Prostate Cancer and Prostatic Diseases

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.

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.

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.

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

Abstract

Background: Prostate cancer in black men is associated with poorer outcomes than their white counterparts. However, most studies reporting this disparity were conducted in localized prostate cancer and primarily in the United States.

Methods: Data regarding prostate cancer incidence and mortality for East London between 2008 and 2010 were obtained from the UK National Disease Registration Service. We further evaluated survival outcomes of 425 cases of mCRPC in St Bartholomew’s Hospital, East London, between 1997 and 2016, and analyzed whether ethnicity impacted on responses to different treatment types.

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.