival data is still immature.
This trial is one of three key studies in the adjuvant setting, alongside CheckMate 274 (nivolumab) and IMvigor 10 (atezolizumab). While AMBASSADOR and CheckMate 274 showed positive DFS outcomes, IMvigor 10 was negative. The perioperative treatment landscape is evolving, with ongoing studies exploring chemotherapy plus immunotherapy and novel agents, particularly for cisplatin-unfit patients.
ctDNA Clearance as a Biomarker in Neoadjuvant Therapy
The VOLGA trial explored ctDNA clearance as a biomarker in patients receiving neoadjuvant durvalumab, tremelimumab, and enfortumab vedotin. Plasma samples were analyzed using a methylation-based liquid biopsy test (Galleri by GRAIL) to assess ctDNA clearance before radical cystectomy.
In this safety run-in phase, seven out of ten patients achieved ctDNA clearance. All nine patients with a pathological complete response or downstaging were ctDNA-negative pre-cystectomy. These findings suggest that ctDNA clearance could potentially guide treatment decisions, such as bladder preservation or omission of adjuvant therapy.
De Santis emphasized the importance of understanding the properties of different ctDNA tests, noting that methylation tests are highly specific and useful for assessing ctDNA clearance, though they may not provide information on actionable alterations.
Implications for Clinical Practice
These studies presented at ESMO 2024 underscore the importance of personalized treatment approaches in bladder cancer. TAR-200 offers a promising bladder-sparing option for NMIBC, while adjuvant pembrolizumab provides a significant benefit in DFS for high-risk muscle-invasive disease. ctDNA clearance shows potential as a biomarker to tailor treatment and de-escalate therapy, ultimately improving outcomes and minimizing side effects for bladder cancer patients.
