Prostate Cancer and Prostatic Diseases: From the Editor

29 July 2021

It is well appreciated that men with bone metastases are at risk for fracture and symptomatic skeletal-related events (SREs), and that men on long-term potent hormonal therapies are at risk for fragility fractures due to ongoing bone loss. However, the utilization of denosumab and zoledronic acid, despite the widespread guideline recommendations for their consideration, remains low internationally. This was recently highlighted at ASCO 2021 with the PEACE3 clinical trial, where the mandated use of bone antiresorptive therapy in this bone mCRPC protocol of enzalutamide +/- radium-223 led to an improvement in the use of these agents in this population from 55% to 97%, and reduced the observed fracture rate at 18 months with enzalutamide alone from 22% to 2.6%, a major reduction in risk.¹

06 July 2021

Genes predisposing to prostate cancer have been investigated now for more than three decades resulting in the identification of ~170 germline susceptibility loci, mostly in mixed European ancestry cohorts.

In this study based on a ‘’narrow/isolated’’ Finnish cohort, 21 low penetrance susceptibility loci were identified, of which 10 are novel. The intronic variant rs2074187 in SP6 was associated not only with overall susceptibility to PrCa (OR 1.66) but also with a higher odds ratio for aggressive PrCa (OR 1.89) and lower odds for non-aggressive PrCa (OR 1.43). Furthermore, the new intergenic variant rs79012498 at 8q24 conferred risk for aggressive PrCa. These are important as they are associated with significant prostate cancer. Such variants may be useful in the stratification of patients for population based screening.

14 May 2021

Every medical school textbook lists three risk factors for developing prostate cancer: age, family history, and race. Specifically, Black men (i.e. those of African ancestry) are at increased risk. On the population level, Black men are ~67% more likely to be diagnosed with prostate cancer than White men. When it comes to aggressive cancers, however, the picture is less clear. Yes, Black men are 2 to 2.5 times more likely to die from prostate cancer than White men. Does that mean the disease is more aggressive or does that reflect poorer access to care and less aggressive treatments? Increasing data suggest that though on the population level among men with prostate cancer, Black men are more likely to die when given equal access and equal treatments, outcomes among men with localized disease are similar between Black and White men. What about men with advanced disease – specifically those with metastatic castration resistant prostate cancer (mCRPC)? Several studies from the United States found that among men with mCRPC, survival was actually better for Black men vs. White men. The question is whether these findings (more cancers, equal aggressiveness, but better survival in mCRPC) are unique to the United States, or can the results be replicated in other countries too?

01 April 2021

For decades, clinicians and researchers alike have been aware of major racial disparities in prostate cancer. Black men in the United States present more often, with higher PSA values, at younger ages, and are more likely to die from prostate cancer than their White counterparts. Within this framework of indisputable facts, there is a lot of discussion to what factors lead to these racial disparities. Is it genetics? Is it social determinants of health? Is it attitudes to the health system due to mistrust from many past horrible failed experiments (i.e. Tuskegee)?

Is it lifestyle differences? Is it all access to care? Recent data from the Veterans Affairs Health System have suggested that when given equal access, outcomes among Black and White men can be similar. While this certainly supports the importance of access to care, this does not mean Black and White men present with equal rates of prostate cancer indicating residual disparities that cannot be explained by access alone. However, as we move forward with newer technologies (MRI, genomics, next generation imaging), whether Black patients truly have equal access to these advances is unknown.

01 March 2021

The ability to predict clinical outcomes prior to starting therapy is the hallmark of precision oncology. The detection of the androgen receptor splice variant 7 (AR-V7) in circulating tumor cells (CTCs) has now been externally and prospectively validated in the multicenter PROPHECY study using both the Hopkins mRNA and the Epic Sciences nuclear protein assays, demonstrating strong and significant associations with worse progression free and overall survival (PFS and OS) and a lack of responses in men with mCRPC,¹ but such AR-V7 positive men can still have good outcomes with taxane chemotherapy.² However, a limitation of CTC AR-V7 detection is that CTCs are required to be present, and nearly half of men with mCRPC have low to absent CTCs despite disease progression. In addition, AR-V7 likely only explains about 20-30% of AR therapy cross-resistance, meaning that other resistance mechanisms such as AR indifference and neuroendocrine transformation/lineage plasticity are also important.

01 February 2021

Biomarkers and more complex integration of panels in so-called molecular or genomic classifiers have reached the level of clinical implication after careful standardization (LDT) and clinical validation. Whether these molecular classifiers are actually used and alter treatment decisions is studied in this manuscript.

A genomic classifier (GC) with prognostic indication, Decipher (Decipher Biosciences), aids in the decision for adjuvant radiotherapy (ART). In this study, the authors show that whereas the decision would have been "observation" in 39% of pre-genomic testing cases, the recommendation changed. The authors conclude that the use of GC substantially altered treatment decision-making, with a number needed to test of only 3.

19 January 2021

The majority of urologists performing radical prostatectomy in developed populations are doing so with robotic platforms. Since adopting this approach, many of us have observed that our patients appear to have less pain and recover more rapidly. If we are brutally honest with ourselves, we have all probably lowered our bar for accepting patients for surgery on the basis of overall health because they seem to handle robotic-assisted surgery better than open surgery. In my own practice, for patients not willing to consider radiotherapy and were frail by my own subjective assessment, I would routinely send these patients for a review by one of my internal medicine colleagues who is by training a geriatrician and has developed a special interest in perioperative medicine. Almost always, these patients were then being cleared for surgery and gradually I have found that I am operating on more of these types of patients apart from just older patients.

03 December 2020

Urethral wall stents were introduced as a minimally invasive intervention for benign prostatic hyperplasia (BPH) in the 1990s. Despite reports of longer-term efficacy in select patients,^1,2 challenges with recurrent occlusion and stent migration^3-5 prevented widespread adoption of this technology.

Over the past 10 years, however, novel designs and new materials have sparked renewed interest in developing the next generation of urethral stents.⁶ These investigators reported updated data on a single-arm study of 81 patients with symptomatic bladder outlet obstruction who received a temporary implantable nitinol device.⁷ The device—composed of three nitinol struts and an anti-migration anchoring leaflet—remained in place for 5 to 7 days, expanding and exerting radial force on the tissue to cause ischemic incisions at the 12, 5, and 7 o’clock positions. Implantation occurred under direct vision through a rigid 19F-22F cystoscope using light intravenous sedation, and removal through an open-ended 22F Foley catheter with topical anesthesia.

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: