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One year ago, in this column, I highlighted the non-metastatic (M0) castration-resistant prostate cancer (CRPC) disease state as a fruitful area for clinical trial exploration.1  As part of that article, I emphasized the concept of testing low toxicity, high efficacy agents from metastatic CRPC in earlier disease states.  Two of the randomized, phase 3 trials have just came out and the results are quite impressive.
Immune checkpoint inhibitors (e.g. anti-PD1/PDL1, anti-CTLA4) have revolutionized the treatment of multiple tumor types, including urothelial and renal cell carcinomas.1, 2 Unfortunately, response rates to anti-PD1/PDL1 therapy are still generally low, although those who do respond or who have stable disease may have long-term durable clinical benefit.  It is likely that combination immunotherapy strategies targeting multiple negative regulators of tumor immune responses will be more effective than anti-PD1/PDL1 monotherapy.
PD-1/PD-L1 antibodies are being studied in every disease state imaginable for patients with urothelial carcinoma.  Atezolizumab, nivolumab, durvalumab and avelumab are all regulatory approved for patients with metastatic disease in the post-platinum chemotherapy setting.1-4  Pembrolizumab is also approved and is the only agent to have demonstrated an overall survival benefit to date when compared to taxane chemotherapy in the post-platinum setting.5  Additionally, atezolizumab and pembrolizumab are approved for patients who are ineligible for cisplatin chemotherapy in the 1st-line. 6,7 
The fibroblast growth factor receptor (FGFR) family has functional roles in regulation of cell proliferation, differentiation, migration, angiogenesis and tumorigenesis.  Activating point mutations of FGFR3 are common (~86%) in low grade and stage bladder tumors.1  However, The Cancer Genome Atlas Research Network identified only 12% of muscle invasive bladder cancers with FGFR3 mutations.2  FGFR3 mutations are also very common in upper tract urothelial tumors, especially of the ureter.3  FGFR1 has been less intensively studied, but increased expression at both the mRNA and protein level is present in a large proportion of bladder tumors.4 
Radium-223 is actually quite capable of dancing on its own without a partner.  It offers an overall survival, symptomatic skeletal events and multiple pain and quality of life benefits for patients with bone metastatic castration-resistant prostate cancer and symptoms.1  Yet, the ALSYMPCA trial, which established the beneficial effects of radium-223, did not mandate regular imaging, so image surveillance expectations are uncertain.  Additionally, prostate-specific antigen (PSA) level does not always associate with clinical outcomes with Radium-223.  Given the mechanism of action of Radium-223, as an alpha-particle emitting radiopharmaceutical that incorporates into areas of osteoblastic activity, it is not surprising that alkaline phosphatase serves as not only a good baseline prognostic marker2 but also a good treatment response biomarker.3
Neoadjuvant chemotherapy use has been on the rise in the last 15 years for patients with high-risk localized urothelial carcinoma.  This is obviously due to randomized control data supporting an overall survival benefit.1,2  However, it has taken significant time for the field to embrace and adopt widespread use of cisplatin-based combination chemotherapy regimens in this setting.  Early reports showed neoadjuvant chemotherapy utilization rates to be 7.6% in 2006, 3 years after the original randomized control trial was published supporting the use of methotrexate, vinblastine, adriamcyin and cisplatin.3 
It is fortunate that we cure the vast majority of men with testicular germ cell tumors.  Estimates show that only approximately 10% of men with metastatic Stage III germ cell tumors are not cured.1  The bad news if that for those who aren’t cured with standard dose combination cisplatin-based chemotherapy with or without eventual high dose chemotherapy with autologous stem cell rescue (stem cell transplant), there are few options.  Palliative chemotherapy is often limited in efficacy, and regimens such as gemcitabine with oxaliplatin have been used.2  
Early attempts at checkpoint inhibition in prostate cancer seemed to offer little promise.  The initial trial with CTLA-4 inhibition with ipilumumab was performed in patients with metastatic castration-resistant prostate cancer (mCRPC) in the post-docetaxel setting and resulted in a HR 0.85, 95% CI 0.72-1.00; p=0.053.1 
For the longest time metastatic hormone-sensitive prostate cancer has been treated with androgen deprivation therapy (ADT).  Recently, the CHAARTED1 trial and STAMPEDE,2 both showed a dramatic survival benefit when 6 cycles of docetaxel was added to ADT.  For the CHAARTED trial, subgroup analyses confirmed survival benefit for those patients with high volume disease, defined as ≥4 bone metastases with at least one in the appendicular skeleton and/or a visceral metastasis. 
For the past few years, most patients have received sunitinib1 or pazopanib2 for new metastatic clear cell renal carcinoma.  Yet, the National Comprehensive Cancer Network (NCCN guidelines)3 also provide other preferred category 1 options in bevacizumab + interferon4 and temsirolimus5 specifically for those patients with poor prognostic features. 
On May 10th, 2017, a shocking thing happened.  A trial that most everyone assumed was a slam-dunk for a phase 3 trial in metastatic or locally advanced urothelial carcinoma bounced off the rim, as it failed to meet its primary endpoint of overall survival.  This trial utilized atezolizumab vs. a taxane in the prior platinum treated setting, with the intention of sealing the victory after atezolizumab gained accelerated FDA approval for response rate and durability of response for this patient population approximately a year ago. 
With the recent regulatory approvals of PD-1 and PD-L1 antibodies for patients with metastatic urothelial cancer, we have significantly expanded treatment options for this patient population.  Atezolizumab is a PD-L1 antibody that not only demonstrated significant responses but has also shown durability of response and clinical benefit through stable disease in a substantial proportion of patients in the post-platinum treated setting, leading to FDA approval in May 2016.1 
Non-metastatic (M0) castration-resistant prostate cancer (CRPC) is truly a misnomer.  It is meant to highlight a prostate cancer disease state that solely exists because of the use of prostate-specific antigen (PSA).  In most fields, patients either have localized disease or radiographically-detectable metastatic disease.  Since PSA is a highly sensitive measure of detection, our field is able to detect microscopic metastases due to limits of standard imaging modalities. 
Recent genome sequencing data in metastatic prostate cancer have led to some significant changes in how we think about advanced disease.  Namely, the Stand Up 2 Cancer (SU2C) International Dream Team discovered that 23% of patients with metastatic castration resistant prostate cancer harbor genetic alterations in genes that lead to homologous recombination deficiency  (HRD) e.g. BRCA2, BRCA1, ATM, etc. [1]  Even more recently, our group at the University of Washington together with others have found 11.8% of patients with metastatic prostate cancer, both hormone-sensitive and castration-resistant, to harbor germline alterations in DNA repair genes. [2]  
Oncology allows for a rare opportunity to connect deeply patients and families—from the outset of treatment, through the course of the disease, sometimes over several years.  Educating each patient and family about the disease and treatments are what I consider to be the most critical part of my job.  Part of that education is emphasizing not only the pros and cons and goals of each treatment, but also the importance of participating in the process of paving the path for the future for others afflicted with the disease. 

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