PURPOSE To assess the relationship among tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti–programmed death protein 1 or ligand 1 (anti–PD-1/L1) antibodies. PATIENTS AND METHODS We examined seven trials in 1,747 patients with metastatic or locally advanced urothelial cancer that led to approval of an anti–PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy, and two enrolled patients who were cisplatin ineligible. The data sets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the investigator. ImAEs were defined as AESIs treated with topical or systemic corticosteroids. RESULTS In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti–PD-1/L1 antibody, whereas a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared with those with no related AESIs (hazard ratio, 0.45; 95% CI, 0.39 to 0.52). Fifty-seven percent of responding patients with a related AESI reported the AESI before documentation of response. CONCLUSION Patients who responded to treatment with an anti–PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not seem to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.

Drugs that target novel surfaces on the androgen receptor (AR) and/or novel AR regulatory mechanisms are promising alternatives for the treatment of castrate-resistant prostate cancer. The 52 kDa FK506 binding protein (FKBP52) is an important positive regulator of AR in cellular and whole animal models and represents an attractive target for the treatment of prostate cancer. We used a modified receptor-mediated reporter assay in yeast to screen a diversified natural compound library for inhibitors of FKBP52-enhanced AR function. The lead compound, termed MJC13, inhibits AR function by preventing hormone-dependent dissociation of the Hsp90-FKBP52-AR complex, which results in less hormonebound receptor in the nucleus. Assays in early and late stage human prostate cancer cells demonstrated that MJC13 inhibits AR-dependent gene expression and androgen-stimulated prostate cancer cell proliferation.immunophilin | FKBP4 | steroid hormone receptor A ndrogens are a major stimulator of prostate tumor growth, and all current therapies act as classic antagonists by competing with androgens for binding the androgen receptor (AR) hormone binding pocket. This mechanism of action exploits the dependence of AR on hormone activation, but current treatment options become ineffective in castrate-resistant prostate cancer (CRPC), although CRPC remains ligand/AR-dependent. Thus, drugs that target novel surfaces on AR and/or novel AR regulatory mechanisms may provide promising alternatives for the treatment of CRPC (reviewed in ref. 1).The maturation of cytoplasmic steroid hormone receptors (SHR) to a mature hormone binding conformation is a highly ordered, dynamic process that involves multiple chaperone and cochaperone components (reviewed in ref. 2), all of which present potential opportunities for therapeutic intervention. The final mature complex in which the receptor is capable of high affinity hormone binding includes heat shock protein 90 (Hsp90), a 23 kDa cochaperone (p23), and one of a class of proteins (termed FKBPs) characterized by their Hsp90-binding tetratricopeptide repeat (TPR) domain. The 52 kDa FK506 binding protein (FKBP52) associates with receptor-Hsp90 complexes by way of a C-terminal TPR domain and is a specific positive regulator of AR, glucocorticoid receptor (GR), and progesterone receptor (PR) signaling (3-5). FKBP52 is required for normal male sexual differentiation and development in mice as the fkbp52-deficient mice (52KO) display characteristics of partial androgen insensitivity syndrome including dysgenic prostate (4, 6). FKBP proteins are validated targets of immunosuppressive drugs. FK506 (Tacrolimus) is used clinically to suppress the immune system following organ transplantation. FK506 binds within the peptidyl-prolyl isomerase (PPIase) catalytic pocket of a related family member, FKBP12. The chemical groups of FK506 that project out from the PPIase pocket allow the FKBP12-drug complex to bind tightly to and inhibit calcineurin, which ultimately leads to immunosupression (7). Although FK506 binding ...

The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin‐containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single‐arm trials, IMvigor210 (atezolizumab) and KEYNOTE‐052 (pembrolizumab). The primary endpoint, confirmed objective response rate, was 23.5% (95% confidence interval [CI]: 16.2%–32.2%) in patients receiving atezolizumab and 28.6% (95% CI: 24.1%–33.5%) in patients receiving pembrolizumab. The median duration of response was not reached in either study and responses were seen regardless of PD‐L1 status. The safety profiles of both drugs were generally consistent with approved agents targeting PD‐1/PD‐L1. Two ongoing trials (IMvigor130 and KEYNOTE‐361) are verifying benefit of these drugs. Based on concerning preliminary reports from these trials, FDA revised the indications for both agents in cisplatin‐ineligible patients. Both drugs are now indicated for patients not eligible for any platinum‐containing chemotherapy or not eligible for cisplatin‐containing chemotherapy and whose tumors/infiltrating immune cells express a high level of PD‐L1. The indications for atezolizumab and pembrolizumab in patients who have received prior platinum‐based therapy have not been changed. This article summarizes the FDA thought process and data supporting the accelerated approval of both agents and the subsequent revision of the indications. Implications for Practice The accelerated approvals of atezolizumab and pembrolizumab for cisplatin‐ineligible patients with advanced urothelial carcinoma represent the first approved therapies for this patient population. These approvals were based on single‐arm trials demonstrating reasonable objective response rates and favorable durations of response with an acceptable toxicity profile compared with available non‐cisplatin‐containing chemotherapy regimens. However, based on concerning preliminary reports from two ongoing phase III trials, the FDA revised the indication for both agents in cisplatin‐ineligible patients. Both are now indicated either for patients not eligible for any platinum‐containing chemotherapy or not eligible for cisplatin‐containing chemotherapy and whose tumors have high expression of PD‐L1.