Prostate Cancer and Prostatic Diseases: From the Editor

03 January 2022

“Eat right and exercise”. As a prostate cancer provider, I can’t count how many times I have given this advice to my patients. I am always afraid when they ask back, “Will it actually help”? The truth is, we don’t know. While increasing data suggest that diet and exercise may modulate prostate cancer risk and even progression in some studies, the totality of the evidence remains weak. Into this void, steps an important paper exploring the role of physical activity (i.e. exercise) and its link with lower rates of progression in men on active surveillance.

In this study, the authors assessed 85 men with low-risk prostate cancer being managed by active surveillance. All men completed a physical activity questionnaire at baseline and were categorized as sedentary (n=24), moderately active (n=46), or active (n=15). The authors then assessed the risk of grade reclassification, commonly used criteria for “progression” among men on active surveillance. The authors found that those who progressed were less physically active (p=0.056). Importantly, over time, the level of physical activity was significantly predictive of who progressed (p=0.033). Indeed, on multivariable analysis, the level of physical activity was the only significant predictor of progression (p=0.016). The authors concluded that physical activity may influence prostate cancer evolution.

02 December 2021

In 2021-2022, many more men globally will receive a potent AR inhibitor in either the metastatic hormone sensitive prostate cancer (mHSPC), non-metastatic castration resistant prostate cancer (nmCRPC), or mCRPC settings, with improved long term outcomes based on multiple positive phase 3 trials of abiraterone, enzalutamide, apalutamide, and darolutamide. This new form of maximal or combined androgen blockade in addition to ADT has extended survival, delaying symptomatic and metastatic progression, improving durable remissions based on PSA and imaging response criteria, major successes for our patients.

With first generation AR inhibitors such as flutamide and bicalutamide, prolonged responses to these therapies often led to anti-androgen withdrawal responses which were observed at progression after the patient stopped these agents. These withdrawal responses were due to point mutations in the ligand binding domains of the AR (such as T877A), turning these older agents into agonists that stimulated AR activity and PSA production. Withdrawal responses typically would last 3-6 months, but occasionally patients would experience prolonged withdrawal responses lasting over a year. However, the prevalence of withdrawal responses to stopping these novel AR inhibitors has not been well described.

08 November 2021

In prostate pre- and post-biopsy decision making, more precision is urgently needed. Whereas expert imaging and biomarker-based risk scores already enable the clinician in this respect, the dilemma remains for those patients that are diagnosed with apparent indolent cancer. Additional diagnostic tools that (de)select patients for active surveillance (AS) would provide a great benefit for the patient.

A commercially available test is Decipher Biopsy. The potential of this test on post-radical prostatectomy decision-making is well documented. This is also shown for other molecular gene expression-based classifiers. This paper describes the outcome of a state-wide registry of patients in AS. The test is significantly associated with time to treatment and time to failure. The paper shows that the Decipher score correlates with Grade Group, NCCN- and CAPRA risk scores.

05 October 2021

As a randomised controlled trial, the PRECISION study¹ showed a clear benefit of an MRI pathway in terms of improved detected of clinically significant prostate cancers and decreased detection of clinically insignificant prostate cancers. However, it seems that not all urologists are convinced by the data or sufficiently motivated to change clinical practice on the strength of this study. That said, it is accepted that access to prostate MRI due to reimbursement issues could play a role in some jurisdictions.

The 2021 EAU Guidelines² have clearly spelt out a recommendation that an MRI should be performed prior to prostate biopsy whether it be those men who are biopsy naïve or have previously had a negative prostate biopsy.  The strength rating for both recommendations is “strong”.  The 2021 NCCN Guidelines³ are a little more guarded in that the recommendation for an MRI prior to prostate biopsy is qualified by the words ‘if available’.  Particularly in the US, 3T MRI is widely available but sadly, it is an issue of reimbursement despite the highest level of evidence to support its routine use prior to prostate biopsy.

07 September 2021

Doctor: “You have prostate cancer.”

Patient: “Doctor, that’s awful. What can I do to help it grow slower and feel better?”

Doctor: “Eat right and exercise.”

Patients: “How much exercise should I do?”

Doctor: “I don’t know.”

While the above is a fictitious discussion between doctor and patient, my guess is that similar discussions occur every day. When diagnosed with cancer, patients want to improve their lifestyle and clamor for any information their provider can give them. Unfortunately, most providers don’t know what advice to give. Even if the provider is knowledgeable and interested, discerning the literature and coming up with an answer to a straightforward question such as “how much exercise” is not an easy task. Into this void, steps the systematic review and meta-analysis by Lopez and colleagues.

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.