Patients with high-risk non-muscle invasive bladder cancer (NMIBC) carry a lifelong risk of recurrence and progression to the potentially lethal muscle-invasive form of the disease [1,2]. The standard of care treatment for high-risk NMIBC is Bacillus Calmette-Guérin (BCG), a live attenuated mycobacterium that activates the innate and adaptive immune system resulting in high rates of complete responses and remains the standard of care [1,3]. Nevertheless, recurrences occur in up to 40%–50% of patients [[4], [5], [6]].

Patients meeting well-defined recurrence criteria after adequate BCG are deemed “BCG-unresponsive” – an important classification as defined by expert opinion as these patients have a substantial risk of progression [[7], [8], [9]]. While the standard of care for these patients is to undergo radical cystectomy (RC), many patients are often either medically unfit for major surgery or refuse. Other nonsurgical treatments are approved such as intravesical treatment with valrubicin or systemic therapy with the immune checkpoint inhibitor pembrolizumab; however these therapies are less commonly used due to efficacy and toxicity concerns, respectively [10,11]. Additional novel agents, such as the recently approved nadofaragene firadenovec, nogapendekin alfa inbakicept and others seeking approval, are not yet available in many clinics and are expensive [12]. Consequently, effective and available bladder-sparing options are of paramount importance.

At the vanguard of BCG-unresponsive treatment are multi-agent chemotherapy protocols. Similar to the justification for combination systemic chemotherapy in advanced bladder cancer, using multiple agents to treat NMIBC may act synergistically and reduce treatment resistance. For example, the combination of gemcitabine and mitomycin C was early evidence of the impact of combining intravesical agents, showing a 68% CR, 1-year RFS of 48%, and 2-year RFS of 38% [13]. Despite the lack of adoption into common practice, this is substantially higher than the long-term RFS and DFS of gemcitabine or mitomycin C alone [14,15]. Another multi-agent protocol success that has been widely transformative is the off-label combination of gemcitabine and docetaxel. In a retrospective analysis of 276 BCG-experienced patients, the authors observed a 46% 2-year RFS, 52% 2-year HG-RFS, and only 7% progression at 2-years [16]. Although these data are retrospective and only 38% of patients were BCG-unresponsive, the robust success of the combination of gemcitabine and docetaxel has made it a commonly used therapy in NMIBC.

Our institution has experience with novel intravesical chemotherapy combinations. Based on extensive in vitro and in vivo work in the laboratory, we conducted and published a phase I trial of combination chemotherapy with cabazitaxel, gemcitabine, and cisplatin (CGC) [17,18]. Prior to the phase II CGC trial, patients with BCG-unresponsive bladder cancer who were unfit or refused radical cystectomy but could not be enrolled due to closed recruitment were offered treatment with a similar combination of intravesical docetaxel, gemcitabine, and cisplatin (DGC). Here, we present the long-term clinical follow-up and sequencing data on from patients with BCG-unresponsive NMIBC treated with DGC.