Authors: Adam Leikensohn, MD & Richa Madurkar, PharmD, BCOP
The treatment landscape for bladder cancer is rapidly evolving. Additional therapeutic options have been recently approved or are in the pipeline for patients in both non-muscle invasive and muscle-invasive settings.
Several emerging therapies warrant close attention in non-muscle invasive bladder cancer (NMIBC), particularly for patients with Bacillus Calmette-Guérin (BCG)-unresponsive disease. Cretostimogene grenadenorepvec, evaluated in the phase III BOND-003 trial, showed a promising complete response (CR) rate of 75.5% at any time. [1] Additionally, the median duration of response was 27.9 months, and the 24-month cystectomy free survival rate was 81.3%. [1] This therapy has been submitted to the FDA with a decision anticipated this year. [2] Detalimogene voraplasmid has also shown a promising CR rate in BCG-unresponsive NMIBC in the ongoing phase II LEGEND trial, with CR rate of 71% at any time. [3] Detalimogene voraplasmid has potential FDA approval anticipated in 2027. [4]
These two novel therapies are entering a crowded market. The current available options in BCG-unresponsive NMIBC include the 2024 approvals of intravesical gene therapies nadofaragene firadenovec-vncg (Adstiladrin) and nogapendekin alfa inbakicept-pmln (Anktiva), and the 2025 approval of a novel gemcitabine intravesical system (Inlexzo). Systemic pembrolizumab (Keytruda) is an additional option in the BCG-refractory setting.
Both newer agents bring novel mechanisms of action to the intravesicular therapy repertoire. Cretostimogene grenadenorepvec is a modified adenovirus that replicates in cancer cells with Rb-E2F pathway alterations. This leads to cell lysis with release of tumor-specific antigens that provoke an anti-tumor immune response. [5][6] Detalimogene voraplasmid is a non-viral gene therapy that alters the local tumor microenvironment and promotes tumor clearance. [7]
Data for both agents are still immature; once available, coverage decisions will require consideration of patient selection, response rates and durability, and total cost of care. The absence of head-to-head comparisons between these agents is expected to make treatment decisions challenging.
In muscle-invasive bladder cancer (MIBC), the recent FDA approval of pembrolizumab (Keytruda) with enfortumab vedotin-ejfv (Padcev) based on results from the EV-303/KEYNOTE-905 trial is a major breakthrough in the perioperative setting for cisplatin-ineligible patients. [8] Prior to this approval, the standard-of-care was neoadjuvant cisplatin-based chemotherapy with or without perioperative durvalumab (Imfinzi) followed by cystectomy. For those who were cisplatin ineligible, which comprised 50% of the MIBC population, cystectomy alone was recommended.[9] In the phase III EV-303/KEYNOTE-905 trial, patients with nonmetastatic MIBC who were cisplatin-ineligible were randomized to perioperative pembrolizumab + enfortumab vedotin (EV) with surgery or surgery and observation. [9] The primary endpoint of 2-year event-free survival (EFS) was significantly improved with pembrolizumab + EV (74.7% vs 39.4%). The estimated 2-year overall survival rate was 79.7% in the pembrolizumab + EV arm compared to 63.1% in the control arm. Pathologic complete response (pCR) rates were 57.1% and 8.6%, respectively. There were no new safety signals with pembrolizumab + EV in the perioperative setting.
This regimen is also gaining traction in the cisplatin-eligible MIBC population based on interim results of the EV-304 study, which showed improved 2-year EFS (79.4% vs 66.2%), 2-year overall survival (OS) (86.9% vs 81.3%), and pCR rate (55.8% vs 32.5%) with this combination compared to neoadjuvant cisplatin + gemcitabine. [10] A cisplatin-free regimen in the neoadjuvant / perioperative setting for MIBC is clinically meaningful in that it reduces toxicity associated with this curative intent treatment. Renal toxicity has been noted in 28% to 36% of patients with a single cisplatin dose of 50 mg/m2, with renal toxicity becoming more prolonged and severe with repeated courses. [11]
Ototoxicity is another significant concern associated with cisplatin. Ototoxicity has been observed in up to 31% of patients treated with a single dose of cisplatin at 50 mg/m2 and tends to become more frequent and severe with repeated doses. [11] Additionally, ototoxicity may be irreversible. Pembrolizumab + EV is not currently approved by the FDA or endorsed by NCCN for the cisplatin-eligible population, but the results from EV-303 and EV-304 may reshape treatment pathways for all patients with MIBC who are planned for cystectomy, regardless of cisplatin eligibility.
Of note, EV-304 did not include the use of perioperative durvalumab. Therefore, it remains unclear if pembrolizumab + EV is superior to durvalumab + cisplatin-based chemotherapy in cisplatin-eligible patients. For context, in the NIAGARA study, durvalumab + gemcitabine + cisplatin similarly showed improved 2-year EFS (67.8% vs 59.8%), 2-year OS (82.2% vs 75.2%), and pCR rates (33.8% vs 25.8%) compared to neoadjuvant gemcitabine + cisplatin for MIBC. [12] That said, cross-trial comparisons between the NIAGARA study and EV-304 should not be relied upon given differences in patient populations and study design. In the durvalumab + cisplatin-containing chemotherapy regimen (NIAGARA study), durvalumab is administered for a total of 12 cycles. In the pembrolizumab + EV regimen (EV-304 study), pembrolizumab is administered for 17 cycles, and EV is administered for 9 cycles. As the costs of cancer treatment continue to rise, total cost of therapy must be a consideration in choosing between the multiple options now available for patients with MIBC. Nevertheless, one cannot lose sight of the comparative acute and chronic toxicities these regimens confer, especially when the intent of therapy is to render the patient cancer-free.
Bladder cancer is undergoing rapid transformation across NMIBC and MIBC treatment paradigms. Novel intravesical therapies and perioperative regimens are showing promising efficacy and provide additional options for several patient populations. Careful patient selection, utilization management strategies, and frequent reassessment as mature and comparative data emerge will be crucial to balance patient access with rising costs of care.
References
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