Substantial advances have been made in the development of therapeutic biomarkers in various cancers, but not in prostate cancer. A germline inherited polymorphic variant (1245A→C) in the HSD3B1 gene was recently reported to correlate with shorter duration of response to androgen-deprivation therapy (ADT) in hormone-sensitive prostate cancer (HSPC). 1 The HSD3B1 gene encodes the enzyme 3β-hydroxysteroid dehydrogenase-1 (3βHSD1), which catalyzes adrenal androgen precursors into dihydrotestosterone, the most potent androgen. 2,3 In the study by Hearn et al, 1 presence of 1 or more variant alleles of the HSD3B1 (1245C) was associated with decreased progression-free survival (PFS) compared with the absence of any variant alleles in 3 cohorts of men with prostate cancer treated with ADT: 2 cohorts with post-prostatectomy biochemical recurrence, and 1 cohort with metastatic HSPC (mHSPC) (total, n = 443). In the present analysis, we provide, to our knowledge, the first independent validation of these results, which have the potential to introduce the first predictive biomarker of response to therapy for this patient population.
Urothelial cancer of the bladder, renal pelvis, ureter, and other urinary organs is the fifth most common cancer in the United States, and systemic platinum-based chemotherapy remains the standard of care for first-line treatment of advanced/metastatic urothelial carcinoma (UC). Until recently, there were very limited options for patients who are refractory to chemotherapy, or do not tolerate chemotherapy due to toxicities and overall outcomes have remained very poor. While the role of immunotherapy was first established in non-muscle invasive bladder cancer in the 1970s, no systemic immunotherapy was approved for advanced disease until the recent approval of a programmed death ligand-1 (PD-L1) inhibitor, atezolizumab, in patients with advanced/metastatic UC who have progressed on platinum-containing regimens. This represents a significant milestone in this disease after a void of over 30 years. In addition to atezolizumab, a variety of checkpoint inhibitors have shown a significant activity in advanced/metastatic urothelial carcinoma and are expected to gain Food and Drug Administration (FDA) approval in the near future. The introduction of novel immunotherapy agents has led to rapid changes in the field of urothelial carcinoma. Numerous checkpoint inhibitors are being tested alone or in combination in the first and subsequent-line therapies of metastatic disease, as well as neoadjuvant and adjuvant settings. They are also being studied in combination with radiation therapy and for non-muscle invasive bladder cancer refractory to BCG. Furthermore, immunotherapy is being utilized for those ineligible for first-line platinum-based chemotherapy. This review outlines the novel immunotherapy agents which have either been approved, or are currently being investigated in clinical trials in UC.
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