Prostate Cancer Academy was held in Los Angeles, California, on September 20 and 21, 2019. Over these two days, urology residents and fellows, LUGPA members, and faculty engaged in discussions on advances in prostate cancer diagnosis and treatment. The seminar emphasized trainee and LUGPA discourse through both didactic and case-based sessions.
For the past three decades, urologists and primary care clinicians have had to reconcile the results from the US-based Prostate, Lung, Colorectal, and Ovarian cancer screening trial and the European Randomized Study of Screening for Prostate Cancer and the conflicting recommendations for early detection that resulted. It was not until 2018 that the United States Preventive Services Task Force changed their D recommendation against prostate-specific antigen (PSA) testing to a C recommendation, now advocating for an individualized approach with an emphasis on discussing the benefits and harms of screening while assessing a patient’s values and preferences. The recommendation change came largely from the recognition of a mortality benefit with a decrease in overtreatment from an increased utilization of active surveillance over the past decade.
In healthy, well-informed men, prostate cancer screening with PSA testing saves lives. However, the optimal age group for screening remains up for question. The American Urological Association (AUA) recommends screening in men between the ages of 55 to 69 years, with earlier testing in “highrisk” patients.1 Meanwhile, Preston and colleagues advocate establishing an earlier baseline PSA after finding the risk of developing lethal prostate cancer in the next 30 years among men with a baseline PSA level below the median 0.72 ng/mL was <2% in men ages 40 to 59 years.2 This coincides with the National Comprehensive Cancer Network (NCCN) recommendations to screen men ages 45 to 75 years.3 It should be noted that major recommendations are based on the aforementioned screening trials that were conducted primarily on white men, and thus may not be generalizable to black men.
Although PSA testing has driven down mortality, the risks of screening must be considered. In 1000 screened US men, 130 will have negative biopsies; 35 will develop bladder, bowel, or sexual side effects from treatment; and 8 will develop a complication from biopsy or treatment. With the advent of improved risk stratification tools and active surveillance, urologists are tasked with transforming the PSA testing and treatment paradigm from a “detect all, treat all” approach to a “detect some, treat some (but not all) cancers.”
Biomarker testing is one strategy to incorporate into PSA screening and should be considered in prebiopsy decision making according to the NCCN. Prostate Health Index (PHI) is one serum-based biomarker test that can lead to reduced biopsies in ~9% to 41% of patients. The 4Kscore® test (OPKO Health, Miami, FL) is another serum blood test that combines clinical factors and has the potential to reduce biopsies by up to 50%. Using urine biomarkers [ExoDx Prostate Test (IntelliScore; Exosome Diagnostics, Waltham, MA)] can also potentially avoid biopsy in 27% of patients, although this testing is still considered investigational. With the goal of fewer negative biopsies and less low-risk cancer detection, clinicians and patients can use these new tools to help improve decision making prior to initial biopsy and repeat biopsy after a prior negative result.
In the active surveillance era, it is incumbent upon the urologist to stratify patients with low- and intermediate-risk prostate cancer to provide better counseling and recommendations for who should undergo treatment and who can safely be given the option of active surveillance. Biomarker and genomic testing can assist in identifying those patients with indolent disease and those who may harbor more aggressive disease.
Validated tissue assays that sequence the genes from biopsy specimens to predict adverse pathology include Decipher® Prostate Cancer Test (GenomeDx Biosciences, San Diego, CA), Prolaris® (Myriad Genetic Laboratories, Salt Lake City, UT), and Oncotype Dx® Genomic Prostate Score (GPS) (Genomic Health, Redwood City, CA). Decipher measures 22 RNA expression biomarkers initially validated to predict the risk of metastasis after radical prostatectomy. Prolaris uses a 31-gene cycle progression signature to predict death from prostate cancer with conservative management at 10 years. Oncotype Dx provides a Genomic Prostate Score (GPS) from 0 to 100 based on 17 genes in androgen signaling, stromal response, proliferation, and cellular organization. A recent study by Kornberg and colleagues found a 27% increased risk of biopsy upgrade for men in a large active surveillance cohort for every 5-unit increase in GPS score.4 Despite the clinical utility of these commercial tests, determining which patients benefit most, whether they are cost effective, and what the long-term outcomes are in using these tests remain questions that need clarification.
Research in genomic subtyping has revealed significantly more tumor heterogeneity in low-risk disease than was previously thought and may help with risk stratification soon. In a large active surveillance cohort, higher risk genomic features characterized 15% of patients initially defined as low risk based on Gleason group.5 In a study by Zhao and colleagues that utilized the PAM50 genetic classifier previously used in breast cancer, they found three reproducible subtypes: basal, luminal A, and luminal B.6 Although the luminal B cancers had the worst clinical prognosis, in their retrospective cohort they found the highest response to androgen deprivation therapy in that subtype. Genetic signatures such as this can add information to cancer grade, stage, and risk for men with low-risk and favorable intermediate-risk disease.
MRI of the prostate is another tool available to urologists to help improve biopsy accuracy and patient risk stratification. MRI is being widely studied as an additional biomarker in the prostate cancer decision-making spectrum. Reports are now interpreted using the PI-RADS™ Prostate Imaging–Reporting and Data System guidelines (version 2), and should be interpreted by experienced radiologists, preferably in the genitourinary system. Any MRI lesion interpreted as PI-RADS 3, 4, or 5 warrants a biopsy.
NYU Langone Health (New York, NY) has one of the largest cohorts of MRI fusion biopsy with more than 5000 biopsies to date. Previously published data in men with a prior negative biopsy revealed MRI targeting detects more high-grade biopsies (Gleason ≥7) than systematic biopsies while detecting similar amounts of Gleason Grade Group 1. This led the AUA, in collaboration with the Society of Abdominal Radiology, to issue a joint statement in 2016 recommending the use of a high-quality MRI in men undergoing repeat biopsy.
Overall outcomes in patients on active surveillance remain quite good, with cancer-specific survival upwards of 98% at 10 years. MRI provides an opportunity to improve upon this strong foundation by providing better risk stratification, prompting earlier treatment when warranted, and potentially avoiding repetitive biopsies without substantial for-cause indications. In men with increasingly suspicious PI-RADS scores, for example, 4 or 5, the likelihood of remaining on active surveillance plummets to 15% compared with men with PI-RADS 1 and 2 scores who remained on active surveillance more than 86% of the time. These data support the use of MRI in the active surveillance cohort to improve risk stratification and monitoring while also improving biopsy accuracy with MRI fusion. However, currently the data is not enough to support the use of MRI in active surveillance monitoring without a prostate biopsy.
Finally, there have been three critical level I trials published in the past 20 years regarding the use of MRI and MRI-targeted biopsy in biopsynaive men. The PROMIS trial, published in 2017, first evaluated men with no previous biopsy with both an MRI- and a TRUS-guided biopsy against a transperineal biopsy reference standard.7 The authors found more missed clinically significant cancers with TRUS-guided biopsy compared with the MRI arm, while possibly allowing 27% of patients to avoid primary biopsy with the use of MRI. The PRECISION trial by Kasivisvanathan and colleagues randomized similar biopsy-naive men to MRI and subsequent MRI-targeted biopsy alone if a suspicious PI-RADS score of 3 to 5 was present, or standard TRUS biopsy.8 This study also avoided biopsy in 28% of men with PI-RADS 1 and 2 lesions, and found more clinically significant prostate cancer in the MRI-targeted arm with less low-risk Gleason 3+3 cancer compared with the TRUS-guided biopsy group. As PI-RADS score increased, the rate of clinically significant cancer detection also meaningfully increased. The final major trial from France assessed the cancer detection rate of TRUS-guided biopsy and cognitive targeting compared with MRI targeting in a group of men who underwent pre-biopsy MRI.9 Results from this trial, MRI-FIRST, showed improved clinically significant cancer detection rate by 7.6% with combination of MRI targeting and TRUS-guided biopsy. As a result, pre-biopsy MRI has been widely accepted in Europe as a risk stratification tool for men with elevated PSA in need of a prostate biopsy.10
In 2019, optimal management of prostate cancer ranges from radical prostatectomy and radiation therapy to targeted focal therapy and active surveillance. Focal ablation is the utilization of physical energy to destroy prostate cancer cells. In the United States, ablative therapy includes high-intensity focused ultrasound (HIFU) ablation, cryotherapy, use of interstitial lasers, irreversible electroporation, and brachytherapy—all of which is overwhelmingly conducted on an outpatient basis. This decreases cost but can also potentially reduce injury to peri-prostatic structures while inducing an anti-tumor response.
Confidence in focal ablation relies on the belief that prostate cancer aggressiveness is defined by an index tumor. This index tumor is best characterized by a high-quality MRI. After identifying a preferably unilateral lesion on imaging, additional selection criteria for focal therapy include Gleason <8 disease concordant with MRI lesion, no pattern 4 in contralateral systematic biopsy, no gross extracapsular extension, and no apical lesions. Like other treatments, formulating a focal ablation treatment plan relies on shared decision making and weighing quality of life and overall outcome goals in the context of how long the patient is expected to live.
Planning the treatment ablation zone depends on the risk of disease and is a balance between treatment-related side effects and oncologic control. Failure of treatment is defined by any focus of pattern 4 disease in the ablation zone. However, Gleason 6 from targeted biopsies in the treatment zone does not necessarily translate to failure, as this result may not have led to treatment in the first place. Current protocol at NYU is mandatory biopsy at 2 years and a for-cause MRI or biopsy prior if a rising PSA warrants further investigation.
Although the data for focal ablation continues to mature, it is important to discuss with patients that although lesions can be successfully ablated, clinically significant recurrence over the patient’s lifetime is still uncertain. Disclosing limitations of focal therapy to patients and its investigational nature, particularly for men in Gleason Grade Group 2, is paramount. However, clinicians can be confident that if closely followed, patients who show evidence of persistent or recurrent disease can be safely treated with standard definitive therapies after focal therapy.
The landscape for detecting recurrent or metastatic prostate cancer has evolved over the past 40 years with radiographic innovations enabling earlier detection of advanced disease. Conventional imaging techniques such as bone scans, MRI, and CT are widely available, but have inherent drawbacks such negative results in low PSA ranges and poor sensitivities for prostate-bed recurrence and lymph node staging.11 Meanwhile, a new wave of positron emission tomography (PET) imaging modalities have emerged as promising tools in the diagnosis of progressive advanced disease.
Prostate-specific membrane antigen (PSMA) PET uses a radiotracer to directly bind to prostate cancer cells, allowing detection even at low PSA levels. In one biochemical recurrence cohort, PSMA-PET showed a 65% detection rate at PSA levels of 0.2 to 0.5 and increased to 100% when PSA rose to more than 2 ng/mL.12 Furthermore, it has shown more than double the detection rate as fluciclovine F18, or AXUMIN PET, in prostatectomy patients with hormone-naive biochemical recurrence and PSA values below 2.
The Radiographic Assessments for Detection of Advanced Recurrence Group, or RADAR, published RADAR III in April 2019,13 its third iteration of recommendations on the use of new imaging modalities for prostate cancer staging. They suggest considering next generation imaging such as PSMA or AXUMIN PET if there is suspicion for metastatic disease in newly diagnosed intermediate- or high-risk patients for whom conventional imaging such as bone scan and CT are negative. Initial RADAR I guidance recommended bone scan when PSA recurred after treatment to levels between 5 and 10 ng/mL. RADAR III now suggests clinicians consider newer imaging modalities for biochemical recurrence of ≥0.5 ng/mL due to the great sensitivity at lower PSA thresholds. Finally, in nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients for whom metastatic therapies are being deliberated, newly approved imaging techniques should be considered when the PSA doubling time is less than 6 months. Questions remain regarding the value of these new imaging tests and the data clinicians are using to support their decision making. However, it appears likely that these new diagnostic technologies will soon transition more care to the non-metastatic stage given the ability to detect earlier micrometastatic disease.
All cancers have genetic origins, whether from spontaneous somatic mutations or from hereditary germ-line mutations that occur initially in eggs and sperm. Hereditary cancer syndromes tend to affect multiple generations and taking a thorough and accurate malignancy history to help identify patients is crucial. The NCCN recommends testing if there is a first-degree relative with prostate cancer diagnosed before the age of 60 years; more than one relative with breast, ovarian, or pancreatic cancer; or more than one relative with Lynch syndrome genotype mutation. Once identified, this information can help promote earlier screening for other cancers and may alter treatment options and strategies.
Identifying patients genetically susceptible for hereditary prostate cancer lies on a spectrum from urologists identifying at risk patients to cancer geneticists offering testing counseling.14 Informed patient consent prior to testing is important because of the significant psychological effects that may result from such a diagnosis. Discussion of GINA, or the Genetic Information Nondiscrimination Act, is also important to reassure patients that by law their genetic information is protected and cannot be used against them in employment or health insurance decision making.
Many prostate cancer–specific panels are now available to help screen. These include tests from GeneDx (Gaithersburg, MD), Invitae Corporation (San Francisco, CA), and Ambry Genetics Corporation (Aliso Viejo, CA). All three test for HOXB13, a developmental gene whose expression levels has been associated with more aggressive disease, as well as BRCA1/2 mutations that result in a 3.33 times excess risk for prostate cancer,15 often in younger men.16 If these panels yield positive results then alternative or earlier testing strategies for prostate cancer should be considered.
Immunotherapy as an option for advanced prostate cancer came in 2010 when sipuleucel-T was first approved. Recombinant prostatic acid phosphatase antigen is processed initially by leukapheresis with the patient’s own blood, and then infused back into the patient a few days later to activate T cells within the body to proliferate and attack prostate cancer cells. The phase III IMPACT trial found a clinically significant 4.1-month survival benefit in minimally symptomatic men with metastatic castrate-resistant prostate cancer (mCRPC) treated with three infusions of sipuleucel-T over a 6-week period.17 This survival benefit is accentuated at lower PSA thresholds, suggesting a greater benefit to earlier treatment.18
Like other cancers in urology, clinical trials of immunotherapy to treat advanced prostate cancer have the potential to provide new treatment options. Ipilimumab, a monoclonal antibody that targets cytotoxic T-lymphocyte–associated protein, just missed statistical significance (P = 0.053) in mCRPC patients who had progressed after docetaxel despite promising phase I/II data.19 Pembrolizumab, a PD-1 inhibitor, has been studied in patients who progressed after both docetaxel and enzalutamide with initial results suggesting some response with acceptable safety.20 Many other trials are underway testing combination therapy in the mCRPC population.
Prostate cancer is a hormonally driven disease with androgen production by prostate cancer cells coinciding with high androgen receptor expression, particularly in castrate-resistant tissue samples.21 Abiraterone, the first novel androgen receptor blocker approved in 2011, was expanded for use in chemotherapy-naive mCRPC after Ryan and colleagues showed longer progression-free survival (16.5 mo vs 8.3 mo; P < 0.001) and overall survival (34.7 mo vs 30.3 mo; P = 0.0033) in men treated the abiraterone and prednisone compared with prednisone alone.22 The PREVIAL trial showed similar improvements with enzalutamide, an irreversible androgen receptor antagonist.23
There is no head-to-head data to guide clinicians in choosing between abiraterone and enzalutamide. However, clinicians should consider toxicity implications with abiraterone causing more hepatic dysfunction and hyperglycemia, whereas enzalutamide can cause more fatigue and potentially more seizures in older men. Although there is no consensus, some experts suggest using abiraterone prior to enzalutamide due to higher response rates with that sequencing and the increased availability of clinical trials that exist with enzalutamide, allowing for potential downstream treatment options. Recent data do not suggest that the combination of the two drugs improves survival.24 Apalutamide and darolutamide are two new drugs that recent trials show promising progression-free survival benefit in nmCRPC men when used early, with overall survival data still maturing.25,26
There also has been a shift toward using these new androgen blockers in men with metastatic hormonesensitive prostate cancer (mHSPC). Data from the past 2 years indicates that abiraterone offers a survival regardless of volume of disease. Similarly, enzalutamide decreases radiographic progression and improves overall survival by 33% when used in conjunction with standard testosterone suppression.27 The landscape for treating M0 and M1 patients based on hormone status will continue to evolve and undoubtedly change how we treat advanced prostate cancer in the near future.
Docetaxal, a taxane chemotherapy that inhibits mitosis through microtubule stabilization, was the first drug to improve overall survival in mCRPC patients after SWOG 99-16 and TAX-327, published in 2004, showed a ~2 month survival benefit.28,29 More recently, Sweeney and colleagues showed that combining docetaxel with androgen deprivation therapy (ADT) in metastatic hormone-naive patients improved overall survival by 17 months in men with high volume disease compared with ADT alone.30 Cabazitaxel, a similar chemotherapy, has very similar response rates and is recommended after progression on docetaxel. Toxicity is less in cabazitaxel, however, trial design limitations do not allow us say cabazitaxel is superior.31
Lastly, radium Ra 223 dichloride is an alpha particle that is highly localized to tumor cells and induces double-strand DNA breaks.32 Approved for use in mCRPC patients with symptomatic bone metastases, there are stringent eligibility and authorization requirements that may make this therapy less accessible despite its benefit. Other honing theranostics are likely on the horizon as imagingbased detection for metastatic disease continues to evolve.