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Fluciclovine PET imaging is the most sensitive imaging modality we have to date that is United States Food and Drug Administration (FDA) approved and available for widespread use. Fluciclovine is a synthetic amino acid that is uptaken by amino acid transporters that are upregulated in many cancer cells, including prostate cancer. A key advantage of fluciclovine is that it has low renal excretion, which is ideal for imaging the pelvis. The sensitivity and specificity of PET imaging with fluciclovine are superior to choline in a direct comparative trial of patients in the biochemically recurrent prostate cancer disease state.1 The FDA approval is in men with suspected prostate cancer recurrence based on elevated prostate-specific antigen (PSA) levels following prior treatment.2

For men with metastatic castration-resistant prostate cancer, there are limited options for treatment after progression on docetaxel chemotherapy.  Fortunately, cabazitaxel is another taxane chemotherapy that offers a survival benefit in the post-docetaxel setting over mitoxantrone in the TROPIC trial.1 The initial concern was a 7.5% febrile neutropenia rate and a 4.9% toxic death rate.  However, this concern has been ameliorated with increased utilization of growth factor prophylaxis, and the PROSELICA trial showed non-inferiority of 20 mg/m2 dosing compared with the 25 mg/m2 dosing in regards to overall survival, with much lower toxicity.2

When docetaxel first emerged on the prostate cancer scene, the world celebrated our first agent that offered an overall survival benefit for patients with metastatic castration-resistant prostate cancer.1,2  Although, there are now many more agents regulatory approved for metastatic castration-resistant prostate cancer, docetaxel remains an important “tool in our toolbox” in our attempts to improve survival and quality of life for our patients.

For the next decade after docetaxel’s approval for metastatic castration-resistant prostate cancer, the field saw multiple combination therapy trials with docetaxel without any success.  This included multiple randomized, phase 3, controlled trials, with no therapeutic agents affording the ability to offer a survival improvement when added to docetaxel.3-11

The identification of oligometastatic prostate cancer is becoming more feasible due to improved imaging technologies. For example, 11C-choline PET/CT imaging has approximately 50% sensitivity for detection at a prostate-specific antigen (PSA) level of 1.5-2.0 ng/mL.1 However, 11C-choline PET/CT imaging is not widely available, as it requires an on-site cyclotron for production. Prostate-specific membrane antigen (PSMA) small molecules tagged with either 68Gallium or 18Fluoride are also highly sensitive with detection felt to begin at PSA levels of 0.2-0.5 ng/mL.2-4  PSMA PET imaging is also not yet widely available. Fluciclovine PET/CT imaging was recently approved by the United States Food and Drug Administration (FDA) for the detection of recurrent prostate cancer. Fluciclovine PET/CT carries the ability to detect prostate cancer starting at a level of around 0.5 ng/mL,5-10 and it is becoming widely available for use. 

COVID-19 has affected everything we do in medicine and science. This certainly includes cancer research, and many clinical trials have placed temporary holds on patient accrual to reserve hospital/intensive care unit beds, preserve personal protective equipment, and limit person-to-person contact. However, we must be optimistic and start to plan for a future when the COVID-19 pandemic calms down. The first wave of clinical trials to reopen must importantly take into account the risk/benefit ratio for the patient.

I’m starting this article out a bit differently than my typical Clinical Trials Portal article. Given the recent events of the world with the COVID-19 pandemic, our lives have all been significantly impacted. This includes daily patient care and clinical research activities, with significant inhibitory effects on our ability to accrue patients and maintain study-related activities for those patients who are already accrued to clinical trials. There are countless considerations for clinical trials at this time, including social distancing, limiting patient/employee touchpoints, scarcity of personal protective equipment, limited hospital bed, and operating room availability, and substantial overall stressors on our health care delivery systems. Many institutions have halted new patient accruals to clinical research trials or devised rational plans that take the above and other important considerations into account. These are critical measures at this juncture, given the potential risk to our society that COVID-19 poses. As a result of this worldwide crisis, I considered forgoing this month’s article.

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. Two years ago, I briefly mentioned enfortumab vedotin in a Clinical Trials Portal article focused on discussing the promising Antibody Drug Conjugate (ADC) class of drugs. 

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.

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