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When this monthly Clinical Trials Portal first started at the beginning of 2017, I focused on what I thought to be one of the newest, hottest areas of clinical investigation in prostate cancer.  This was capitalizing on the discovery that 23% of patients with metastatic castration-resistant prostate cancer (mCRPC) harbor alterations in DNA repair genes that result in homologous recombination deficiency (HRD) e.g. BRCA1/2, etc.1 
We now know better than to treat everyone with low-risk prostate cancer with definitive local therapy.  But, we also know there is a clear benefit to radical prostatectomy over watchful waiting for those with high-risk disease who are healthy enough to benefit from such an intervention.1  Additionally, there is data from multiple randomized trials to show that adding androgen deprivation therapy (ADT) to definitive external beam radiation (EBRT) leads to a survival benefit.2, 3 
It has now been 8 years since sipuleucel-T demonstrated an overall survival benefit in the randomized phase 3 IMPACT trial.1  This was a welcome new option for patients with metastatic castration-resistant prostate cancer and the health care providers that treated them.  However, there were some findings that were not considered standard in the field at the time.  First off, there was no improvement in time to progression, and sipuleucel-T also did not offer a significant PSA decline rate.  Additionally, sipuleucel-T was limited in regulatory approval to those patients with asymptomatic or minimally symptomatic disease, creating a smaller window of opportunity to identify patients appropriate for treatment with sipuleucel-T.
Prostate-specific membrane antigen (PSMA) is a 750 amino acid type II transmembrane glycoprotein expressed in normal human prostate epithelium.  However, PSMA is overexpressed on virtually all prostate cancer cells.  Poorly differentiated, metastatic and castration-resistant prostate cancers harbor even higher expression.  Hence, not only is PSMA a potentially good target for diagnostic imaging but also for targeted therapy.  The field of PSMA PET imaging offers significant promise and is currently being utilized for detection and may off potential to direct oligometastatic disease ablation. 

Just recently, we discussed neoadjuvant systemic therapy for cisplatin-ineligible patients with muscle-invasive urothelial carcinoma of the bladder.1  For those patients “unfit” for cisplatin with at least one of the following criteria: creatinine clearance <60 ml/min, grade ≥2 hearing loss, grade ≥2 neuropathy, ECOG performance status 2, and/or New York Heart Association Class III heart failure,2 there are no good options other than cystectomy alone.  Yet, we know the outcomes are not ideal for these patients with cystectomy alone.  Finding systemic therapies that may improve outcomes for these patients is clearly an unmet need in the field.

Three randomized phase 3 trials of adjuvant therapy for high-risk renal cell carcinoma have led to conflicting results.  S-TRAC was the one trial with a positive outcome, as sunitinib prolonged disease-free survival (DFS) by a median of 1.2 years compared with placebo (6.8 versus 5.6 years; HR 0.76, 95% CI 0.59-0.98, p=0.03).1  Based on these results, the US FDA approved sunitinib for the adjuvant treatment of patients with high-risk renal cell carcinoma.  However, the ASSURE trial revealed negative results as median DFS was 5.8 years for sunitinib, 6.2 years for sorafenib and 6.6 years for placebo.2  The PROTECT trial also had negative results as pazopanib compared to placebo had a HR 0.86; 95% CI
Although urothelial carcinoma of the bladder represents the fourth most common malignancy in men, 70% of these cases are non-muscle invasive (NMIBC).  Most of these patients will have outstanding outcomes, however, up to 70% will recur after initial treatment and 10-20% will progress to muscle-invasive bladder cancer (MIBC).1  Once a patient has MIBC, then treatment options become more intense, with discussions of definitive cystectomy, chemotherapy, and radiation, all of which carry greater morbidity and cost. 

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