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Background Cabozantinib can enhance the effect of abiraterone in preclinical prostate cancer models. This study aimed to define the recommended phase 2 dose (RP2D) and preliminary efficacy of abiraterone + cabozantinib in mCRPC. Methods Patients with progressive mCRPC with 0-2 prior chemotherapy regimens but no prior CYP17A1 or MET inhibitor received abiraterone acetate at 1000 mg daily with prednisone 5 mg BID in combination with cabozantinib at 20, 40, or 60 mg daily in a dose-escalation 3 + 3 open-label phase 1 design (Part A). After tolerable doses were defined, cohorts were expanded to better define toxicity and efficacy (Part B). Results There were no dose-limiting toxicities (DLTs) in the first 4 weeks at any of the three dose levels in Part A. Two of the three patients at the 60 mg dose level required dose reductions beyond cycle 2 due to fatigue. In Part B, nine more patients were accrued to each of the 20 and 40 mg doses. Of the 12 patients treated at the 40 mg dose, only one DLT (grade 3 Lipase elevation) was observed in cycle 1. The median time to radiographic progression was 12.88 months (95% CI:5.42- not estimated [NE]) in the 20 mg cohort and 22.01 months (95% CI:15.44-NE) in the 40 mg cohort. Median overall survival was 23.29 months (95% CI:19.06-NE) in the 20 mg cohort and 39.08 months (95% CI:17.38-NE) in the 40 mg cohort. Conclusions Based on tolerability and preliminary efficacy, 40 mg cabozantinib plus 1000 mg abiraterone daily is the RP2D.

Cytotoxic chemotherapy has been the only systemic treatment of locally advanced and metastatic urothelial carcinoma for decades. Long-term survival remains stagnant around 12–14 months for patients with advanced disease who have progressed on or recurred after receiving first-line platinum-based chemotherapy. Improving clinical outcomes for patients with urothelial carcinoma in all disease settings requires the development of novel treatments, especially for patients who failed on first-line chemotherapy. Since the discovery of intravesical Bacillus-Calmette Guerin (BCG) in the 1970s for non-muscle invasive disease, there have not been any major breakthrough drugs that exploit the immune-sensitivity of bladder cancer until recently. Immune-checkpoint inhibitors targeting the programmed death 1/programmed death-ligand 1 (PD-1/PD-L1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) pathways have shown significant anti-tumor activity, tolerable safety profiles and durable, long-term responses in clinical trials. Atezolizumab, avelumab, durvalumab, nivolumab and pembrolizumab are promising PD-1/PD-L1 blockade drugs under investigation that will redefine the standard of care for bladder cancer. CTLA-4 inhibitors are also under investigation in this setting. Atezolizumab, approved in May 2016, and nivolumab, approved in February 2017, are the first Food and Drug Administration (FDA)-approved immune-checkpoint inhibitors in bladder cancer for platinum-pretreated patients based on phase II data. On March 16, 2017, results from the phase III trial KEYNOTE-045 demonstrated that survival was significantly longer in patients treated with pembrolizumab when compared with the standard second-line chemotherapy. Research into biomarkers such as PD-L1 expression, messenger RNA subtype, mutational and neoantigen load and gene signature expression will be crucial to determining why some patients respond to immunotherapy and others do not. This review article describes the advances in immunotherapy since the development of BCG, presents results from clinical trials investigating immune-checkpoint inhibitors and discusses biomarkers and prognostic factors associated with response to these new drugs.