Learning Objectives

At the conclusion of the activity, participants will be able to:

• Optimally use prostate specific antigen (PSA) and other biomarkers to minimize unnecessary testing and biopsy when screening men who are at average risk for prostate cancer.
• Apply the principles of “risk-adapted” screening for men at elevated risk for prostate cancer based on race, family history, early in life PSA, polygenic risk scores and specific genetic mutations (eg BRCA1/2).
• Identify the roles of MRI, high frequency ultrasound and novel transperineal approaches to improve prostate biopsy.
• Treat men with locally advanced prostate cancer with multimodal approaches and how to choose and sequence hormonal, chemotherapeutic, immunologic and/or targeted approaches (eg PARP inhibitors) in men with metastatic and castrate resistant prostate cancer.
• Explain how to choose and sequence secondary and tertiary hormonal, chemotherapeutic, immunologic and/or targeted therapies (eg PARP inhibitors) in men with metastatic and castrate resistant prostate cancer.

Our course reviewed prostate cancer screening with prostate specific antigen (PSA) and other biomarkers, techniques of biopsy and imaging of prostate cancer using magnetic resonance imaging (MRI), microultrasound and positron emission tomography (PET) scans, and treatment of advanced and recurrent prostate cancer.

There are multiple markers designed to improve our ability to identify men at high risk for prostate cancer who should be aggressively screened. Genetic testing looking at various single nucleotide polymorphisms (SNPs) (aka polygenomic risk score using, for example, PROMPT test) and/or looking for high-penetrance abnormalities in DNA repair genes (such as BRCA1 and 2) can significantly assess an individual’s risk for prostate cancer and guide when to start screening. Individuals with high polygenomic risk scores or defects in these genes should be screened starting at age 40 and annually.

New data support PSA screening annually in African American (AA) men. AA men are significantly less likely to present with M1 prostate cancer or die from prostate cancer with annual screening over a 5-year period as opposed to less frequent opportunistic PSA testing. While this was not randomized, it is important given that AA men are at high risk for developing more aggressive prostate cancer and were under-represented in the prospective PSA screening studies (PLCO and ERSPC).¹

If any patient has an elevated PSA, multiple serum and urinary biomarkers are available to provide the patient with an individualized risk assessment for prostate cancer. These biomarkers by and large perform similarly to avoid 20%–40% of benign biopsies at a cost of missing a small proportion (usually less than 5%) of clinically significant cancers.

The urine tests are PCA3, ExoDx^® and SelectMDx.^2,3 Each requires collection of first catch urine. In all cases, an elevated value is associated with increased risk. The utility of the test is primarily to avoid biopsy in men with a low value since they are less likely to have significant disease. Similarly, serum based tests such as PHI and 4KScore may be used to guide biopsy wdecisions. Their utility is particularly useful in conjunction with MRI.

Comparison among the available biomarkers is difficult as head-to-head studies are not presently available. For now practitioners should individually evaluate the properties of the available reflex biomarkers and choose the one that works best in their practice.

Prostate biopsy has changed dramatically because of the widespread recognition that conventional transrectal ultrasound (TRUS)-guided transrectal biopsy in the office often misses prostate cancer entirely and when it detects prostate cancer often under or overestimates tumor volume and/or Gleason score. Moreover, there is a concerning increase in infectious complications from transrectal biopsy. For these reasons, transperineal biopsy has had a resurgence. Contemporary approaches to transperineal biopsy can be performed under local anesthesia using the Precision Point or other transperineal access system. More comprehensive grid-guided template biopsies usually require sedation. Transperineal biopsy has a high detection rate as it enables assessment of all parts of the prostate. It has been studied in comparison to conventional biopsy for detection of cancer and for followup of patients on active surveillance; men having transperineal biopsy had a higher detection of significant cancer on initial biopsy and on followup biopsy (if on active surveillance) compared to those having conventional TRUS biopsy.⁴

Image-guided biopsy has been increasingly used. In comparison with conventional TRUS, MRI-targeted biopsy identifies more clinically significant cancer and a fewer insignificant cancers. The AUA, European Association of Urology and National Comprehensive Cancer Network recommend MRI imaging if available for biopsy naïve patients. Combined targeted and systematic cores are recommended; biopsy naïve patients with a normal MRI still require systematic biopsy. In patients with a prior negative biopsy, a negative MRI may avoid a repeat biopsy particularly if reflex biomarkers are favorable. Image-guided biopsy may also be performed using microultrasound, a 29 megahertz probe which results in a 300% improvement in resolution. It enables real-time targeting of suspicious regions of the prostate without image fusion and is completely under the control of the urologist. Microultrasound images of the prostate are categorized using the Prostrate Risk Identification using Micro Ultrasound (PRIMUS) system which is analogous to the Prostate Imaging–Reporting and Data System classification for MRI. The learning curve for microultrasound ranges between 15 and 40 cases. Microultrasound biopsies may be performed transrectally or transperineally and can also include fusion biopsies of MRI suspicious regions. Microultrasound yields similar sensitivity and negative predictive value to MRI in several single institution and 1 multi-institutional study.⁵

New data show that docetaxel may significantly reduce and possibly eliminate radiation induced cancers which are often lethal. In a randomized study a subgroup of men with a PSA level <4 ng/ml were identified who had aggressive high-grade prostate cancer and whose survival seemed be prolonged when docetaxel was added to the standard treatment using radiation and hormonal therapy. This hypothesis is currently being tested using a meta-analysis of previously published randomized trials evaluating the impact of docetaxel when added to standard of care therapy (radical prostatectomy or radiation therapy [RT]/androgen deprivation therapy) on overall survival in men with high-risk prostate cancer.⁶

Three randomized trials published in September 2020 in Lancet and Lancet Oncology concluded that delivering RT after surgery for prostate cancer when the PSA rises signaling recurrence (ie early salvage RT) as opposed to when the PSA is undetectable (ie adjuvant RT) did not compromise subsequent cancer progression.

However, these trials may have missed the benefit of adjuvant RT due to lack of power because a minority of men (9%–17% of the study cohorts) were found to have adverse factors at prostatectomy which are associated with cancer progression and death from prostate cancer. Such men are those with high grade (Gleason score 8 to 10) prostate cancer that also extends outside the prostate (ie through the capsule, into the seminal vesicles, bladder neck or anterior rectal wall) or has spread into the pelvic lymph nodes.⁷

Moroever, men with adverse pathology at prostatectomy comprise the vast majority of men who go on to die from prostate cancer and therefore have the most to gain from adjuvant RT. Yet given the results of the 3 randomized trials, many physicians are no longer offering adjuvant RT, even in men with adverse pathology at surgery.

New data evidence to support that delivering adjuvant as compared to early salvage RT can reduce the risk of death by decreasing death from prostate cancer in men found to have adverse pathology at surgery.

These data should heighten awareness that men with adverse pathology at surgery may experience shortened survival due to an increase in death from prostate cancer if physicians wait for the PSA to rise to deliver RT (ie early salvage RT).

PET scanning has enhanced management of prostate cancer patients by more accurately staging intermediate and high risk patients and by allowing targeted salvage therapy in men with biochemical recurrence after primary treatment with surgery or radiation. Both prostate specific membrane antigen (PSMA) PET scans and fluciclovine PET scans are useful in the latter setting.^8,9

The management of castrate resistant prostate cancer is becoming increasingly complex. A particularly notable change in recent years has been the introduction of novel hormonal agents into the castrate sensitive metastatic space as well as utilization of novel hormonal therapies for those with nonmetastatic castrate resistant disease. This changes the choices available for those now diagnosed with castrate resistant disease as well. Genetic alterations are important from several perspectives and a variety of guideline committees have suggested that all men with metastatic prostate cancer should have germline genetic testing.

With regard to castrate resistant metastatic prostate cancer in 2020 and 2021 there were 2 particularly notable developments. Poly ADP ribose polymerase (PARP) inhibitors were approved by the U.S. Food and Drug Association for those with selected homologous recombination repair defects, with patients harboring BRCA2 mutations having a high response rate in particular. Of note, patients with mismatch repair gene alterations (eg MSH2, MSH6) may respond robustly to PD1 inhibitors.¹⁰ Importantly, there has been a rise in the importance of molecularly targeted radiation therapy, especially PSMA-targeted radioisotopes that now have been shown to prolong survival in advanced castrate resistant prostate cancer despite multiple prior therapies.¹¹ FDA approvals are anticipated for this innovative therapy in 2022. Other targeted therapies are in development.