Prostate Cancer and Prostatic Diseases: From the Editor

02 November 2020

Treatments for prostate cancer have rapidly evolved over the past nearly 10 years. Prior to this, the only approved life-prolonging agent for advanced prostate cancer was docetaxel. However, that all changed with the approval of abiraterone and enzalutamide. Both drugs showed profound benefits for men with metastatic castration-resistant prostate cancer (mCRPC). For these men, survival was measured in months and thus, the long-term toxicity of any therapies was not relevant. Acute toxicities were generally mild and manageable. As such, these agents made a huge impact and became widely used.

Newer data suggest that both abiraterone and enzalutamide also improve survival when given to men with metastatic castration-sensitive prostate cancer (mCSPC). For these men, survival is not measured in months, but rather years. As such, long-term toxicities become more relevant and are of keen interest.

01 October 2020

Gupta and colleagues report in Prostate Cancer and Prostatic Diseases (PCAN) the characterization of Androgen Receptor (AR) null metastatic castration-resistant prostate cancer (AR null mCRPC) using a novel immunohistochemical assay combined with AR genotyping as part of the MSK-Impact next-generation sequencing panel at Memorial Sloan Kettering Cancer Center. Patients were selected to have non-neuroendocrine prostate cancer (NEPC) in order to identify a subgroup of adenocarcinoma patients that have lost AR expression. Such findings could identify those men less likely to benefit from AR inhibitors and who may benefit from alternative approaches. In this retrospective study of 26 men with mCRPC who underwent sequencing and AR IHC, 5 patients (19%) demonstrated loss of AR protein expression, which is in line with prior autopsy and mCRPC genomic survey studies of the prevalence of NEPC-like biomarkers in this setting.

10 September 2020

We are seeing an increasing number of studies evaluating the role of fluorinated ligands for prostate-specific membrane antigen (PSMA) PET/CT. Data to this point in time has not shown any convincing diagnostic advantage or disadvantage with the use of either fluorine F 18 (F18 DCFPyL) and gallium (Ga) Ga68 HBEDD-11 PSMA PET/CT tracers although the former has obvious logistical benefits in busy nuclear medicine departments. This study by Witkowska-Patena and colleagues is amongst the first studies to look at a relatively new fluorinated tracer in the form of F18 PSMA-1007. This tracer is already becoming commercially readily available and well before we have good data on its utility and capability.

The justification for yet another PSMA tracer appears to be sound although this is not specifically discussed in the paper. The potential advantage of F18 PSMA-1007 is that there is significantly lower urinary excretion of the tracer; as a result, there is the minimization of tracer within the urine that could potentially impact the interpretation of tracer uptake in areas adjacent to the urinary tract.

31 August 2020

The role of testosterone and prostate cancer is that of a "Janus head." Whereas the disease is driven by androgens, there is still conflicting data on the role of testosterone in relation to prostate cancer development. The debate is ongoing.

Sarkar and colleagues study the effect of testosterone therapy (TT) in men that were treated with curative intent (radiation therapy or surgery). From a significant cohort(~70,000 men) a group of men undergoing TT was compared to those who did not, and biochemical recurrence was used as an endpoint. The authors recognize the limitation that this an observational type of study, as time on testosterone, and serum testosterone values were not available.

08 July 2020

In the constant search for better approaches to treat and ultimately prevent prostate cancer, it is essential that we better understand the underlying etiology of prostate cancer. In times like this, I am often discouraged by the common mantra that the only known risk factors for prostate cancer are “age, race, and family history”. Surely, there must be other risk factors. Over time, certain risk factors have revealed themselves – obesity (aggressive prostate cancer), diet (likely, but exact details still evolving), and smoking (aggressive prostate cancer) to mention a few. One common factor, but certainly not the only factor, linking obesity, diet, and smoking is they all increase inflammation. If true that increased inflammation drives more prostate cancer, then it begs the question of whether other conditions that are clearly inflammatory-related are linked with prostate cancer. With this background in mind, Ge and colleagues tested the association between inflammatory bowel disease (IBD) and prostate cancer risk.

11 June 2020

Active surveillance (AS) is an alternative to definitive therapy for patients with the National Comprehensive Cancer Network very low-risk, low-risk, and favorable intermediate-risk prostate cancer.¹ However, 20% to 30% of AS patients will grade progress on follow-up biopsy or undergo treatment within five years.^2-5 Prevention of grade progression in AS patients would decrease treatment incidence, reduce costs of care, and improve health-related quality of life in men on active surveillance.

5-alpha-reductase inhibitor (5ARI) therapy is one potential intervention to prevent progression in AS patients. Robust data demonstrate that 5ARIs diminish grade progression and the use of definitive treatment in AS patients.⁶ Nevertheless, the U.S. Food and Drug Administration black box label warning of possible risks of the incident high-grade disease remains, and the use of 5ARIs in men on AS to prevent progression has not been widely embraced. 

14 May 2020

Black men face a pandemic of prostate cancer risk and lethality which will still be present long after COVID passes. As compared to White men, Black American men have a high risk of presenting with aggressive and metastatic disease and suffer a 2.4 fold higher risk of prostate cancer-specific mortality, and a nearly 10-fold higher risk of death from prostate cancer as compared to Asian American men. This disparity in outcomes is present in both rural and urban regions¹ in the United States and some of the highest global regions of prostate cancer mortality are in Africa and the Caribbean. This racial disparity may be linked to differences in biology^2,3, access to care⁴, differences in treatment receipt, comorbidities, differences in risks and exposures, and differences in screening and early detection. 

In light of this observed disparity, Krimphove and colleagues⁵ from Harvard analyzed the National Cancer Database for all men with metastatic or locally advanced prostate cancer between 2004-10 and compared outcomes by race. Overall, Black men were more likely to have metastatic disease in this cohort as compared to locally advanced disease, were less likely to receive surgery or radiation, were more likely to be uninsured, were more likely to be treated locally, and to have not completed a high school education.

07 May 2020

It is now a decade ago that Provenge (sipuleucel-T), an autologous active cellular immunotherapy, was approved by the FDA. Many unanswered questions, still needed to be resolved. When to give this to which patient, i.e. timing and predictive patient characteristics are issues that need to be resolved.

03 March 2020

Much of the push to perform transperineal prostate biopsy has been driven by concerns about increasing rates of sepsis associated with the transrectal approach to needle biopsy.

Historically, the strategy to minimize the infective complications of prostate biopsy had relied upon using more and more potent antibiotic regimens to combat growing bacterial resistance. A more recent approach to mitigate the risk of sepsis has been to use the more potent antibiotics in a targeted manner guided by rectal swabs prior to biopsy. However, the concept of chasing increasing antibiotic resistance with increasingly powerful antibiotics is a strategy that will never win. 

The transperineal approach to prostate needle biopsy is a logical way forward given that the risk of biopsy sepsis is minimal. It should be the standard of care approach to prostate biopsy but there is a reluctance to change practice and much of this is based upon the arguments that expensive equipment is necessary and that a general anesthetic is necessary. Recent advances are seeing these issues overcome.

09 February 2020

In the past 10 years, the number of new treatment options for metastatic castration-resistant prostate cancer (mCRPC) has exploded. Prior to 2010, only one agent – docetaxel – had been shown to extend survival for mCRPC patients. Now, a decade later, we have many such agents beyond docetaxel, including abiraterone, enzalutamide, sipuleucel-T, radium-223, and cabazitaxel. In addition, two other agents have shown significant benefits in other disease settings prior to mCRPC – apalutamide and darolutamide. While all extend survival, in the mCRPC setting the added months of life, on average, range from ~2 to 5. Thus, if all the new agents are added together, it is well over a year of added life. However, can the survival months merely be added together? Alternatively, do you get the biggest bang with the first agents and subsequent agents add little? This is an important unanswered question.

13 January 2020

Multiparametric magnetic resonance imaging (mpMRI) is a robust staging modality for high-risk prostate cancer. Less clear is whether pre-operative mpMRI may potentially improve radical prostatectomy outcomes by providing actionable information for planning neurovascular bundle excision, bladder neck sparing, and extent of staging lymph node dissection.

To address this question, these investigators performed a novel, single-center survey study of six urologic oncologists. Study participants were given two surveys incorporating 41 case studies of patients with clinically localized prostate cancer who underwent pre-operative mpMRI prostate followed by robot-assisted laparoscopic prostatectomy and extended pelvic lymph node dissection.

02 December 2019

Many adverse events have been described in men receiving androgen deprivation therapy (ADT), ranging from loss of bone density, hot flushes, cardiovascular risk, metabolic syndrome, cognitive dysfunction, and even less common risks such as deep vein thrombosis and colorectal cancer development. In the January 2019 edition of PCAN, Liu and colleagues describe a novel potential decreased risk of autoimmune diseases with ADT. This is intriguing for several reasons:

28 October 2019

The dilemma that resulted from the widespread use of serum prostate-specific androgen (PSA) testing was the identification of a significant number of men with indolent pure red cell aplasia (PrCa). After a significant period of overtreatment, the implementation of active surveillance (AS) has partly solved that issue. However, 25-50 % of AS patients will undergo an intervention. The follow up is rather invasive including serum PSA and repeat biopsies.

Models based on clinical parameters can be used to predict repeat biopsy outcome, yet improved methods to asses the risk to predict adverse pathology are needed. Candidate tools are improved imaging and biomarkers. In the past decade, molecular urine biomarkers were introduced in clinical practice (i.e.Prostate Cancer Gene 3 (PCA3) and TMPRSS2 erg).

09 October 2019

This Australian study is the largest published experience of the use of Ga68 PSMA PET/CT imaging in the context of previous primary radiotherapy for prostate cancer. 

This study evaluated 276 men who had undergone a Ga68 PSMA PET/CT for which the majority had PSA biochemical failure (mean PSA 3.60 ng/mL, range 0.01–83 ng/mL). Overall, 86% (239/276) men had positive scans with morethan half having evidence of local disease recurrence. Clearly, there are some limitations given that in the relatively small number of 33 men who underwent a prostate biopsy, only 28 men (85%) were confirmed to histological recurrence. Lymph node metastases were identified in 122 men (44%) of which 49 men had positive lymph nodes that were located outside the template for an extended pelvic lymph node dissection. Bone metastases were documented in 50 men.

09 September 2019

Androgen deprivation therapy (ADT) is standard treatment for advanced and metastatic prostate cancer. While it is very effective for cancer control, it has many side effects. Commonly known side effects include loss of libido, fatigue, osteoporosis, and hot flashes. Additionally, ADT has metabolic side effects. Imagine a young athlete using steroids to have a competitive advantage. They gain muscle mass and lose fat. Now imagine the same man 50 years later undergoing ADT for his prostate cancer – it will have the exact opposite effects – gain of fat mass and loss of muscle mass.

These changes are coupled with a ~40% increased relative risk of diabetes. While exercise can help preserve muscle mass, to date, no treatment has been shown to prevent this metabolic sequela. Given one of the fundamental problems from ADT is problems with controlling sugar, what if people simply didn’t eat sugar?

There is tremendous growth in interest in the ketogenic diet, an extreme form on a low carbohydrate (i.e. sugar) diet. Proponents often tout it as the cure-all for diabetes, obesity, and possibly even cancer. Opponents argue that it is not sustainable, is bad for the environment, and it simply can’t be healthy to eat all that fat. Where

08 August 2019

Radiotherapy is a mainstay of treatment for localized prostate cancer. Biochemical recurrence after radiotherapy, defined as a prostate-specific antigen (PSA) rise of ≥ 2 ng/mL above nadir, occurs in up to 40% of intermediate- and high-risk patients within 10 years of treatment (Eur. Urol. 67, 1009–1016 (2015). Patients with biochemical recurrence are at increased risks of metastases and death (J. Clin. Oncol. 23, 6992–6998 (2005)).

In patients with biochemical recurrence after radiation, biopsy-proven localized disease, and no evidence of metastases, salvage prostatectomy may potentially improve survival and delay initiation of androgen deprivation therapy. This National Cancer Institute-sponsored multi-institutional study, CALGB 9687 (Alliance), prospectively evaluated the efficacy and morbidity of salvage prostatectomy in 41 men between 1997 and 2006 (Prostate Cancer Prostatic Dis. 2019 May; 22(2):309-316). At a median follow-up 91 months, these investigators observed robust 2-, 5- and 10-year progression-free survival rates of 51%, 39%, and 33% respectively; and 2-, 5- and 10-year overall survival rates of 100%, 89%, and 52%, respectively.

11 July 2019

A pressing issue facing men with a rising PSA despite hormone therapy is whether to pursue more potent androgen receptor inhibition. While novel PET imaging such as PSMA scans are reducing the size of this M0 CRPC population, this setting remains fairly common in regions of the world where PSA screening is common and men are treated for initially localized prostate cancer. Relapsed disease is first manifested as a PSA rise, and many urologists and oncologists will utilize androgen deprivation therapy (ADT) prior to the onset of visible metastases on standard CT/MRI or technetium bone scans. We know that most of these men have metastases, but these metastases remain small and below the limit of detection of these scans. We also know that most of these men will likely die of metastatic prostate cancer over the next 4-8 years, and therapies that can delay or prevent prostate cancer-specific mortality are needed.

Recent phase 3 trials suggest that both apalutamide, enzalutamide, and darolutamide can delay metastasis-free survival (MFS) significantly in such men with M0 CRPC who have rapid PSA doubling times (<10 mo) and an elevated PSA of 2.0 or higher. These men may have disease in their prostates or regional nodal

06 June 2019

To speak with Bob Dylan, ‘’..times they are a changing..’’, particularly when it comes to our insight in the genetic changes in prostate cancer. In the early days of molecular genetics studies of prostate cancer, scientists often referred to prostate cancer as being very different from other cancers, e.g. mutations in TP53 were rarely found in this malignancy. With the large scale introduction of next-generation sequencing and the impressive SU2C initiative, focusing on metastatic/advanced cancers, it was shown that prostate cancer was not that of a ‘’cancer genetic outlier’’. TP53-, Rb mutations ánd a rather high frequency of aberrations in genes encoding DNA repair proteins were found in advanced prostate cancer (metastatic CRPC).

A straight forward hypothesis is that these mutations have prognostic significance, i.e. mutations in pivotal cancer pathways are associated with clinical-, pathological stage, and grade, which in turn are a good proxy/surrogate for the outcome of the disease. Marshall and colleagues¹ focussed on DNA repair gene mutations and ‘mined’ existing DNA sequencing information (TCGA, NatureGenetics via cBioportal) to test this hypothesis. There appeared to be a clear correlation between pathological stage (pT3/4 versus pT2) and Gleason Grade groups (GG ≥ 3 versus GG 1-2). In the cT≥3 ánd GG ≥3 tumors in >20% DNA repair gene mutations were identified. Interestingly there appeared

13 May 2019

It has now been over 20 years since holmium enucleation of the prostate was first described. Since then, several other energy sources have been described to perform endoscopic enucleation and more recently there has been a shift to performing the surgery using an enbloc resection technique instead of individual lobar resection. At the end of the day, it probably doesn’t make a great deal of difference as to which energy source is used to perform endoscopic enucleation of the prostate (EEP) and as to whether tissue removal was by individual lobes or enbloc. They are all achieving the same anatomical removal of tissue and are a basically similar principle of technique.

There have been systematic reviews and meta-analyses evaluating individual energy sources to perform EEP versus transurethral resection of the prostate (TURP). The study by Zhang and colleagues is novel in that for the first time, we have an analysis that takes the stance that all of the EEP techniques are essentially equivalent, and therefore creating a very powerful comparison with TURP.

08 April 2019

The Fountain of Youth is thought to be a mystical spring that restores youth upon its drinkers. It has been searched for dating back to before the ancient Romans. Many people spent their lives chasing it – just ask Ponce De Leon! We now know the Fountain of Youth does not exist. In more recent times, the Fountain of Youth has been replaced by various remedies such as elixirs, oils, ointments, and herbs. More recently, people have turned to pharmaceuticals, of which statins has been one of the most touted. Statins are currently the most widely prescribed class of medicines. However, unlike various treatments of the past, statins are very effective. Specifically, they acutely block cholesterol production thereby lowering serum cholesterol levels typically by ~25%. In turn, this leads to dramatic reductions in heart disease risk.

Given the presumed importance of cholesterol in cancer pathways (it is the precursor for androgens as well as important in cell signaling pathways), there are multiple reasons to believe statins have anti-prostate cancer properties. While multiple studies have examined the role of statins in prostate cancer, often with mixed results, no prior study has examined this relationship in men undergoing active surveillance.