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Prostate cancer is a disease that universally responds to androgen deprivation therapy (ADT), as it is driven by androgens and their interaction with androgen receptors (AR). However, over time, prostate cancer will become resistant to ADT, delineating the castration-resistant disease state. The field has adapted to address this problem with even more potent hormonal therapies to cope with adrenal and intracrine androgen production. Hence, agents like abiraterone acetate, enzalutamide and apalutamide have regulatory approval in various prostate cancer disease states. However, when the disease eventually becomes resistant to these agents, multiple other mechanisms are at play that drives resistance.
They say prostate cancer has a “cold” tumor microenvironment. Prostate cancer generally harbors low mutational complexity,1 resulting in less cytotoxic T cell infiltration into the tumor microenvironment. Hence, the term “hot” vs. “cold” tumor implies how generally inflamed the tumor microenvironment is with immune cells. It certainly would be of interest to the field to develop a therapy that could redirect cytotoxic T cells to the prostate tumor microenvironment to “heat” things up against the tumor and increase antitumor activity. Bispecific antibodies have the potential to accomplish this goal.
For patients with metastatic castration-sensitive prostate cancer, it is clear that early treatment intensification by adding agents like docetaxel or abiraterone acetate to androgen deprivation therapy (ADT) offers overall survival benefit. The CHAARTED1 and STAMPEDE2 trials both demonstrated a dramatic survival benefit with 6 cycles of docetaxel added to ADT. In the long term survival analysis of the CHAARTED trial, the benefit was confined to those patients with high volume disease, defined as ≥4 bone metastases with at least one in the appendicular skeleton and/or a visceral metastasis.3 The last time I wrote about
The importance of the androgen receptor (AR) in prostate cancer is without debate.  Androgen deprivation therapy is essentially the original “targeted therapy” in all of oncology.  This has been further emphasized with the next generation of regulatory-approved androgen- and AR-targeted agents, such as abiraterone acetate, enzalutamide, and apalutamide.  Certain spliced-variants of the AR, such as ARv7, have potential to serve as a disease biomarker, offering prognostic value with potential for predicting resistance to agents like abiraterone acetate and enzalutamide.1  However, therapeutic attempts to target ARv7 have been fraught with challenges when agents like galeterone and niclosamide have been utilized.2
Back in May 2017, I wrote an article for this column in response to the press release that atezolizumab did not offer a survival benefit over taxane chemotherapy in the IMvigor 211 randomized, phase 3 trial, for patients in the post-platinum locally-advanced or metastatic urothelial carcinoma setting.1  At the time, we didn’t understand what had happened to lead to this negative result, especially since the phase 12 and 23 atezolizumab data had been so promising.  Additionally, we had just seen survival benefit with pembrolizumab in the same clinical disease state.4  Eventually, we learned the problem…clinical trial design. 
Fluciclovine is a synthetic amino acid that is uptaken by amino acid transporters that are upregulated in many cancer cells, including prostate cancer.1  Fluciclovine is not metabolized or incorporated into newly synthesized proteins,2 and it is ideal for labeling with 18F for imaging purposes.   A key advantage is that it has low renal excretion, which is optimal for imaging the pelvis.  Sensitivity and specificity of PET imaging with fluciclovine appear superior to choline in a direct comparative trial of patients in the biochemically recurrent prostate cancer disease state.3  However, a greater impact of an imaging agent can be measured when key treatment decisions are altered based on findings from that imaging modality. 
Previously, I’ve written Clinical Trials Portal articles about the concept of PARP inhibition in men with prostate cancer, with a strong focus on the biologic selection of patients with homologous recombination deficiency as most likely candidates for response to such agents.1,2  About 1.5 years ago, I wrote an article highlighting ongoing PD-1/PD-L1 antibody combination trials in prostate cancer.3  At that time, the goal was to consider intelligent combinations with immune-oncology agents in what has essentially been considered an immune “cold” prostate tumor microenvironment.  Hence, multiple trial partners in combination with PD-1/PD-L1 antibodies were proposed and referenced at that time.
We have known for decades that androgen deprivation offers remarkable efficacy and palliation for men with advanced prostate cancer.  Yet, soon after Charles Huggins Nobel Prize-winning discovery, many case series started emerging, describing paradoxical benefits of testosterone supplementation for patients with prostate cancer.1,2  These clinical observations seem so counterintuitive given that androgen deprivation therapy is the hallmark of treatment for advanced prostate cancer.  Yet, there may be supportive biological rationale to this surprising observation.
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. 
We are now using PARP inhibitors for DNA repair-deficient patients with breast, ovarian, fallopian tube or primary peritoneal cancer.  In the realm of genitourinary oncology, we are meticulously exploring PARP inhibition, particularly for enriched patient populations with prostate cancer.  This is due to the fact that DNA repair deficiency occurs in approximately 23% of men with metastatic castration-resistant prostate cancer,1 and approximately 12% of men with metastatic prostate cancer harbor germline alterations.2
The title of this article is admittedly ironic and amusing. It goes back to the term “watchful waiting” of low and very low-risk prostate cancer. Although we were waiting for either something bad to happen or more often nothing exciting to happen due to indolent prostate cancer, the term “watchful” may have been a misnomer, as it is unclear if or how patients were being watched. The modern term of “active surveillance” is probably a more accurate term. It implies that patients are indeed, being surveyed by some accepted “active” script, usually with PSA testing and intermittent prostate needle biopsies. What that script looks like differs based on national
Antibody drug conjugates (ADCs) are a promising method of selective intensification of therapy, offering increased drug concentration to the target with minimal collateral damage to healthy tissue.1   Structurally, ADCs are monoclonal antibodies specific for a tumor antigen connected by a linker molecule to a cytotoxic drug payload.  After endocytotic internalization of the complex, the linker is degraded in a lysosome, releasing the cytotoxic payload.  There are now many FDA approved ADCs, including brentuximab vedotin for anaplastic2 and refractory Hodgkin lymphomas,3 trastuzumab emtansine
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.

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