Learning Objectives

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

• Cite important new publications in this field during the past year.
• Identify the relative strengths and weaknesses of the reports.
• Appraise how new studies relate to the existing state-of-the-art in clinical practice.
• Analyze whether they and their colleagues should consider changing their practice based on the new information.

Several important new publications addressed major prostate cancer (PC) topics in 2020–2021.

Screening

Up to age 76, prostate specific antigen (PSA) screening was associated with a lower all-cause mortality rate, except for men with cognitive dysfunction.¹

Genetics/Genomics

Categories of genetic-based biomarkers include common germline single-nucleotide polymorphisms, rare germline genetic mutations (eg BRCA1/2, HOXB13), and somatic (tumor) gene expression panels (eg Oncotype Dx®, Decipher®). For PC risk assessment, a polygenic risk score incorporating 269 PC risk single-nucleotide polymorphisms is more accurate for assessing risk for PC than is the family history, which is recommended by National Comprehensive Cancer Network® guidelines.^2,3 Most of the single-nucleotide polymorphisms work across races, and 50% of aggressive tumors occur in men in the top 20th percentile of the polygenic risk score.² A study reported that polygenic risk score is associated with conversion from active surveillance (AS) to treatment.⁴ Rare highly penetrant germline variants (eg BRCA2, ATM) also are associated with risk, and together the common and rare variants lead to more precise estimates of the lifetime risk of PC.^2,3,5 Plasma cell-free DNA may become important for managing patients with advanced PC, as it is prognostic for overall survival, selecting therapy, and response to therapy.⁶ It may be more helpful than repeated biopsies.

Health Disparities

Outside the equal-access Veterans Administration (VA) system, Black men were more likely to present with metastatic disease and had correspondingly higher PC mortality rates, but these differences were not observed in the VA system.⁷ However, VA studies of men who were potential candidates for AS reported that Black patients were more likely to have intermediate risk disease, less likely to receive conservative management, and more likely to receive definitive therapy within 5 years.⁸ Most of the racial disparities appear to be due to sociodemographic factors.⁷ Among those managed with AS, Black men were reported to have more frequent disease reclassification and/or progression and definitive treatment but not more metastasis or higher PC-specific mortality.⁹ A multi-institutional AS study outside the VA system found no association of race with conversion to treatment.¹⁰ Thus, AS appears comparably safe for Black and White men.¹¹ PSA velocity was reported to be associated with Gleason grade progression and metastases, but the thresholds were lower for Black men.¹²

Biopsy

Transperineal prostate biopsy is being increasingly adopted (in a third of urologists recently polled) to reduce the risk of sepsis (even without antibiotics) and, with fusion guidance, to provide an improved sampling of the apical and anterior regions of the prostate.¹³ The challenges of transperineal biopsy are patient comfort, the need for a template, increased time, overhead and difficulties with insurance coverage. Transperineal biopsy involves a substantial learning curve for where and how to achieve local anesthesia, which takes practice and experience. Currently, about half are performed under intravenous sedation.

Lymph Node Metastases

Several studies failed to find clear benefits from extended pelvic lymph node dissection, while others demonstrated a benefit associated with radiotherapy to involved pelvic nodes (see Radiotherapy section below).^14-16 With the emergence of prostate-specific membrane antigen (PSMA)-positron emission tomography (PET) imaging, the management of nodal metastases may become an increasingly important issue.

Imaging

Magnetic Resonance Imaging (MRI): MRI increases the accuracy of diagnosing PC but does not identify which men need treatment, and serial prostate MRI alone in patients on AS is not sufficiently accurate to reliably rule out or rule in tumor reclassification or progression.¹⁷ Biparametric MRI protocols are quicker, less expensive and more accurate than those using ultrasound plus PSA alone.¹⁸ A study of men who never had a biopsy compared standard systematic ultrasound versus MRI-targeted biopsy taking only 2–3 cores from the MRI region of concern and found that the targeted biopsy alone was noninferior to systematic biopsies.¹⁹ Over a third of MRI patients avoided a biopsy, and there were 50% fewer low-grade diagnoses. Other studies have shown that adding systematic biopsies is of value and should remain part of the process. It is not unusual to find significant cancers in the systematic cores even in areas that have a normal MRI appearance. MRI is not sufficiently accurate to substitute for surveillance biopsies but is helpful overall.^20,21 Patients with high Prostate Imaging–Reporting and Data System (PI-RADS™) lesions and negative initial biopsies should have repeat MRI scans, and if the high PI-RADS abnormalities persist undergo a repeat biopsy (including peri-lesion biopsies), as nearly two-thirds of these may reveal cancer.^22,23 Positive target biopsies should be counted as being only 1 positive core (ie the most extensively involved core).

PSMA PET: The PSMA PET scans (gallium and fluorine) may have a large impact on patient management because of their high sensitivity and specificity.^24–28 One study reported that half of the patients with positive PSMA PET scans had a serum PSA <0.2 ng/uL.²⁶ The most accurate platform would include the PSMA PET with MRI (rather than computerized tomography) that increases the sensitivity for high-risk tumors.²⁸

Radiation Therapy

In the FLAME trial, men receiving higher doses to MRI-defined tumor nodules had a twofold reduction in biochemical failure and no additional toxicity.²⁹ In the POP-RT study, the treatment of pelvic lymph nodes improved biochemical control and distant-metastasis-free survival at the cost of a mild increase in late genitourinary toxicity.³⁰ In the PROSINT trial, men receiving treatment in a single fraction or 5 fractions had similar biochemical outcomes and toxicity.³¹ In the postoperative setting, 3 randomized studies evaluated the role of adjuvant radiation in men with high-risk disease after prostatectomy.^32–34 The largest of these (RADICALS), as well as a meta-analysis, showed that early salvage therapy when needed did not compromise outcomes and spared a significant proportion of men from unnecessary treatment.^32,35 The SAKK 09/10 study demonstrated that dose escalation from 64 to 70 Gy did not improve biochemical outcomes and added toxicity.³³ The EMPIRE-1 study suggested that using fluciclovine PET improved biochemical outcomes compared to conventional imaging when used to select men and to plan postoperative radiation.³⁴ In the setting of oligo-recurrence in regional lymph nodes, the GETUG07 study demonstrated ∼50% biochemical control at 3 years’ followup with pelvic radiation and 6 months of hormonal therapy (ADT).³⁶ In the setting of metastatic disease, a secondary analysis of the STAMPEDE trial suggested that survival is improved after prostate radiation, particularly in men with lymph node only or 3 or fewer bony metastases.³⁷

Advanced Disease

Men with locally advanced disease account for ∼15% of patients with newly diagnosed PC and have a relatively poor cancer-specific mortality. In a prospective neo-adjuvant trial for patients with high-risk disease given either 6 months of ADT with apalutamide + abiraterone/prednisone + leuprolide vs abiraterone/prednisone + leuprolide, adding the third agent didn’t make a difference, but there was a remarkable 20% complete response or minimal residual disease rate.³⁸ A meta-analysis of neo-adjuvant trials found that 60% of patients were without biochemical recurrence after 3 years.³⁹ In patients who achieve a complete response/minimal residual disease, there is a large difference in the recurrence rate (8% vs 50%). Thus, in the neoadjuvant setting a robust response to ADT is a good indicator of outcomes. Oral relugolix is a luteinizing hormone-releasing hormone antagonist.⁴⁰ A trial of relugolix vs leuprolide showed that relugolix achieved superior testosterone suppression and it occurred faster, whereas the cardiovascular side effects were lower. A meta-analysis also showed that cardiovascular events are more frequent with the luteinizing hormone-releasing hormone agonists than with the antagonists.⁴¹ The high cost of relugolix limits its adoption. Enzalutamide is superior to bicalutamide in Black patients, but bicalutamide can be safely used to prevent testosterone flare-ups in Black patients.⁴² For castrate-sensitive PC, abiraterone and apalutamide have the best results for survival, and these agents do not seem to cause a cognitive decline.⁴³ Zoledronic acid and denosumab are approved for preventing or delaying skeletal-related events.⁴⁴ Zoledronic acid may compromise renal function, whereas, denosumab may cause hypocalcemia. Osteonecrosis of the jaw occurs at approximately the same rate with both agents. Denosumab is far more expensive. In patients with castrate-resistant disease, these agents improve overall survival in addition to reducing skeletal-related events and should be used in all patients with bone metastases who are castration-resistant.⁴⁵ In a study of olaparib (a PARP inhibitor used in patients with homologous DNA repair deficiency mutations such as BRCA1/2) vs abiraterone/enzalutamide (crossover), in which 30% of patients had some type of pathogenic mutation, there was a significant improvement in overall survival, especially in patients with BRCA mutations.⁴⁶ Another study reported that for patients with a mutation other than BRCA, cabazitaxel had an advantage.⁴⁷ A trial comparing lutetium-177-PSMA-617 (a radioligand therapy targeting PSMA) with standard care using ADT in patients who had PSMA highly expressed on their metastases, there was a highly significant survival advantage for the lutetium arm.²⁷ This radioligand treatment is not yet U.S. Food and Drug Administration-approved. Immunotherapy has been disappointing for PC. However, a study of nivolumab plus ipilimumab for metastatic castrate-resistant PC showed a 25% response rate in the pre-chemotherapy setting with a better response rate in patients whose tumors had a high mutational burden.⁴⁸ This regimen was quite toxic.