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Prostate-specific membrane antigen (PSMA) is highly expressed by poorly differentiated, metastatic, and castration-resistant prostate cancer cells,1 creating a good imaging and therapeutic target.  177Lutetium (Lu) is a beta-emitting radionuclide that induces DNA strand breaks and cellular lethality.In the situation of 177Lu-PSMA-617, 177Lu is linked to a 617, which is a small molecule targeting vector that binds to PSMA.  Once bound to the receptor on the target cell membrane, in this case, prostate cancer cell, the complex is internalized.3  Hence, the lethal radiopeptide is delivered internally to induce DNA breaks and eventual apoptosis.
Adenosine triphosphate (ATP) is that all-important organic compound that we first learn about in biology class back in secondary school, and we revisit countless times in our college and medical school biochemistry courses.  It is found in all known forms of life, is utilized for intracellular energy transfer, and is often loosely referred to as the “molecular unit of currency.”1  In eukaryotes, ATP is produced through the process of cellular respiration, which oxidizes glucose to carbon dioxide via glycolysis, the tricarboxylic acid (TCA) cycle, and oxidative phosphorylation.  Additionally, the breakdown of fatty acid molecules, or beta-oxidation, can also produce ATP.  In the absence of oxygen, anaerobic respiration can produce ATP, albeit less efficiently.
Abiraterone acetate has demonstrated benefit across the metastatic prostate cancer spectrum when combined or layered on conventional androgen deprivation therapy. Whether it be metastatic castration-sensitive (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) in either the pre-or the post-docetaxel setting, the overall survival benefit is certain.1-4 Attempts to advance to the next level with additional agents added to abiraterone acetate, in the first-line mCRPC setting, have been met with mixed results. At this time, other than the continuing foundation of androgen deprivation therapy, there is no therapeutic agent regulatory approved for combination with abiraterone acetate.
Adjuvant therapy trials for urothelial carcinoma have traditionally been challenging to perform.  Radical cystectomy is a significantly morbid procedure that leads to high complication and readmission rates.   Hence, many patients are not fit to receive any adjuvant therapy after definitive local therapy due to a compromised health situation. At this time, neoadjuvant chemotherapy is still the definitive standard.1 However, not all patients receive neoadjuvant therapy for a multitude of reasons.  For those who did not receive neoadjuvant cisplatin combination chemotherapy, common sense warrants strong consideration of adjuvant therapy as long as a patient is fit and interested.
I have previously discussed the use of antibody-drug conjugates for selective tumor cell intensification of urothelial carcinoma therapy in a Urotoday Clinical Trials Portal article.1 Similarly, I’ve also focused on enfortumab vedotin before, and enfortumab vedotin is now FDA approved on the accelerated pathway for patients with locally advanced or metastatic urothelial carcinoma in the post-platinum chemotherapy and post-PD-(L1) antibody therapy setting.2 Yet, even as new data continues to emerge on the use of enfortumab vedotin in various settings, we should take time to evaluate the development of other promising antibody-drug conjugates.

Activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway has been strongly linked with prostate cancer progression and metastatic potential.1 Loss of the inhibitory phosphatase, PTEN, leading to hyperactivation of PI3K/AKT/mTOR oncogenic signaling, occurs in 40-50% of metastatic castration-resistant prostate cancer.1,2 Not surprising is the fact that PTEN loss in patients with metastatic castration-resistant prostate cancer is associated with a worse prognosis and less benefit from androgen receptor (AR) blockade.3 Likewise, PTEN loss and subsequent Akt activation confer radiation4 and chemotherapy5, 6 resistance.

Cabozantinib, an oral tyrosine kinase inhibitor against MET and vascular endothelial growth factor receptor 2 (VEGFR2), is an agent that was initially met with enormous enthusiasm by the prostate cancer community. The early data showed dramatic bone scan responses, where bone metastases would almost magically disappear after cabozantinib treatment on subsequent restaging bone scans. As this was an unfamiliar, yet welcome phenomenon, the field eagerly began working on the development of this agent.

It has now been approximately a year and a half since the United States Food and Drug Administration (FDA) granted accelerated approval to erdafitinib for patients with locally advanced or metastatic urothelial carcinoma, with susceptible fibroblast growth factor receptor 3 (FGFR3) or FGFR2 genetic alterations after progression during or following platinum chemotherapy.1 The label is inclusive of patients within 12 months of neoadjuvant or adjuvant platinum chemotherapy. Additionally, the label includes companion diagnostic information for a jointly approved therascreen® FGFR RGQ RT-PCR kit, for this specific therapeutic indication.

Over the last few years, the evidence has been mounting for the role of DNA repair in prostate cancer. What started with the Stand Up 2 Cancer (SU2C) International Dream Team discovery of 23% homologous recombination repair gene alteration rate in metastatic castration-resistant prostate cancer (mCRPC), followed by the identification of an 11.8% germline alteration rate in metastatic prostate cancer, has now led to broad sweeping successes with the introduction of PARP inhibitors to our clinics.1,2 

The TRITON2 trial demonstrated a 43.5% objective response rate with rucaparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and a deleterious BRCA1 or BRCA2 alteration.3 This trial led to the United States Food and Drug Administration (FDA) granting accelerated approval to rucaparib for the

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.

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. 

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