Salvage Therapy for Prostate Cancer: AUA/ASTRO/SUO Guideline Part III: Salvage Therapy After Radiotherapy or Focal Therapy, Pelvic Nodal Recurrence and Oligometastasis, and Future Directions.

PURPOSE: The summary presented herein covers recommendations on salvage therapy for recurrent prostate cancer intended to facilitate care decisions and aid clinicians in caring for patients who have experienced a recurrence following prior treatment with curative intent. This is Part III of a three-part series focusing on evaluation and management of suspected non-metastatic recurrence after radiotherapy (RT) and focal therapy, evaluation and management of regional recurrence, management for molecular imaging metastatic recurrence, and future directions. Please refer to Part I for discussion of treatment decision-making and Part II for discussion of treatment delivery for non-metastatic biochemical recurrence (BCR) after radical prostatectomy (RP). MATERIALS AND METHODS: The systematic review that informs this Guideline was based on searches in Ovid MEDLINE (1946 to July 21, 2022), Cochrane Central Register of Controlled Trials (through August 2022), and Cochrane Database of Systematic Reviews (through August 2022). Update searches were conducted on July 26, 2023. Searches were supplemented by reviewing electronic database reference lists of relevant articles. RESULTS: In a collaborative effort between AUA, ASTRO, and SUO, the Salvage Therapy for Prostate Cancer Guideline Panel developed evidence- and consensus-based guideline statements to provide guidance for the care of patients who experience BCR after initial definitive local therapy for clinically localized disease. CONCLUSIONS: Continuous and deliberate efforts for multidisciplinary care in prostate cancer will be required to optimize and improve the oncologic and functional outcomes of patients treated with salvage therapies in the future.

Salvage Therapy for Prostate Cancer: AUA/ASTRO/SUO Guideline Part I: Introduction and Treatment Decision-Making at the Time of Suspected Biochemical Recurrence after Radical Prostatectomy.

PURPOSE: The summary presented herein covers recommendations on salvage therapy for recurrent prostate cancer intended to facilitate care decisions and aid clinicians in caring for patients who have experienced a recurrence following prior treatment with curative intent. This is Part I of a three-part series focusing on treatment decision-making at the time of suspected biochemical recurrence (BCR) after radical prostatectomy (RP). Please refer to Part II for discussion of treatment delivery for non-metastatic BCR after RP and Part III for discussion of evaluation and management of recurrence after radiotherapy (RT) and focal therapy, regional recurrence, and oligometastasis. MATERIALS AND METHODS: The systematic review that informs this Guideline was based on searches in Ovid MEDLINE (1946 to July 21, 2022), Cochrane Central Register of Controlled Trials (through August 2022), and Cochrane Database of Systematic Reviews (through August 2022). Update searches were conducted on July 26, 2023. Searches were supplemented by reviewing electronic database reference lists of relevant articles. RESULTS: In a collaborative effort between AUA, ASTRO, and SUO, the Salvage Therapy for Prostate Cancer Panel developed evidence- and consensus-based statements to provide guidance for the care of patients who experience BCR after initial definitive local therapy for clinically localized disease. CONCLUSIONS: Advancing work in the area of diagnostic tools (particularly imaging), biomarkers, radiation delivery, and biological manipulation with the evolving armamentarium of therapeutic agents will undoubtedly present new opportunities for patients to experience long-term control of their cancer while minimizing toxicity.

Salvage Therapy for Prostate Cancer: AUA/ASTRO/SUO Guideline Part II: Treatment Delivery for Non-metastatic Biochemical Recurrence After Primary Radical Prostatectomy.

PURPOSE: The summary presented herein covers recommendations on salvage therapy for recurrent prostate cancer intended to facilitate care decisions and aid clinicians in caring for patients who have experienced a recurrence following prior treatment with curative intent. This is Part II of a three-part series focusing on treatment delivery for non-metastatic biochemical recurrence (BCR) after primary radical prostatectomy (RP). Please refer to Part I for discussion of treatment decision-making and Part III for discussion of evaluation and management of recurrence after radiotherapy (RT) and focal therapy, regional recurrence, and oligometastasis. MATERIALS AND METHODS: The systematic review that informs this Guideline was based on searches in Ovid MEDLINE (1946 to July 21, 2022), Cochrane Central Register of Controlled Trials (through August 2022), and Cochrane Database of Systematic Reviews (through August 2022). Update searches were conducted on July 26, 2023. Searches were supplemented by reviewing electronic database reference lists of relevant articles. RESULTS: In a collaborative effort between AUA, ASTRO, and SUO, the Salvage Therapy for Prostate Cancer Panel developed evidence- and consensus-based guideline statements to provide guidance for the care of patients who experience BCR after initial definitive local therapy for clinically localized disease. CONCLUSIONS: Optimizing and personalizing the approach to salvage therapy remains an ongoing area of work in the field of genitourinary oncology and represents an area of research and clinical care that requires well-coordinated, multi-disciplinary efforts.

Racial inequities in the quality of surgical care among Medicare beneficiaries with localized prostate cancer.

BACKGROUND: US Black men are twice as likely to die from prostate cancer as men of other races. Lower quality care may contribute to this higher death rate. METHODS: Sociodemographic and clinical data were obtained for men in Surveillance, Epidemiology, and End Results-Medicare diagnosed with clinically localized prostate cancer (cT1-4N0/xM0/x) and managed primarily by radical prostatectomy (2005-2015). Surgical volume was determined for facility and surgeon. Relationships between race, surgeon and/or facility volume, and characteristics of treating facility with survival (all-cause and cancer-specific) were assessed using multivariable Cox regression and competing risk analysis. RESULTS: Black men represented 6.7% (n = 2123) of 31,478 cohort. They were younger at diagnosis, had longer time from diagnosis to surgery, lower socioeconomic status, higher prostate-specific antigen (PSA), and higher comorbid status compared with men of other races (p < .001). They were less likely to receive care from a surgeon or facility in the top volume percentile (p < .001); less likely to receive surgical care at a National Cancer Institute-designated cancer center and more likely seen at a minority-serving hospital; and less likely to travel ≥50 miles for surgical care. On multivariable analysis stratified by surgical volume, Black men receiving care from a surgeon or facility with lower volumes demonstrated increased risk of prostate cancer mortality (hazard ratio, 1.61; 95% confidence interval, 1.01-2.69) adjusting for age, clinical stage, PSA, and comorbidity index. CONCLUSIONS: Black Medicare beneficiaries with prostate cancer more commonly receive care from surgeons and facilities with lower volumes, likely affecting surgical quality and outcomes. Access to high-quality prostate cancer care may reduce racial inequities in disease outcomes, even among insured men. PLAIN LANGUAGE SUMMARY: Black men are twice as likely to die of prostate cancer than other US men. Lower quality care may contribute to higher rates of prostate cancer death. We used surgical volume to evaluate the relationship between race and quality of care. Black Medicare beneficiaries with prostate cancer more commonly received care from surgeons and facilities with lower volumes, correlating with a higher risk of prostate cancer death and indicating scarce resources for care. Access to high-quality prostate cancer care eases disparities in disease outcomes. Patient-centered interventions that increase access to high-quality care for Black men with prostate cancer are needed.

DNA methylation and cis-regulation of gene expression by prostate cancer risk SNPs.

Genome-wide association studies have identified more than 100 SNPs that increase the risk of prostate cancer (PrCa). We identify and compare expression quantitative trait loci (eQTLs) and CpG methylation quantitative trait loci (meQTLs) among 147 established PrCa risk SNPs in primary prostate tumors (n = 355 from a Seattle-based study and n = 495 from The Cancer Genome Atlas, TCGA) and tumor-adjacent, histologically benign samples (n = 471 from a Mayo Clinic study). The role of DNA methylation in eQTL regulation of gene expression was investigated by data triangulation using several causal inference approaches, including a proposed adaptation of the Causal Inference Test (CIT) for causal direction. Comparing eQTLs between tumors and benign samples, we show that 98 of the 147 risk SNPs were identified as eQTLs in the tumor-adjacent benign samples, and almost all 34 eQTL identified in tumor sets were also eQTLs in the benign samples. Three lines of results support the causal role of DNA methylation. First, nearly 100 of the 147 risk SNPs were identified as meQTLs in one tumor set, and almost all eQTLs in tumors were meQTLs. Second, the loss of eQTLs in tumors relative to benign samples was associated with altered DNA methylation. Third, among risk SNPs identified as both eQTLs and meQTLs, mediation analyses suggest that over two-thirds have evidence of a causal role for DNA methylation, mostly mediating genetic influence on gene expression. In summary, we provide a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PrCa risk SNPs. We observe that a substantial portion of germline eQTL regulatory mechanisms are maintained in the tumor development, despite somatic alterations in tumor genome. Finally, our mediation analyses illuminate the likely intermediary role of CpG methylation in eQTL regulation of gene expression.

A Patient-Centered Approach to Research Prioritization in Prostate Cancer.

PURPOSE: Research priorities are often set by expert clinicians and researchers. We sought to apply an established process in patient-centered research to engage survivors and their caregivers in prioritizing research topics in prostate cancer. MATERIALS AND METHODS: A prostate cancer patient survey network, formed in partnership with Us TOO and the National Alliance of State Prostate Cancer Coalitions, engaged in a series of mixed-methods studies to prioritize comparative effectiveness research questions. This was accomplished through an iterative process that included 2 survey rounds and multidisciplinary working groups. RESULTS: There were 591 and 706 survey respondents in the first and second rounds, respectively, with most having had localized prostate cancer (58.1%). Survey participants represented 45 states in the U.S. Five of the top 11 prioritized research questions related to treatment decision making and/or survivorship care. The following had the highest overall importance ratings: What is the comparative effectiveness of different 1) strategies to improve counseling regarding the side effects of prostate cancer treatment, 2) tools for decision making in localized prostate cancer and 3) sequences of treatments for metastatic prostate cancer? CONCLUSIONS: We present a unique, patient-centered list of prioritized research questions among prostate cancer patients and their caregivers. These research questions may inform funding decisions for organizations that support research, and should be considered as priorities for clinicians, researchers and institutions conducting prostate cancer research. Prostate cancer is a common disease that affects 1 in 9 men over their lifetime. Researchers usually identify questions to study without asking men with prostate cancer. We asked survivors of prostate cancer and their caregivers to help us. They identified research questions and topics that are important to them. Researchers can focus on this list of questions to help men with prostate cancer. Groups who pay for research studies can make these questions their priority.

Does Clinical Evidence of Heterogeneity Impact Treatment Selection? A Case Study of Abiraterone for Metastatic Prostate Cancer.

BACKGROUND: Two pivotal randomized controlled trials (RCTs) demonstrate that abiraterone acetate + prednisone (AAP) combined with androgen deprivation therapy (ADT) significantly extends the survival of men with metastatic hormone-sensitive prostate cancer (mHSPC) compared with ADT alone. Their subgroup analyses indicate that the survival benefit is significant for younger men but not older men. We aimed to assess whether publication of the RCTs was associated with differential real-world AAP utilization by age groups. METHODS: Using TriNetX electronic medical records data collected from 43 healthcare organizations across the United States, we performed a difference-in-differences event study among men with newly diagnosed mHSPC observed from June 2014 to June 2019. Eligible subjects were identified based on a comprehensive published algorithm. We analyzed the change in utilization rate of AAP before versus after publication of the RCTs among men aged <70 years versus ≥70 years, adjusting for demographic factors and clinical conditions. RESULTS: Our study included 6,888 men with newly diagnosed mHSPC with 12,738 observations, of whom 46% were aged <70 years. The prepublication trends of AAP utilization were similar between the age groups, whereas publication of the RCTs was associated with a 3.5% higher adjusted uptake rate of AAP among younger men (95% CI, 1.2%-5.8%) relative to older men. This estimate reflects an uptake rate nearly 3 times higher than would have been expected had younger men followed the same utilization trends as older men. The estimates remained consistent throughout the postpublication period. CONCLUSIONS: Our study suggests that publication of the RCTs was associated with faster uptake of AAP among younger versus older men with newly diagnosed mHSPC, despite the absence of clinical guidance for differential treatment selection. This finding highlights the importance of confirmatory studies among older men, considering the uncertainties of subgroup analyses in RCTs.

Oncologic outcomes among Black and White men with grade group 4 or 5 (Gleason score 8-10) prostate cancer treated primarily by radical prostatectomy.

BACKGROUND: The aim of this study was to describe pathologic and short-term oncologic outcomes among Black and White men with grade group 4 or 5 prostate cancer managed primarily by radical prostatectomy. METHODS: This was a multi-institutional, observational study (2005-2015) evaluating radical prostatectomy outcomes by self-identified race. Descriptive analysis was performed via nonparametric statistical testing to compare baseline clinicopathologic data. Univariable and multivariable time-to-event analyses were performed to assess biochemical recurrence (BCR), metastasis, cancer-specific mortality (CSM), and overall survival between Black and White men. RESULTS: In total, 1662 men were identified with grade group 4 or 5 prostate cancer initially managed by radical prostatectomy. Black men represented 11.3% of the cohort (n = 188). Black men were younger, demonstrated a longer time from diagnosis to surgery, and were at a lower clinical stage (all P < .05). Black men had lower rates of pT3/4 disease (49.5% vs 63.5%; P < .05) but higher rates of positive surgical margins (31.6% vs 26.5%; P = .14) on pathologic evaluation. There was no difference in BCR, CSM, or overall survival over a median follow-up of 40.7 months. Black men had a lower 5-year cumulative incidence of metastasis-free survival (93.6%; 95% confidence interval [CI], 86.5%-97.0%) in comparison with White men (85.8%; 95% CI, 83.1%-88.0%), which did not persist in an age-adjusted analysis. CONCLUSIONS: Black and White men with high-grade prostate cancer at diagnosis demonstrated similar oncologic outcomes when they were managed by primary radical prostatectomy. Our findings suggest that racial disparities in prostate cancer mortality are not related to differences in the efficacy of extirpative therapy.

Downgrading from Biopsy Grade Group 4 Prostate Cancer in Patients Undergoing Radical Prostatectomy for High or Very High Risk Prostate Cancer.

PURPOSE: We examined rates of Grade Group 4 downgrading at radical prostatectomy among men diagnosed with high and very high risk prostate cancer at biopsy. MATERIALS AND METHODS: A pooled cohort of 1,776 patients from 3 tertiary referral centers who underwent radical prostatectomy for National Comprehensive Cancer Network® high risk (prostate specific antigen greater than 20 ng/ml, or Grade Group 4-5, or clinical stage T3 or greater) or very high risk (primary Gleason pattern 5, or more than 4 biopsy cores with Grade Group 4-5, or 2 or more high risk features) disease from 2005 to 2015 were reviewed. Overall 893 patients with Grade Group 4 disease at biopsy were identified and 726 patients were available for analysis. Multivariable logistic regression models were fit to determine factors associated with downgrading to Grade Group 3 or less at radical prostatectomy. RESULTS: Overall 333 (45%) cases were downgraded to Grade Group 3 or less at radical prostatectomy. Of these cases 198 (27%) had concordant Grade Group 4 biopsy and radical prostatectomy pathology and 195 (27%) were upgraded at radical prostatectomy to Grade Group 5. Of high risk cases with biopsy Grade Group 4 disease 49% had any downgrading vs 29% of very high risk cases (p <0.0001). Downgrading to Grade Group 2 or less occurred in 16% (98 of 604) of high risk and 7% (8 of 122) of very high risk cases (p <0.01). Downgraded cases had a lower prostate specific antigen, fewer positive biopsy cores and lower clinical stage (p <0.01). On multivariable analysis fewer positive biopsy cores were significantly associated with downgrading at radical prostatectomy (p <0.01). CONCLUSIONS: In this cohort of patients with high risk/very high risk prostate cancer, downgrading from biopsy Grade Group 4 at radical prostatectomy occurred less frequently than in other published reports. Any downgrading was significantly less common in very high risk compared to high risk patients, and downgrading to Grade Group 2 or less occurred in a minority of cases in high risk and very high risk patients.

African American Race is Not Associated with Risk of Reclassification during Active Surveillance: Results from the Canary Prostate Cancer Active Surveillance Study.

PURPOSE: In a large, prospective, multi-institutional active surveillance cohort we evaluated whether African American men are at higher risk for reclassification. MATERIALS AND METHODS: The Canary PASS (Prostate Active Surveillance Study) is a protocol driven, active surveillance cohort with a prespecified prostate specific antigen and surveillance biopsy regimen. Men included in this study had Gleason Grade Group 1 or 2 disease at diagnosis and fewer than 5 years between diagnosis and enrollment, and had undergone 1 or more surveillance biopsies. The reclassification risk, defined as an increase in the Gleason score on subsequent biopsy, was compared between African American and Caucasian American men using Cox proportional hazards models. In the subset of men who underwent delayed prostatectomy the rate of adverse pathology findings, defined as pT3a or greater disease, or Gleason Grade Group 3 or greater, was compared in African American and Caucasian American men. RESULTS: Of the 1,315 men 89 (7%) were African American and 1,226 (93%) were Caucasian American. There was no difference in the treatment rate in African American and Caucasian American men. In multivariate models African American race was not associated with the risk of reclassification (HR 1.16, 95% CI 0.78-1.72). Of the 441 men who underwent prostatectomy after a period of active surveillance the rate of adverse pathology was similar in those who were African American and Caucasian American (46% vs 47%, p=0.99). CONCLUSIONS: Of men on active surveillance who followed a standardized protocol of regular prostate specific antigen testing and biopsy those who were African American were not at increased risk for pathological reclassification while on active surveillance, or for adverse pathology findings at prostatectomy. Active surveillance appears to be an appropriate management strategy for African American men with favorable risk prostate cancer.