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The United States Food and Drug Administration (FDA) granted accelerated approval to enfortumab vedotin (Padcev®, manufactured and marketed by Astellas Pharma US, Inc., Northbrook, Illinois 60062; distributed and marketed by Seattle Genetics, Inc., Bothell, WA 98021) on December 18, 2019, for patients with locally advanced or metastatic urothelial cancer who have previously received platinum chemotherapy and a PD-L1 inhibitor.

With all the randomized trial data supporting a survival benefit of androgen deprivation therapy with primary radiation to the prostate, it is unfortunate that the same results have not been achieved in combination with radical prostatectomy. The data has been replicated in multiple randomized controlled trials, confirming that addition of androgen deprivation therapy in a neoadjuvant, concurrent and adjuvant fashion to definitive primary local radiation leads to a survival benefit for men with high-risk prostate cancer.

177Lu-PSMA-617 has been introduced before in this column as a PSMA-targeted radioligand therapy.1 A Phase II Australian trial treated 30 men with metastatic castration-resistant prostate cancer who had variable lines of exposure to agents such as abiraterone, enzalutamide, docetaxel and/or cabazitaxel.Seventeen (57%) patients achieved a prostate-specific antigen (PSA) decline ≥50%. Fourteen (82%) of 17 patients with measurable disease had an objective response. Toxicities were generally mild with grade 1 dry mouth in 26 (87%) patients, grade 1/2 transient nausea in 15 (50%) patients and grade 1/2 fatigue in 15 (50%) patients. Grade 3/4 events were rare, but thrombocytopenia did reach that level in 4 (13%) patients.

Results from a first-line chemoimmunotherapy trial in patients with metastatic urothelial carcinoma were recently presented at the 2019 European Society of Medical Oncology (ESMO) Congress.1 These early results from the IMvigor 130 trial provide the first hints that novel combination therapy offers benefit for patients with locally advanced or metastatic urothelial carcinoma. This trial randomized patients to atezolizumab plus platinum/gemcitabine (Arm A) vs. atezolizumab monotherapy (Arm B) vs. placebo plus platinum/gemcitabine (Arm C).

At the European Society of Medical Oncology (ESMO) Congress 2019, the randomized phase 3 CARD trial was presented, with a simultaneous publication in the New England Journal of Medicine.1  This trial randomized 255 men with metastatic castration-resistant prostate cancer in a 1:1 fashion, who previously received docetaxel and an Androgen-Signaling-targeted Inhibitor (ASI), either abiraterone or enzalutamide, to cabazitaxel 25 mg/m2 plus prednisone and granulocyte colony-stimulating factor or the other ASI. 

The Future of CDK4/6 Inhibitors for Prostate Cancer May Need to Draw Inspiration from Goldilocks and the Three Bears -- Cyclin dependent kinases (CDKs) and D-type cyclins (CCND) have a critical role in cell cycle progression from G1 to S phase.1 Several tumors have been shown to have alterations of proteins involved in the activity and regulation of this complex. Multiple small molecule inhibitors have been developed to target CDK 4/6, including ribociclib, palbociclib and abemaciclib.2 These agents are now regulatory approved in combination with aromatase inhibitors or fulvestrant for patients with metastatic breast cancer.
Whenever the term, HER2, is mentioned, people immediately think, “breast cancer.” With the regulatory approvals of trastuzumab and ado-trastuzumab emtansine, oncologists now have multiple approaches to address HER2 amplified breast cancers. However, HER2 overexpression in gastric cancer has also led to a demonstration of trastuzumab treatment benefit in that disease. We’ve often heard about HER2 amplification in urothelial bladder cancer, yet it seems as if we’ve had no major advances in this area.
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.

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