Prostate Cancer-specific Mortality Research Articles

Abstract 781: DNA methylation patterns between aggressive and indolent prostate tumors from Puerto Rican men

Abstract Background: In 2020, approximately 191,930 new prostate cancer (PCa) cases and 33,330 deaths are estimated in the US only. Hispanic/Latinos (H/L) are the second largest racial/ethnic group in the US. A previous study reported that prostate cancer-specific mortality rate among Puerto Rican men with prostate cancer is higher than ones of non-Hispanic Whites and non-Hispanic Blacks. The aims of this study are to: (1) assess the methylation patterns between aggressive and indolent PCa, (2) to study the methylation status of DNA repair genes between these groups, and (3) to assess the ancestry proportions of the study participants. Variations in methylation patterns will be detected between study groups. Methods: Archived formalin fixed paraffin-embedded (FFPE) prostate tumors (n=24) were collected through the Puerto Rico Biobank. Tumor specimens were classified as aggressive (n=11) and indolent (n=13) cases based on the Gleason scores (6+7(3+4) vs. 7(4+3)+8+9). Tumor areas and adjacent normal tissue were annotated on the H&E slides by a pathologist and extracted by macro-dissection. The Illumina 850K DNA methylation platform was used to measure DNA methylation patterns. The raw data was processed using minfi and normalized. Amount of missing values, histogram of β-values, principal component analysis (PCA) was to assess quality and to detect outliers. Results: A PCA model clearly separated the normal samples from the tumor samples. One of the most significantly differently methylated genes was AOX1. Further comparisons using TCGA PRAD data base revealed the predictable negative correlation between the gene expression and the average β-values. Regarding the PCa aggressiveness, 23 probes were identified as potential candidates using a p<0.001 and a Δβ-value of 0.2 as cut-off. These probes where located in six hypermethylated genes; RREB1, FAM71F2, JMJD1C, COL5A3, RAE1, GABRQ, and eleven hypomethylated; COL9A2, FAM179A, SLC17A2, PDE10A, PLEKHS1, TNNI2, OR51A4, RNF169, SPNS2, ADAMTSL5, and CYP4F12. Of the 179 candidate DNA repair genes. We found two significant differentially methylated DNA repair genes: JMJD1C and RNF169 between groups. The results from the ancestry proportions for African, European, and Indigenous American were: 24.1%, 64.2%, and 9% respectively. Conclusion: The identification of DNA methylation patterns related to PCa in Puerto Rican (PR) H/L men along with specific patterns related to aggressiveness and DNA repair constitutes a pivotal effort on the understanding of PCa disparities in this population. This constitutes a unique effort to provide an overview regarding methylation and ancestry patterns in PR H/L men. Acknowledgements; supported by U54 CA163071 and U54 CA163068-07 Citation Format: Jong Y. Park, Gilberto Ruiz-Deya, Jarline Encarnacion, Juile Dutil, Liang Wang, Carmen Ortiz Sanchez, Ryan Putney, Anders Berglund, Youngchul Kim, Jaime Matta. DNA methylation patterns between aggressive and indolent prostate tumors from Puerto Rican men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 781.

Testosterone Therapy in Men with Biochemical Recurrence and Metastatic Prostate Cancer: Initial Observations

Introduction: Although prostate cancer (PCa) has long been considered an absolute contraindication for testosterone therapy (TTh), growing literature suggests TTh may be safely offered to men with localized PCa. We here present a single-center series of men treated with TTh for relief of symptoms, despite having more advanced disease, namely biochemical recurrence (BCR) or metastatic PCa (MET). Methods: We identified men treated with TTh with BCR, MET, or adjuvant androgen deprivation therapy (ADT). Consent included risks of rapid PCa progression and death. Laboratory and clinical results were analyzed. Results: Twenty-two men received TTh: 7 with BCR, 13 with MET, and 2 with adjuvant ADT. Median age was 70.5 years (range 58–94). Median TTh duration was 12 months (range 2–84) overall, including 20 months for BCR and 9.5 months for MET. Mean serum testosterone (T) increased from 210 to 1111 ng/dL. Median PSA (interquartile range) increased from 3.1 ng/mL (0.2–4.5) to 13.3 ng/mL (3.4–22) in the BCR group, 6.3 ng/mL (1.2–31) to 17.8 ng/mL (6.2–80.1) in the MET group, and <0.1 to 0.3 ng/mL in the ADT group. All patients reported symptom relief, especially improved vigor and well-being. Overall mortality was 13.6% and PCa-specific mortality was 4.5% during the period of TTh and 6 months after discontinuation. Seven of 10 with follow-up imaging within 12 months showed no progression. Five men have died: three during TTh and two succumbed at 2 years or longer after discontinuing TTh. One of the three deaths during TTh was PCa-specific. Three men developed significant bone pain at 7–41 months; two discontinued TTh and one continued, after focal radiation. There were no cases of rapid-onset complications, vertebral collapse, or pathological fracture. Conclusions: These initial observations indicate TTh was not associated with precipitous progression of PCa in men with BCR and MET, suggesting a possible role for TTh in selected men with advanced PCa whose desire for improved quality of life is paramount.

Predicting prostate cancer specific-mortality with artificial intelligence-based Gleason grading

BackgroundGleason grading of prostate cancer is an important prognostic factor, but suffers from poor reproducibility, particularly among non-subspecialist pathologists. Although artificial intelligence (A.I.) tools have demonstrated Gleason grading on-par with expert pathologists, it remains an open question whether and to what extent A.I. grading translates to better prognostication.MethodsIn this study, we developed a system to predict prostate cancer-specific mortality via A.I.-based Gleason grading and subsequently evaluated its ability to risk-stratify patients on an independent retrospective cohort of 2807 prostatectomy cases from a single European center with 5–25 years of follow-up (median: 13, interquartile range 9–17).ResultsHere, we show that the A.I.’s risk scores produced a C-index of 0.84 (95% CI 0.80–0.87) for prostate cancer-specific mortality. Upon discretizing these risk scores into risk groups analogous to pathologist Grade Groups (GG), the A.I. has a C-index of 0.82 (95% CI 0.78–0.85). On the subset of cases with a GG provided in the original pathology report (n = 1517), the A.I.’s C-indices are 0.87 and 0.85 for continuous and discrete grading, respectively, compared to 0.79 (95% CI 0.71–0.86) for GG obtained from the reports. These represent improvements of 0.08 (95% CI 0.01–0.15) and 0.07 (95% CI 0.00–0.14), respectively.ConclusionsOur results suggest that A.I.-based Gleason grading can lead to effective risk stratification, and warrants further evaluation for improving disease management.

Incidence and mortality trends of metastatic prostate cancer: Surveillance, Epidemiology, and End Results database analysis.

In the past decade, prostate cancer screening decreased, raising the concern of delays in diagnosis and leading to an increase in new cases of metastatic prostate cancer. This study evaluated whether these changes may have impacted trends in metastatic prostate cancer incidence and survival. Metastatic prostate cancer diagnoses from 2008-2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) 18 registries. Age-adjusted incidence rates per 100 000 were calculated by time periods and demographic variables. Two-year all-cause and prostate cancer-specific mortality were calculated for patients diagnosed from 2008-2014, and multivariable Cox proportional hazards models were used to evaluate the impact of demographic and clinical variables. Incidence rates of metastatic prostate cancer increased by 18% from 2008-2009 to 2014-2016 (incidence rate ratio [IRR]=1.18, 95% confidence interval [CI] 1.14-1.21). This trend was observed across multiple subgroups but was greatest in non-Hispanic Whites and patients living in counties 0-10% below poverty level. There was an overall decreased risk of all-cause and prostate cancer-specific mortality, but unmarried men and men living in counties >20% below poverty level showed statistically significant increased risk of prostate cancer-specific mortality. Non-Hispanic Whites and the wealthiest subgroups had the largest increase in incidence of metastatic prostate cancer since 2008. Despite trends of decreased risk of prostate cancer-specific mortality, we found certain populations experienced increases in mortality risk. Studies exploring the role of socioeconomic factors on screening and access to newer treatments are needed.

Decreased ATM Protein Expression Is Substantiated with PTEN Loss in Defining Aggressive Phenotype of Prostate Cancer Associated with Lethal Disease

BackgroundAtaxia Telangiectasia Mutated (ATM) serine/threonine protein kinase is a known tumor suppressor, involved in DNA damage repair. It has prognostic and predictive therapeutic implications and is associated with aggressive prostate cancer (PCa). ObjectiveTo investigate the prognostic value of ATM protein expression in PCa patients and assessed the combined value of ATM, ERG, and PTEN status. Design, setting, and participantsThis study consisted of 303 patients with incidental, locally advanced, and castrate-resistant PCa by transurethral resection of the prostate (TURP). Outcome measurements and statistical analysisTURP samples from 303 PCa patients were assessed by immunohistochemistry (IHC for ATM, ERG, and PTEN. Individual and combined marker status were correlated with International Society of Urological Pathology Gleason grade group, overall survival (OS), and PCa-specific mortality (PCSM). Results and limitationsDecreased ATM expression (negative/weak intensity) occurred in 164/303 (54.1%) patients, and was associated with shorter OS and higher PCSM (p = 0.015 and p = 0.001, respectively). Negative/weak ATM expression was significantly associated with PCSM with a hazard ratio of 2.09 (95% confidence interval 1.34–3.27, p = 0.001). Assessment of Combined ATM/PTEN expression showed improved prognostic power to predict OS and PCSM, independent of Gleason grade groups. ConclusionsDecreased ATM protein expression is associated with poor outcomes in advanced PCa patients. Patients with combined low ATM/PTEN negative expression are at the highest risk for reduced OS and PCSM. Assessing the combined status of ATM/PTEN by IHC in PCa patients may aid in risk stratification relative to OS and PCSM. Moreover, since ATM plays an integral role in DNA damage response pathways, future studies will enhance our understanding of how outcomes of patients with altered ATM and PTEN expression can be improved further with poly-ADP ribose polymerase inhibitors (PARPi), combinations of PARPi and androgen receptor–targeted therapies, as well as platinum-based chemotherapies. Patient summaryLower ATM intensity is associated with increased cancer-specific mortality in prostate cancer patients. Patients with lower ATM and PTEN negative expression showed decreased overall survival and increased cancer mortality compared with controls.

Prostate‐specific antigen levels of ≤4 and &gt;4 ng/mL and risk of prostate cancer‐specific mortality in men with biopsy Gleason score 9 to 10 prostate cancer

Defining workup beyond usual clinical practice that may improve treatment outcomes in men with a prostate-specific antigen (PSA) level of ≤4 ng/mL (vs >4 ng/mL) and Gleason score (GS) 9 to 10 prostate cancer (PC) remains to be determined. Between February 25, 1992, and February 25, 2016, 17,632 men with clinical T1-4 PC with a biopsy GS of 6 to 10 underwent radical prostatectomy at a single academic center. Multivariable Fine and Gray regressions were used to evaluate the risk of prostate cancer-specific mortality (PCSM) with an interaction model evaluating the prognostic significance of PSA ≤ 4 ng/mL versus PSA > 4 ng/mL among men with PC with a biopsy GS of 9 to 10 versus ≤8, with adjustments made for the time-dependent use of adjuvant and/or salvage radiation therapy and androgen deprivation therapy (ADT) in addition to known PC prognostic factors. There was a significant interaction in men with a biopsy GS of 9 to 10 versus ≤8 and a PSA level of ≤4 ng/mL versus >4 ng/mL (adjusted hazard ratio [AHR], 2.87; 95% confidence interval [CI], 1.02-8.08; P = .046). Specifically, among men with a biopsy GS of 9 to 10 and a PSA level of ≤4 ng/mL versus >4 ng/mL, there was a significantly higher rate of PCSM (AHR, 2.59; 95% CI, 1.19-5.67; P = .017); however, there was no significant difference in the risk of PCSM in men with a biopsy GS ≤ 8 and a PSA level of ≤4 ng/mL versus >4 ng/mL (AHR, 0.90; 95% CI, 0.46-1.78; P = .771). Moreover, the time-dependent use of postoperative ADT was also associated with an increased risk of PCSM (AHR, 10.76; 95% CI, 6.88-16.81; P < .0001). Some men with PSA ≤ 4 ng/mL and a biopsy GS of 9 to 10 may have pathologic or genetic variants that make them less amenable to a cure with current standards of care. Additional workup assessing for small cell, neuroendocrine, and genetic variants should be considered.

P0990 - Prostate cancer specific mortality in the ERSPC trial: What is the role of screening result and adherence

P0990 - Prostate cancer specific mortality in the ERSPC trial: What is the role of screening result and adherence

PCN140 Hospital Competition and Quality of Prostate Cancer Care

Hospital competition is important for addressing the variation in quality and cost. We examined the association of hospital competition with process of care (time to treatment, treatment type) and outcomes (mortality, emergency room (ER) use and cost) in Medicare fee-for-service beneficiaries with prostate cancer. This was a population-based cohort study of Surveillance, Epidemiological, and End Results (SEER)-Medicare data from 1995- 2016, linked with American Medical Association, and American Hospital Association data. Eligible patients were men aged ≥66 years with localized or advanced stage prostate cancer. Hirschman-Herfindahl index was computed for all serving hospitals based on number of competitors, i.e., number of hospitals situated within the hospital referral region. Outcomes were overall and prostate cancer-specific survival, ER visits, and cost. We used Cox proportional hazard models and competing risk models for assessing survival, Poisson models for count data, and GLM (log-link) models for cost data. Propensity score and instrumental variables were used to minimize potential biases. Of 434,264 patients, 85% were localized and 15% were advanced stage. Hospitals within high competition area were more likely to perform surgery, whereas those in low competition area used radiation therapy. Among localized disease patients, low hospital competition was associated with higher hazard of overall mortality (HR=1.08, 95% CI=1.07 - 1.10) and prostate cancer-specific mortality (HR=1.13, 95% CI=1.09 - 1.17), higher odds of ER visits (OR=1.13, 95% CI=1.11 - 1.15), and higher cost (OR=1.18, 95% CI=1.10 – 1.21). Similar results were observed for advanced stage patients. Higher scores on OI were associated with higher total medical costs per capita per year, and not associated with overall mortality. We observed that higher hospital competition is associated with improved quality of care and lower cost among patients with localized or advanced stage prostate cancer. Policy measures should be implemented to improve hospital competition.

Disparities in prostate cancer diagnosis, treatment, and survival among men with disabilities: Retrospective cohort study in South Korea

BackgroundDisparities in cancer care have not been well documented for individuals with disability. ObjectiveTo investigate potential disparities in the diagnosis, treatment, and survival of prostate cancer (PC) patients according to disability status. MethodsA retrospective cohort study using disability registration data linked to Korean National Health Insurance and national cancer registry data. Totals of 7924 prostate cancer cases among patients with disabilities (diagnosed between 2005 and 2013) and 34,188 PC patients without disability were included. ResultsWhile overall PC stage distribution at diagnosis was similar, unknown stage was more common in patients with severe disabilities compared to those without disabilities (18.1% vs. 16.2%, respectively). People with disabilities were less likely to undergo surgery (33.1% vs. 38.6%, respectively; adjusted odds ratio [aOR] 0.79, 95% confidence interval [CI] 0.74–0.84), and more likely to receive androgen deprivation therapy (ADT) (57.9% vs. 55%, respectively; aOR 1.10, 95% CI 1.04–1.16) compared to those without disabilities. This was more evident for people with severe brain/mental impairment (aORs 0.29 for surgery; 1.52 for ADT). Patients with disabilities had higher overall mortality (adjusted hazard ratio [aHR] 1.20; 95% CI, 1.15–1.25), but only slightly higher PC-specific mortality after adjustment for patient factors and treatment (aHR 1.11, 95% CI 1.04–1.18) than people without disability. ConclusionsPC patients with disabilities underwent less staging work-up and were more likely to receive ADT than surgical treatment. Overall mortality of PC patients with disabilities was greater than those of PC patients without disability, but PC-specific mortality was only slightly worse.

P1221 - Post radical prostatectomy radiation therapy with androgen deprivation therapy does not improve 10-Year overall and prostate cancer specific mortality compared to androgen deprivation therapy alone

P1221 - Post radical prostatectomy radiation therapy with androgen deprivation therapy does not improve 10-Year overall and prostate cancer specific mortality compared to androgen deprivation therapy alone

The role of testosterone replacement therapy and statin use, and their combination, in prostate cancer.

Previous studies have reported conflicting results in the associations of testosterone replacement therapy (TTh) and statins use with prostate cancer (PCa). However, the combination of these treatments with PCa stage and grade at diagnosis and prostate cancer-specific mortality (PCSM) and by race/ethnicity remains unclear. We identified non-Hispanic White (NHW, N = 58,576), non-Hispanic Black (NHB, n = 9,703) and Hispanic (n = 4,898) men diagnosed with PCa in SEER-Medicare data 2007-2011. Pre-diagnostic prescription of TTh and statins was ascertained for this analysis. Multivariable-adjusted logistic and Cox proportional hazards models were used to evaluate the association of TTh and statins use with PCa stage and grade and PCSM. 22.5% used statins alone, 1.2% used TTh alone, and 0.8% used both. TTh and statins were independently, inversely associated with PCa advanced stage and high grade. TTh plus statins was associated with 44% lower odds of advanced stage PCa (OR 0.56, 95% CI 0.35-0.91). As expected, similar inverse associations were present in NHWs as the overall cohort is mostly comprised NHW men. In Hispanic men, statin use with or without TTh was inversely associated with aggressive PCa. Pre-diagnostic use of TTh or statins, independent or in combination, was inversely associated with aggressive PCa, including in NHW and Hispanics men, but was not with PCSM. The findings for use of statins with aggressive PCa are consistent with cohort studies. Future prospective studies are needed to explore the independent inverse association of TTh and the combined inverse association of TTh plus statins on fatal PCa.

The prognostic value, sensitivity, and specificity of multiparametric magnetic resonance imaging before salvage radiotherapy for prostate cancer

AimTo determine the operational characteristics of pelvic magnetic resonance imaging (MRI) prior to salvage radiation therapy (SRT) for biochemically recurrent prostate cancer following radical prostatectomy. Methods and materialsWe reviewed the medical records of 386 patients who underwent MRI prior to SRT. We assessed associations of pre-SRT MRI findings with biochemical recurrence (BCR), distant metastasis (DM), prostate cancer-specific mortality (PCSM), and salvage androgen deprivation therapy (ADT) use following SRT. The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of MRI for detecting local recurrence were also calculated. ResultsPre-SRT MRI was positive for local recurrence in 216 patients (56%), indeterminate in 46 (12%), and negative in 124 (32%). On univariate analysis, BCR following SRT was significantly less likely for patients with positive (HR: 0.58, 95% CI: 0.42–0.8) or indeterminate (HR: 0.6: 0.36–1) MRI findings, compared to patients with negative imaging (p = 0.003). These associations remained significant on multivariate analysis (p < 0.05) and across pre-SRT PSA groups.For the entire cohort, the sensitivity of MRI for local recurrence was 61.0% (53.5–68.1%), specificity 60.0% (44.3–73.0%), PPV 86.1% (78.9–91.5%) and NPV 27.6% (19.0–37.5%). Sensitivity of MRI was better in men with higher pre-SRT PSA (80.0% for PSA > 1.0), and specificity was improved with lower pre-SRT PSA (73.9% for PSA 0.1–0.5). ConclusionsPositive or indeterminate MRI findings prior to SRT were associated with improved biochemical control following SRT, across PSA levels. The sensitivity and specificity of MRI for local recurrence were 61% and 58.7%, respectively.

Association of increased intensity of prostate-specific antigen screening in younger African American men with improved prostate cancer outcomes.

5004 Background: African-American (AA) men are substantially more likely to present with lethal prostate cancer (PCa) at younger ages than non-Hispanic White men. Despite this disparity, AA men are poorly represented in the prostate-specific antigen (PSA) screening studies on which evidence-based PCa screening guidelines are based. This limits proper PSA screening guidance for AA men, especially for those younger than 55. We examined associations of PSA screening intensity with disease severity at diagnosis and prostate cancer-specific mortality (PCSM) in AA men &lt; 55 years of age. Methods: The earliest recommended age to begin discussion of PSA screening is 40 years. We identified AA men aged 40-55 years, diagnosed with PCa from 2004 to 2017 within the Veterans Health Administration. PSA screening was identified using procedural codes. Screening intensity was defined as percentage of years screened within the pre-diagnostic observation period. This included up to 5 years prior to diagnosis. Multivariable logistic regression assessed the influence of PSA screening intensity on metastatic disease at diagnosis. Lead-time correction using published screening-dependent lead times was performed. PCSM was evaluated using Fine-Gray regression and non-cancer death as a competing event. Additional analysis was performed stratifying PSA screening into ‘High’ and ‘Low’ groups centered on the mean. Results: The cohort included 4,654 AA men at a mean age of 51.8 years with mean PSA screening rate of 53.2%. The pre-diagnostic observation period ranged from 1 to 5 years (median = 5 years). Median follow-up was 7 years. At diagnosis, there was a higher prevalence of Gleason sum ≥ 8 (Grade Group ≥ 4) and metastatic disease in the ‘Low’ group compared with the ‘High’ group ([Gleason sum ≥ 8 (Grade Group ≥ 4)]: 18.6% vs. 14.4%, p &lt; 0.01; Metastatic disease at diagnosis: 3.7% vs. 1.4%, p &lt; 0.01). Increased PSA screening intensity was associated with significantly reduced odds of metastatic disease at diagnosis (odds ratio: 0.61, 95% confidence interval (CI) = [0.47-0.81], p &lt; 0.01) and decreased risk of PCSM (sub-distribution hazard ratio: 0.75, 95% CI = [0.59-0.95], p = 0.02). Conclusions: In this large national cohort of AA men aged 40 to 55 years, PSA screening increased intensity was associated with decreased risk of lethal disease and metastases at time of diagnosis and decreased PCSM. These data support the hypothesis that PSA screening and early prostate cancer detection may improve outcomes in younger AA men.

Radiation and androgen deprivation therapy with or without docetaxel in the management of non-metastatic unfavorable-risk prostate cancer: A prospective randomized trial.

5011 Background: For men with unfavorable-risk non-metastatic (M0) prostate cancer (PC) the addition of docetaxel to radical prostatectomy (RP) or radiation therapy (RT) and androgen deprivation therapy (ADT) has been studied in 6 randomized controlled trials with negative or inconclusive results. Specifically, an overall survival (OS) benefit with a non-significant reduction in PC-specific mortality (PCSM) has been observed in two of the 6 studieswhere &gt; 80% of the patients had high-grade PC. A plausible hypothesis for the OS benefit and a non-significant reduction in PCSM is that docetaxel reduces PCSM in the small subset of men with low prostate-specific antigen (PSA)-producing, high-grade PC that may be resistant to conventional ADT while also reducing non-PCSM by reducing death from RT-induced cancers. Given that docetaxel even at low doses (i.e. 20 mg/m2) is a potent radiosensitizer,it is plausible that it can sterilize cells that survive RT-induced damage and later develop into RT-induced cancers. Therefore, while docetaxel is not recommended when managing men with unfavorable-risk prostate cancer given inconclusive results from prior randomized trials, unstudied benefits may exist. Methods: This multicenter international randomized phase 3 trial (National Clinical Trial # 00116142) assigned 350 men with T1c-4N0M0 unfavorable-risk PC to receive ADT+RT and Docetaxel (60 mg/m2 q3 weeks for 3 cycles before RT and 20 mg/m2 weekly during RT) versus ADT+RT (1:1 ratio). Collection of data at each follow-up visit on second cancer incidence and survival status was recorded. We evaluated the treatment effect of adding docetaxel to ADT+RT on the primary endpoint of OS and the incidence of RT-induced cancers and explored whether the treatment effect impacted OS differed differently within PSA subgroups ( &lt; 4, &gt; 20 versus 4-20 ng/mL) using the interaction test for heterogeneity adjusted for age and known PC prognostic factors. Results: After a median follow-up of 10.2 years, 89 men died (25.43%); of these 42 from PC (47.19%). While OS was not significantly increased on the docetaxel arm [restricted mean survival time over 10-years was 9.11 versus 8.82 years with a difference of 0.29 (95% CI: -0.19, 0.76) years (p = 0.22)], significantly fewer RT-induced cancers were observed [10-year estimates: 0.61% versus 4.90%: age-adjusted HR of 0.13: 95% CI: 0.02, 0.97; p = 0.046]. For men with a PSA &lt; 4 ng/mL versus 4-20 ng/mL the treatment effect of adding docetaxel to ADT+RT on OS differed significantly [Adjusted HR: 0.27, 1.51; pinteraction = 0.047] due to less PCSM on the docetaxel arm [0/13 (0.00%) versus 4/14 (28.57%)] among men with PSA &lt; 4 ng/mL. Conclusions: Adding docetaxel to ADT+RT did not prolong OS in men with unfavorable-risk PC, but decreased RT-induced cancer incidence, and may prolong OS in the subgroup of men with a PSA &lt; 4 ng/mL by reducing PCSM. Clinical trial information: NCT00116142.

Post radical prostatectomy prostate-specific antigen doubling-time kinetics: Observations of increasing versus decreasing doubling times.

e17002 Background: Biochemical recurrence (BCR) following radical prostatectomy (RP) is an unreliable predictor of distant metastatic progression or prostate cancer (PC) death, consequently resulting in overtreatment. Further, little has been published about active surveillance (AS) specific management recommendations. Herein, we validate the practicality of using the kinetics (change) of PSA doubling time (PSADT) to direct continued observation versus intervention. Methods: In a retrospective cohort analysis of 406 men with BCR (defined as adjuvant therapy or PSA &gt; 0.2 ng/dl, x2), 284 men were monitored post RP with PSADT graphs for all patients, and the PSADT was characterized as increasing vs decreasing. Receiver-operator characteristic (ROC) curves were generated to assess the sensitivity/specificity/positive predictive value/negative predictive value of PSADT progression on treatment and prostate cancer specific mortality at 10 years post-RARP, respectively. Results: The median follow-up was 7.6 (IQR: 4.6-10.6) years. Of 284 men, 109 (38%) and 175 (62%) were in the no treatment versus treatment groups, respectively. 87% of men receiving treatment had a decreasing PSADT and 100% men with PCSM had a decreasing PSADT. ROC analysis showed 0.870 sensitivity and 1.0 specificity when predicting secondary treatment (AUC = 0.935) and 0.857 sensitivity and 0.50 specificity when predicting PCSM (AUC = 0.679). Conclusions: A decreasing PSADT is a sensitive and specific metric for predicting the need for secondary intervention. We also found all men who died of PC had a decreasing PSADT. Lastly an increasing DT predicts a benign course without need for treatment. The current findings suggest that the kinetics of PSADT, increasing versus decreasing, is an accurate metric for the need of treatment. A direct comparison between PSADT kinetics and PSADT is needed.

Adjuvant Low-dose Statin Use after Radical Prostatectomy: The PRO-STAT Randomized Clinical Trial.

Statin use is reportedly associated with the risk of prostate cancer, outcomes after treatment, and prostate cancer-specific mortality. We sought to determine the efficacy of adjuvant atorvastatin in prostate cancer after radical prostatectomy. In this randomized, double-blind trial, we assigned patients with pathologic high-risk prostate cancer to receive either low-dose atorvastatin (20 mg/day, n = 183) or placebo (n = 181) for 1 year after radical prostatectomy. The primary endpoint was the 1-year biochemical recurrence rate. The secondary endpoints included the 5-year biochemical recurrence-free survival and changes in lipid, testosterone, and sex hormone binding globulin levels. From October 2012 through January 2019, a total of 364 patients underwent randomization. Among 59 total primary end points, 30 (16.4%) and 29 (16.0%) occurred in the atorvastatin and placebo groups, respectively. Atorvastatin did not significantly reduce the primary endpoint of 1-year biochemical recurrence [HR, 0.96; 95% confidence interval (CI), 0.58-1.60]. During a median follow-up of 24 months, 131 patients experienced biochemical recurrence (68 in the atorvastatin group and 63 in the placebo group), representing Kaplan-Meier estimated event rates of 24.0% and 25.4% in the atorvastatin and placebo groups, respectively, at 24 months (HR, 1.00; 95% CI, 0.71-1.41). We observed no significant between-group differences in the testosterone and sex hormone binding globulin levels. Among patients with high-risk pathologic features after radical prostatectomy for prostate cancer, 1-year adjuvant use of atorvastatin was not associated with a lower risk of disease recurrence compared with that for placebo. (ClinicalTrials.gov number, NCT01759836).See related commentary by Murtola and Siltari, p. 4947.

Integrating Prostate-specific Antigen Kinetics into Contemporary Predictive Nomograms of Salvage Radiotherapy After Radical Prostatectomy

BackgroundSalvage radiotherapy (SRT) is an established treatment for men with biochemical recurrence following radical prostatectomy (RP). There are several risk factors associated with adverse outcomes; however, the value of postoperative prostate-specific antigen (PSA) kinetics is less clear in the ultrasensitive PSA era. ObjectiveTo characterize the impact of PSA kinetics on outcomes following SRT and generate nomograms to aid in identifying patients with an increased risk of adverse clinical outcomes. Design, setting, and participantsA multi-institutional analysis was conducted of 1005 patients with prostate cancer treated with SRT after RP, with a median follow-up of 5 years. Outcome measurements and statistical analysisVariables examined include immediate postoperative PSA, postoperative PSA doubling time (DT), and pre-SRT PSA, in addition to previously identified predictive factors. Multivariable survival analyses were completed using Fine-Gray competing risk regression. Rates of biochemical failure (BF), distant metastasis (DM), and prostate cancer–specific mortality (PCSM) were estimated by the cumulative incidence method. Nomograms were generated from multivariable competing risk regression with bootstrap cross-validation. Results and limitationsFactors associated with BF after SRT include PSA DT <6 mo, initial postoperative PSA ≥0.2 ng/ml, higher pre-SRT PSA, lack of androgen deprivation therapy, a higher Gleason score (GS), negative margins, seminal vesicle invasion, lack of pelvic nodal radiation, radiation total dose <66 Gy, a longer RP to SRT interval, and older age (p < 0.05 for each). Factors associated with DM include PSA DT <6 mo, pre-SRT PSA, a higher GS, and negative margins. Factors associated with PCSM include PSA DT not calculable or <6 mo and a higher GS. Nomograms were generated to estimate the risks of BF (concordance index [CI] 0.74), DM (CI 0.77), and PCSM (CI 0.77). Limitations include retrospective nature, broad treatment eras, institutional variations, and multiple methods available for the estimation of PSA DT. ConclusionsPostoperative PSA kinetics, particularly pre-SRT PSA and PSA DT, are strongly associated with adverse oncologic outcomes following SRT and should be considered in management decisions. Patient summaryIn this report of men with prostate cancer who developed a prostate-specific antigen (PSA) recurrence after prostatectomy, we found that PSA levels after surgery and how quickly a PSA level doubles significantly impact the chance of prostate cancer recurrence after salvage radiation therapy. Based on this information, we created a tool to calculate a man’s chance of cancer recurrence after salvage radiation therapy, and these estimations can be used to discuss whether additional treatment with radiation should be considered.

Using Exercise and Nutrition to Alter Fat and Lean Mass in Men with Prostate Cancer Receiving Androgen Deprivation Therapy: A Narrative Review.

Fat mass (FM) gain and lean mass (LM) loss are common side effects for patients with prostate cancer receiving androgen deprivation therapy (ADT). Excess FM has been associated with an increased risk of developing obesity-related comorbidities, exacerbating prostate cancer progression, and all-cause and cancer-specific mortality. LM is the predominant contributor to resting metabolic rate, with any loss impacting long-term weight management as well as physical function. Therefore, reducing FM and preserving LM may improve patient-reported outcomes, risk of disease progression, and ameliorate comorbidity development. In ADT-treated patients, exercise and nutrition programs can lead to improvements in quality of life and physical function; however, effects on body composition have been variable. The aim of this review was to provide a descriptive overview and critical appraisal of exercise and nutrition-based interventions in prostate cancer patients on ADT and their effect on FM and LM. Our findings are that FM gain and LM loss are side effects of ADT that could be reduced, prevented, or even reversed with the implementation of a combined exercise and nutrition program. However, the most effective combination of specific exercise and nutrition prescriptions are yet to be determined, and thus should be a focus for future studies.

Patterns of Clinical Progression in Radiorecurrent High-risk Prostate Cancer

The natural history of radiorecurrent high-risk prostate cancer (HRPCa) is not well-described. To better understand its clinical course, we evaluated rates of distant metastases (DM) and prostate cancer-specific mortality (PCSM) in a cohort of 978 men with radiorecurrent HRPCa who previously received either external beam radiation therapy (EBRT, n = 654, 67%) or EBRT + brachytherapy (EBRT + BT, n = 324, 33%) across 15 institutions from 1997 to 2015. In men who did not die, median follow-up after treatment was 8.9 yr and median follow-up after biochemical recurrence (BCR) was 3.7 yr. Local and systemic therapy salvage, respectively, were delivered to 21 and 390 men after EBRT, and eight and 103 men after EBRT + BT. Overall, 435 men developed DM, and 248 were detected within 1 yr of BCR. Measured from time of recurrence, 5-yr DM rates were 50% and 34% after EBRT and EBRT + BT, respectively. Measured from BCR, 5-yr PCSM rates were 27% and 29%, respectively. Interval to BCR was independently associated with DM (p < 0.001) and PCSM (p < 0.001). These data suggest that radiorecurrent HRPCa has an aggressive natural history and that DM is clinically evident early after BCR. These findings underscore the importance of further investigations into upfront risk assessment and prompt systemic evaluation upon recurrence in HRPCa. Patient summaryHigh-risk prostate cancer that recurs after radiation therapy is an aggressive disease entity and spreads to other parts of the body (metastases). Some 60% of metastases occur within 1 yr. Approximately 30% of these patients die from their prostate cancer.

Active surveillance in prostate cancer management: where do we stand now?

Prostate cancer (PCa) is the most common cancer in men, with a steadily rising incidence, affecting on average one in six men during their lifetime. The increase in morbidity is related to the increasing overall life expectancy, prostate-specific antigen testing, implementation of new molecular markers for cancer detection and the more frequent application of multiparametric magnetic resonance imaging. There is growing evidence demonstrating that active surveillance (AS) is an alternative to immediate intervention in patients with very low- and low-risk prostate cancer. Ongoing reports from multiple studies have consistently demonstrated a very low rate of metastases and prostate cancer specific mortality in selected cohorts of patients. As a matter of fact, AS has been adopted by many institutions as a safe and effective management strategy. The aim of our review is to summarize the contemporary data on AS in patients affected with PCa with the intention to present the most clinically useful and pertinent AS protocols.