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The clinical data surrounding inhibition of PD-1/PD-L1 in prostate cancer is evolving.  In the past, I have written a couple of articles about both single-agent and combination approaches for metastatic castration-resistant prostate cancer (mCRPC).1, 2  The field has evolved to the point where we recognize that single-agent PD-1/PD-L1 inhibition is unlikely to yield a major benefit for an unselected population.  In the KEYNOTE-199 trial, pembrolizumab yielded 5% and 3% objective response rates in patients with PD-L1 positive and negative tumors, respectively.3  

The topic of metastatic castration-sensitive prostate cancer has been on the forefront of clinical research in prostate cancer for many years now.  In 2017, and again in 2019, I wrote Clinical Trials Portal articles on the topic of metastatic castration-sensitive prostate cancer, summarizing the key ongoing trials during those times.1, 2  We now know that early treatment intensification with the addition of either docetaxel, abiraterone acetate, enzalutamide or apalutamide to androgen deprivation therapy (ADT) offers a significant overall survival benefit.  Docetaxel is the only agent that may have questionable benefit for low volume metastatic prostate cancer, with benefit perhaps being restricted to high-volume metastatic disease only, defined as ≥4 bone metastases with at least one in the appendicular skeleton and/or a visceral metastasis.3

The majority of urothelial carcinomas occur in the lower urinary tract, yet 5-10% originate in the upper urinary tract, including the renal calyces, renal pelvis, and ureters.1  Although upper and lower urinary tract urothelial carcinoma may share similar histology, the natural history differs, and upper tract disease often has a higher incidence of local invasion at diagnosis.2  Risk factors for upper tract urothelial carcinoma are similar to those of the lower tract, but there are some unique risk factors are associated with environmental exposures.  For example, Taiwan has an extremely high incidence of upper tract urothelial carcinoma, with a counterintuitive 1:2 male-to-female ratio due to arsenic-contaminated water, termed Blackfoot disease.  Additionally, in both Taiwan and the Balkan countries, exposure to the Aristolochic herbs (fangchi and clematis) is carcinogenic, leading to progressive renal fibrosis and upper tract urothelial carcinoma.4, 5

Avelumab initially received regulatory approval for patients with metastatic urothelial carcinoma in the post-platinum chemotherapy setting based on an objective response rate of 16.5%.1  In the post-platinum chemotherapy setting, both nivolumab and pembrolizumab also currently retain their regulatory approval status.  However, the situation where avelumab has the strongest data is in the maintenance-switch setting.  I initially discussed that topic in a Urotoday Clinical Trials Portal article almost 4 years ago.2  Of course, everything discussed in that article has been completed, and all highlighted trials were positive.

PSMA PET imaging has now achieved regulatory approval in the United States.  On December 1, 2020, the United States (US) Food and Drug Administration (FDA) granted a limited approval to the University of California, Los Angeles and the University of California, San Francisco, for 68Ga-PSMA-11 PET imaging for patients “with suspected prostate cancer metastasis who are potentially curable by surgery or radiation therapy” and for patients with “suspected prostate cancer recurrence based on elevated serum PSA levels.”1  More recently, on May 27, 2021, a second PSMA imaging agent, PYLARIFY® (piflufolastat F 18) injection (also known as 18F-DCFPyL or PyL), received FDA approval for the exact same indication.2  Although neither 68Ga-PSMA-11 and PYLARIFY® (piflufolastat F 18) injection (also known as 18F-DCFPyL or PyL) are widely available yet, both likely soon will be, and they will change how we think about and treat patients with prostate cancer and both high-risk localized disease and biochemical recurrence.

The “abscopal effect” in cancer is frequently discussed, although very rarely seen.  While the term is used quite loosely, it technically is a situation where an untreated metastatic tumor will shrink concurrently while another site is undergoing a localized treatment.  Most commonly, radiation therapy is referenced as that local treatment.  Although the exact mechanism is unknown, it is postulated that the immune system is responsible for such an effect.1

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.


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