Systematic Review of Immune Checkpoint Inhibition in Urological Cancers: Beyond the Abstract

Traditionally, the systemic treatment of advanced and metastatic urothelial cell cancer (UCC), renal cell carcinoma (RCC), and prostate cancer (PC) consists of chemotherapy, targeted therapy, and androgen deprivation therapy, respectively. Although these treatment modalities have improved patient outcome, most patients will eventually experience progressive disease. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that are able to reactivate the immune system against tumor cells by targeting PD-1/L1 and CTLA-4 signaling. These agents have shown efficacy in the treatment of a variety of solid tumors and may provide a novel treatment strategy for patients with advanced and metastatic urological cancers. In this systematic review, 22 phase 1–3 clinical trials were identified. Six randomized clinical trials (RCT) were discussed in detail (one trial on UCC, three trials on RCC, and two trials on PC) to study the efficacy and safety of ICIs in urological cancers.

For second-line treatment of advanced UCC, only high-level evidence for the efficacy of pembrolizumab is currently available from one phase 3 RCT. Treatment with pembrolizumab is superior over investigator’s choice of chemotherapy with an overall survival (OS) benefit of 2.9 months and a favorable safety profile. Although nivolumab and atezolizumab have already been approved by the U.S. Food and Drug Administration (FDA) on the basis of previous non-randomized phase 2 clinical trials, high-level evidence for the use of these agents as second-line treatment for advanced UCC is currently lacking. Recent preliminary results from a phase 3 RCT did not show improved outcomes for atezolizumab as compared with investigator’s choice of chemotherapy, thereby underscoring the need for comparator controlled studies before introducing new agents in the clinic. For second-line treatment of advanced RCC, an OS benefit of 6 months was shown for the ICI nivolumab as compared with everolimus in a phase 3 RCT, thereby replacing everolimus as second-line treatment in clinical practice. On the contrary, ICIs appear less promising for the treatment of metastatic castration-resistant prostate cancer (mCRPC), as the only phase 3 RCTs have not reported clinical benefit of ipilimumab as compared with placebo. 

In conclusion, ICIs have expanded the treatment armamentarium for second-line treatment of advanced and metastatic UCC and RCC, whereas the results for mCRCP are rather disappointing until now. Future directions will include combination therapies, treatment with ICIs for earlier disease stages (e.g. first-line, neoadjuvant and adjuvant treatment), and the development of tools to better select patients with urological cancers for treatment with ICIs. 

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Written by: Maud Rijnders, Ronald de Wit, Joost L Boormans, Martijn P J Lolkema, Astrid A M van der Veldt