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Aims To perform a systematic evaluation of the applicability, validity and reliability of the long PCR- RFLP of 16 S- ITS-23 S r RNA genes for bacterial genotyping using both sequences retrieved from public genome databases and the experimental data obtained on bacterial cultures. Methods and Results 3301 Full-length sequences of 16 S- ITS-23 S r RNA genes were retrieved from 885 published bacterial genomes. Copy numbers of the whole set of 16 S- ITS-23 S r RNA genes per genome ranged from 1 ( n = 161) to 14 ( n = 4) with an average of 3·71. Their length varied greatly, from 4319 to 6568 bp with an average of 4952 bp. Computer-simulated RFLP analyses of the 16 S- ITS-23 S fragments flanked by the conserved primers 27 F and 2241 R suggested Msp I, Rsa I, Hha I and Taq I as the most appropriate enzymes for long PCR- RFLP analysis of the 16 S- ITS-23 S sequence. Msp I was used to screen over 900 bacterial cultures isolated from the Huguangyan Maar Lake in southern China. An experimental sequencing of 16 S r RNA genes of the isolates possessing a unique RFLP band pattern proved the broad applicability and high resolution of this approach. Conclusions These results indicate that long PCR- RFLP of 16 S- ITS-23 S r RNA genes is a potentially universal and reliable bacterial genotyping tool with a high resolution. Significance and Impact of the Study The methodology of long PCR- RFLP of 16 S- ITS-23 S r RNA genes will facilitate the exploration and tracing of cultivable microbial diversity in natural environments. [ABSTRACT FROM AUTHOR]

The FORMULA-509 trial randomized patients receiving salvage radiation between 6 months of GnRH agonist plus bicalutamide or 6 months of GnRH agonist plus AAP/Apa. Here we evaluate factors associated with testosterone recovery after trial treatment and the impact of testosterone recovery on patient-reported HRQoL. Testosterone was evaluated prior to treatment, at 3 months, at 6 months (end of systemic treatment), and at least every six months after treatment. Validated Expanded Prostate Cancer Index Composite (EPIC)-26 questionnaire was administered at baseline, end of treatment, and 1 year after completion of treatment. A change of 4 or more was considered a clinically meaningful change in the hormonal function domain. Log-rank test compared testosterone recovery between treatment groups. Wilcoxon rank sum and chi-square compared characteristics between those who did and did not recover testosterone. Multivariate logistic regression evaluated factors associated with lack of testosterone recovery. Chi-square evaluated frequency of clinically meaningful change in hormonal function. Three hundred forty-five patients were randomized (172 bicalutamide; 173 AAP/Apa). Median follow-up was 34 (6-53) months. There was no difference in testosterone recovery (>190 ng/dL) between treatment groups (p = 0.10). 52.6% [95% CI = 42.7-58.0] of patients recovered testosterone 6 months after treatment (bicalutamide: 51.2%; AAP/Apa 54.0%); 74.5% [69.8-79.2] 12 months (70.5%; 78.6%); 81.9% [77.7-86.1] 18 months (77.7%; 86.2%); and 88.8% [85.4-92.3] 30 months after treatment (85.8%; 91.9%). On univariate analysis, older age (median 67 vs 63 years; p<0.01), lower baseline testosterone (median 274 vs 379 ng/dL; p<0.01) and higher PSA at enrollment (median 0.3 vs 0.2; p = 0.02) were associated with lack of testosterone recovery 1 year after treatment. Race, Gleason score, and treatment arm were not associated with testosterone recovery. On multivariate analysis, age at enrollment, baseline testosterone, and PSA at enrollment remained significant (all p <0.05). In the subset of patients who completed EPIC-26 1 year after treatment (n = 219), those patients who did not have testosterone recovery were more likely to report a clinically meaningful decline in hormonal function relative to baseline than those who did achieve testosterone recovery, but it was not statistically significant (59% vs. 43% reporting clinically meaningful functional decline, p = 0.06). The addition of AAP/Apa did not lengthen time to testosterone recovery. Older men or those with lower baseline testosterone or higher PSA prior to treatment were less likely to recover testosterone 1 year after treatment. Patients who did not have testosterone recovery at 1 year were more likely to report decline in hormonal function. [ABSTRACT FROM AUTHOR]

Precision medicine (PM) has revolutionized oncology; however, tumor biomarkers are derived primarily from a homogenous population, not reflective of the diverse cancer population. NRG Oncology (NRG) has completed large practice changing clinical trials and encouraged biospecimen collection. We evaluated differences between patients who participated in NRG prostate cancer (PCa) trials versus those who also participated in biospecimen collection. Our hypothesis was that disparities exist in the NRG biobank collection that could further compound inequities in PM. NRG PCa trials closed before 2015 were analyzed for patients who consented to biospecimen collection. We used t-tests and chi-square tests for continuous and categorical variables, respectively. Spearman correlation coefficients were used to assess the association between zip code area deprivation index (ADI; assessed continuously and categorized by highest quartile vs lowest 3 quartiles) and median income for model testing. Logistic regression models were used to assess the effect of various demographic factors. Of 6721 randomized patients, 5485 (81.6%) consented to biospecimen collection. A smaller proportion of non-White patients consented to specimen collection as compared to those who did not consent (17.6% vs. 25.9%, respectively; p<0.0001). Furthermore, patients who resided in neighborhoods with a greater socioeconomic disadvantage, as indicated by a higher ADI, were also less likely to consent to specimen collection, when compared to those who had a lower ADI (45.7% vs. 41.5%, respectively; p = 0.0004), however, there was no difference in zip code median income between the two groups. In univariate logistic regression models, ADI (categorical and continuous) was associated with a decreased likelihood for specimen consent (OR = 0.85, OR = 0.99, respectively, p<0.05 for both). Hispanic/Latino (OR = 0.61, OR = 0.56) and non-White patients (OR = 0.59, OR = 0.57) were less likely to consent to biospecimen collection in models with ADI as a predictor (categorical and continuous, respectively, p<0.001 for all). Non-White patients were less likely to consent to specimen collection (OR = 0.54; p<0.0001) in the model with median income as a predictor, where median income was not significantly associated with likelihood of specimen consent. Although >80% of NRG PCa trial participants consented to biospecimen collection, patients who were non-White, Hispanic/Latino or who lived in zip codes with higher ADI were less likely to participate in specimen collection. Recognition and further understanding of these disparities can lead to targeted, sustainable improvements for biospecimen collection on NRG PCa clinical trials so that biorepositories and PM approaches can better reflect the trial participants and overall population. [ABSTRACT FROM AUTHOR]

Oligometastatic castration-sensitive prostate cancer (omCSPC) is a heterogeneous disease. Recently, a multimodal artificial intelligence (MMAI) algorithm (ArteraAI Prostate Test), which incorporates digital pathology and clinical information, has been shown to be prognostic in localized prostate cancer. Here, we evaluated the association between the MMAI score and vector features (VF) of the score with genomics in omCSPC. We correlated somatic pathogenic mutations and ArteraAI MMAI scores from 168 omCSPC patients (133 metachronous and 35 synchronous). RNAseq profiling was performed on a subset of 65 metachronous patients. Somatic nonsynonymous pathogenic mutations from panel DNAseq were identified using Mutect2 and ClinVAR database. Pair-end reads of RNAseq were aligned to Human reference (hg38) using HISAT2. To identify the differentially mutated genes associated with patients with high/low MMAI scores, samples are binned separately based on the median or quartile of the MMAI score, and Fisher's exact test is used to evaluate differentially mutated genes between bins. Differential expression of genes were evaluated using DEseq2 and gene set enrichment analysis. Uniform manifold approximation and projection (UMAP) was applied to 128 VFs from the MMAI score and correlated with mutations using Wilcoxon test. Median follow-up was 34.7 months. Patients with high MMAI scores (top quartile) had worse overall survival compared to those with low MMAI scores (bottom three quartiles, P = 0.017). MMAI scores were significantly higher in synchronous than those with metachronous omCSPC (p<0.05). DNAseq showed high MMAI score (top median or quartile) had a trend towards more WNT pathway (APC/CTNNB1) mutations or had significantly more BRCA2/ATM mutations than those with low MMAI scores (P = 0.13 and P = 0.008, respectively). Low MMAI (

The luminal B (LumB) breast cancer subtype is a prognostic and potentially predictive biomarker. LumB is inherently a cell subtype (as its name suggests) but has mostly been studied as a bulk tumor subtype, in large part because tumor profiling techniques have only recently begun to offer single-cell resolution. We sought to leverage single-cell proteomic data from two large cohorts with known long-term clinical outcomes to determine whether enrichment of the LumB cell subtype was associated with resistance to endocrine therapy in breast cancer. Imaging mass cytometry data from a training cohort (METABRIC) and separate validation cohort were obtained and integrated. Patients with non-metastatic breast cancer who received surgery and adjuvant hormone therapy were included. Cell subtypes were defined using the Phenograph cell-clustering approach. Per-sample "cell fraction" of a given cell subtype was defined as cell count of that subtype divided by total number of cancer cells in the sample. The optimal cutpoint for defining LumB cell enrichment in the training cohort was determined using the maximally selected rank statistic approach, and the same cutpoint was used in the validation cohort. Distant metastasis free survival (DMFS) was the clinical endpoint for all univariate and multivariable (cause-specific proportional hazards) survival analyses. Resistance to endocrine therapy was defined at time of data collection as disease progression within 58 months of initiating endocrine therapy. Single-cell expression data for 1,335,512 cells from 929 breast cancer tumor biopsies comprising two cohorts were aggregated and harmonized. Single-cell clustering analysis revealed 34 distinct breast, stromal, and immune cell subtypes. Ten breast cancer cell subtypes demonstrated a co-expression pattern of hormone receptor positivity (HR+) and either Ki-67+ or HER2+, most consistent with a LumB or "LumB-like" expression profile. 353 patients in the training cohort and 161 patients in the validation cohort received adjuvant endocrine therapy and had long-term clinical follow-up. In the training cohort, patients with LumB-enriched tumors demonstrated shorter 10-year DMFS than those with LumB non-enriched tumors (70% vs. 82%, P<0.05). On multivariable analysis, LumB cell enrichment was prognostic of 10-year DMFS (HR 1.73; 95% CI, 1.04 to 2.87) independently of other known prognostic factors including tumor grade, T-stage, and lymph node positivity status. In the validation cohort, LumB cell enrichment was associated with resistance to endocrine therapy (33% vs. 18%, chi-square P<0.05). Enrichment of LumB cells was associated with resistance to hormone therapy in two independent breast cancer cohorts. Our single-cell biomarker for LumB enrichment can be used to identify patients less likely to demonstrate durable response to hormone therapy and who may benefit from treatment intensification through other strategies. [ABSTRACT FROM AUTHOR]

Lutetium (177Lu) vipivotide tetraxetan ([177Lu]Lu-PSMA-617) plus protocol-permitted standard of care (SoC) significantly improved radiographic progression-free survival (rPFS) and overall survival (OS) in patients with previously treated, prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer (mCRPC). Androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs) may alter PSMA expression and radiosensitivity. PSMAddition will assess the efficacy and safety of [177Lu]Lu-PSMA-617 plus SoC vs SoC alone in metastatic hormone-sensitive prostate cancer (mHSPC). PSMAddition (NCT04720157) is an international, prospective, open-label, randomized, phase 3 trial in mHSPC. Eligible patients are treatment-naive or minimally treated candidates for hormonal therapy who have PSMA-positive disease (per [68Ga]Ga-PSMA-11 positron emission tomography/computed tomography), an Eastern Cooperative Oncology Group performance status of 0–2, and adequate major organ function. Patients with rapidly progressing tumors requiring chemotherapy are excluded. Eligible patients are randomized 1:1 to [177Lu]Lu-PSMA-617 (7.4 GBq Q6W; max 6 cycles) plus SoC or SoC alone (ARPI + ADT). Stratification factors are tumor volume (high/low), age (≥ 70/< 70 years), and previous/planned prostatectomy or radiation treatment of the primary prostate tumor (yes/no). The primary endpoint is rPFS, per Blinded Independent Review Committee. Upon centrally confirmed radiographic progression (rPD), patients receiving SoC alone can crossover to receive [177Lu]Lu-PSMA-617. The planned sample size (n = 1126) provides 95% power to detect a hazard ratio of 0.7 for rPFS after 418 events (overall one-sided significance level of 0.025). The key secondary endpoint is OS; other endpoints include the proportion of patients with a prostate-specific antigen (PSA) decline of ≥ 90% from baseline, time to development of mCRPC, composite progression-free survival (radiographic, clinical, or PSA progression), safety and tolerability, and health-related quality of life. Imaging and biospecimen (tissue and blood) collection is embedded for correlative analysis. A second [68Ga]Ga-PSMA-11 scan will be performed in both arms at time of rPD for imaging biomarkers. [177Lu]Lu-PSMA-617-treated patients can enroll in a separate long-term safety follow-up study. Enrollment is complete; 1144 patients have been randomized. TBD. TBD. [ABSTRACT FROM AUTHOR]

Oligometastatic castration-sensitive prostate cancer (omCSPC) is a state of limited metastatic disease. Several randomized trials have demonstrated improvements in progression-free survival in patients with omCSPC treated with metastasis-directed therapy (MDT). However, clinical outcomes remain heterogenous and response to MDT is variable, raising the need for prognostic and predictive biomarkers. A multimodal artificial intelligence (MMAI) biomarker (ArteraAI Prostate Test) that leverages digital pathology and clinical variables was recently trained using data from patients with localized prostate cancer and found to be prognostic. Here, we evaluated this biomarker in omCSPC. We performed an international multi-institution retrospective review of 221 men with omCSPC who were evaluated with MMAI scoring. The primary objective was to compare overall survival (OS) between patients with high- and low-MMAI score (stratified by median score). OS was defined as the time from diagnosis of omCSPC to death of any cause, calculated with the Kaplan-Meier method and compared using the log-rank test and Cox regression. The secondary objective was to evaluate MMAI score as predictive for MDT treatment effect in a subset of patients enrolled in the STOMP and ORIOLE randomized clinical trials. Given too few OS events for this subset, we evaluated MMAI for metastasis-free survival (MFS), defined as time of randomization to development of a new radiographically detected metastasis or death of any cause and analyzed using Cox regression. An interaction test was performed between treatment arm and MMAI score. Median follow-up of the surviving patients was 38.0 months. Patients with high MMAI (>0.527) were found to have higher PSA (5.8 vs 2.9, P = 0.005), higher Gleason score (68.2% vs 38.8% Grade Group ≥4, p<0.001), more likely to have de novo metastatic disease (28.2% vs 8.1%, p<0.001), and more likely to have bone metastases (55.5% vs 39.6%, P = 0.019). Patients with a high MMAI had a significantly worse OS (HR = 4.38, 95% CI = 1.24-15.56; P = 0.022) with a median OS of 108.4 mo. vs "not reached" (P = 0.012). In the STOMP and ORIOLE subset (N = 51; median follow-up = 61 months), MMAI was not prognostic for MFS (HR = 1.24, 95% CI = 0.64-2.43, P = 0.52). MMAI however was predictive for MDT benefit as patients with high (HR = 0.32, 95% CI = 0.12-0.90; P = 0.03), but not low (HR = 1.59, 95% CI = 0.63-4.04; P = 0.33) MMAI demonstrated improvement in MFS when treated with MDT (p-interaction = 0.02). We have shown for the first time that the ArteraAI MMAI biomarker is prognostic for OS in patients with omCSPC. Further, MMAI appears to be predict benefit of MDT with high MMAI demonstrating a greater improvement in MFS following MDT over observation. Further work in validating these findings is warranted to allow for greater personalization in the management of patients with omCSPC. [ABSTRACT FROM AUTHOR]

The randomized FORMULA-509 trial demonstrated that for patients with a PSA > 0.5 after prostatectomy receiving salvage radiation and 6 months of GnRH Agonist, the addition of abiraterone acetate plus prednisone (AAP) and apalutamide (Apa) improved metastasis-free survival compared to bicalutamide. Here we present the patient-reported health-related quality of life (HRQoL) results through three years. Validated questionnaires were administered at baseline, end of treatment, and 1 and 3 years after completion of treatment. Patients completed Expanded Prostate Cancer Index Composite (EPIC)-26, PROMIS Fatigue, and Saint Louis University Mental Status Exam (SLUMS). EPIC-26 is scored from 0 to 100 with 100 indicating higher function. PROMIS Fatigue is scored using a standardized T score with higher score indicating greater fatigue. SLUMS is scored from 0 to 30 with 27 to 30 interpreted as normal, 21 to 26 as mild neurocognitive disorder and 20 or less as dementia. Scores between treatment arms were compared using the t-test. Results were interpreted using established thresholds for clinically meaningful differences (4-6 for EPIC-26 hormonal domain, 5-10 for PROMIS Fatigue). Three hundred forty-five patients were randomized (172 bicalutamide and 173 AAP/Apa). Completion rates at baseline, end of treatment, 1 year, and 3 years, were 96%, 80%, 70%, and 57% for EPIC-26; 95%, 79%, 67%, and 57% for PROMIS Fatigue; and 96%, 80%, 70%, and 34% for SLUMS. From baseline to end of treatment, both arms demonstrated clinically meaningful declines in EPIC-26 hormonal domain (median change -15 bicalutamide; -15 AAP/Apa) and increase in PROMIS Fatigue (median change 6 bicalutamide; 7.4 AAP/Apa). From end of treatment to 1 year after treatment patient-reported HRQoL improved to near baseline for both EPIC-26 hormonal function (bicalutamide median score baseline = 95, end = 75, 1 year = 90; AAP/Apa baseline = 95, end = 75, 1 year = 90) and fatigue (bicalutamide median score baseline = 43.1, end = 48.6, 1 year = 46.0; AAP/Apa baseline = 43.1, end = 51.0, 1 year = 46.0) with further improvement in EPIC-26 hormonal function at 3 years (bicalutamide = 95.0; AAP/Apa = 95.0) and stable fatigue at 3 years (bicalutamide = 46.0; AAP/Apa = 46.0). The cMedian SLUMS score was within normal range at baseline (27 bicalutamide; 27 AAP/Apa), end of treatment (28, 28) and 1 (27, 27) and 3 (27, 27) years after treatment. There was no difference in patient-reported hormonal function, fatigue, or mental status between treatment arms, at end of treatment (P = 0.40; P = 0.78; and P = 0.41, respectively), 1 year after treatment (P = 0.78; P = 0.89; and P = 0.76), and 3 years after treatment (P = 0.45; P = 0.95; and P = 0.86). The addition of AAP/Apa improved oncologic outcomes without causing a detectable difference in patient-reported hormonal function, fatigue, or mental status compared to bicalutamide through three years after treatment. [ABSTRACT FROM AUTHOR]

Standard of care management for metastatic castration sensitive prostate cancer (mCSPC) includes androgen deprivation therapy (ADT) with docetaxel or second-generation anti-androgen therapy. Recently, randomized data has demonstrated radiotherapy to the prostate is associated with an improvement in overall survival among patients with low-volume metastatic disease. Tumor genomics represents an additional dimension to understand the clinical trajectory of patients with mCSPC. Herein we aim to evaluate a high-risk genomic signature for its ability to predict response to prostate directed therapy (PDT). We performed a single institution retrospective review of men with low-volume mCSPC who underwent next-generation sequencing of their tumor. Patients were classified according to the presence of high-risk (HiRi) mutation including pathogenic mutations in either TP53, ATM, BRCA1/2 , or Rb1. Our primary endpoint was to determine the effect of PDT on overall survival (OS) in patients with and without a HiRi mutation. Survival analysis was performed with the Kaplan-Meier method compared with log-rank test and multivariable cox regression. Interaction between HiRi mutation and PDT was evaluated. A total of 101 patients with synchronous low-volume CSPC were included in our analysis with a median follow-up of 44 months. Approximately half of patients were found to have a HiRi pathogenic mutation (48.5%) with TP53 mutations accounting for 75.5% of HiRi mutations. On multivariable cox regression PDT was associated with improvement in OS (HR = 0.37, 95% CI 0.16-0.88; p = 0.03). When stratified by presence of HiRi mutation, PDT was not associated with any clinical outcome. Patients with HiRi mutations demonstrated a median OS of 73 vs 66.8 months (p = 0.28) for no PDT and PDT, respectively. Conversely, patients without a HiRi mutation demonstrated a significant improvement in median OS of 60 vs 105.3 months (p<0.01) for no PDT and PDT, respectively. The p-value for interaction for OS between PDT and HiRi mutation was statistically significant (p<0.01). Here we have identified a high-risk genomic biomarker that appears predictive for response to PDT in men with synchronous low-volume mCSPC. Further work validating these results with prospective randomized data is warranted. [ABSTRACT FROM AUTHOR]

Testosterone (T) kinetics and its relationship with clinical outcomes has not been studied in trials using salvage radiotherapy and androgen deprivation therapy (ADT). We performed a secondary analysis of the NRG Oncology/RTOG 0534 SPPORT trial, which compared prostate bed radiotherapy (PBRT) (arm 1), PBRT + short-term androgen deprivation therapy (ADT) (arm 2), or PBRT + pelvic lymph node radiotherapy (PLNRT) + short-term ADT (arm 3). We assessed longitudinal serum T levels and the impact of testosterone recovery (TR) on clinical outcomes. ADT was given for 4-6 months in arms 2 and 3, starting 2 months prior to radiotherapy. The trial excluded patients with baseline T < 40% of the lower limit of normal. TR was defined in 3 ways: 1) return to non-castrate level (>50 ng/dL), 2) return to normal level (>300 ng/dL), and 3) return to baseline level. Time to TR was estimated using cumulative incidence and death without an event considered a competing risk. Unadjusted and adjusted hazard ratios and 95% confidence intervals (CIs) were calculated using Cox proportional hazards model. Freedom from progression (FFP) was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A total of 1699 patients with T at baseline and at least 1 follow-up assessment were included. The median age was 64 years (IQR 59 - 69), 12.8% were black, 14.9% had diabetes, and 54.1% were former or current smokers. Median baseline T in arms 1, 2 and 3 was 320 ng/dL (IQR 239 - 424), 319 ng/dL (IQR 237 - 438) and 330 ng/dL (IQR 252 - 446), respectively. At 6 months, median T in arms 1, 2 and 3 was 290 ng/dL (IQR 210 - 390), 190.4 ng/dL (IQR 66 - 296) and 191 ng/dL (IQR 40.5 - 313). At 2 years, in arms 2 and 3, TR to non-castrate, normal and baseline levels were 95%, 55% and 23%, respectively. At 5 years, in arms 2 and 3, TR to non-castrate, normal and baseline levels were 98%, 73% and 42%, respectively. FFP was superior in arms 2 and 3 vs. arm 1 in patients with TR by all three definitions. In patients with recovered T to normal levels by 2 years (n = 904), the 5-year FFP rates were 71.8% (95% CI 66.9-76.6) in arm 1, 77.2% (72.1-82.2) in arm 2, and 86.3% (82.3-90.3) in arm 3 (arm 2 vs arm 1: HR 0.74, 95% CI 0.56-0.98, p = 0.034; arm 3 vs arm 1: HR 0.54, 95% CI 0.40-0.72, p<.0001). This work represents the largest study of T kinetics in patients treated with salvage radiation and ADT. Approximately half of patients did not normalize their T levels by 2 years. Our data validate an incremental and meaningful FFP benefit of adding short-term ADT and PLNRT to PBRT independent of T recovery. [ABSTRACT FROM AUTHOR]

FORMULA-509 was designed to evaluate whether adding six months of AAP and Apa to a GnRH Agonist could improve outcomes compared to six months of bicalutamide plus GnRH Agonist for patients with unfavorable features receiving SRT for a detectable PSA post-RP. FORMULA-509 is an investigator-initiated, multi-center, open-label, randomized trial. Patients had PSA ≥0.1 post-RP and one or more unfavorable features (Gleason 8-10, PSA >0.5, pT3/T4, pN1 or radiographic N1, PSA doubling time <10 months, negative margins, persistent PSA, gross local/regional disease, or Decipher High Risk). All patients received SRT plus 6 months of GnRH agonist and randomization was to concurrent bicalutamide 50 mg or AAP 1000 mg/5 mg + Apa 240 mg QD. Radiation to pelvic nodes was required for pN1 and optional for pN0. The primary endpoint was PSA progression-free survival (PFS) and secondary endpoint was metastasis-free survival (MFS) determined by conventional imaging. The study was powered to detect a HR of 0.50 for PFS and a HR of 0.30 for MFS, each with 80% power and one-sided type I error of 0.05. Stratification was by PSA at study entry (>0.5 vs.≤0.5) and pN0 vs pN1. Analyses within these subgroups were pre-planned and utilized two-sided p-values. Three hundred forty-five participants (332 evaluable) from 9 sites were randomized from 11/24/2017 to 3/25/2020 (172 bicalutamide, 173 AAP/Apa). Median follow-up was 34 (6-53) months; 29% were pN1 and 31% had PSA >0.5 ng/mL. The HR for PFS was 0.71 (90% CI 0.49-1.03), stratified one-sided log-rank p = 0.06 (3-year PFS was 68.5% bicalutamide vs 74.9% AAP/Apa). The HR for MFS was 0.57 (90% CI 0.33-1.01), stratified one-sided log rank p = 0.05 (3-year MFS was 87.2% bicalutamide vs 90.6% AAP/Apa). In a pre-planned analysis by stratification factors, AAP/Apa was significantly superior for patients with PSA >0.5 for PFS [HR 0.50, (95% CI 0.27-0.95), p = 0.03 (2-sided); 3-year PFS 46.8% bicalutamide vs. 67.2% AAP/Apa] and for MFS [HR 0.32 (95% CI 0.13-0.84), p = 0.02 (2-sided); 3-year MFS 66.1% bicalutamide vs. 84.3% AAP/Apa.] No statistically significant benefit was detected in pre-planned analyses of stratification subgroups defined by PSA≤0.5, pN0, or pN1. Adverse events were consistent with the known safety profiles of the agents being studied, with more rash and hypertension in the AAP/Apa arm. Although this primary analysis did not meet the pre-specified threshold for statistical significance, it does strongly suggest that the addition of AAP/Apa instead of bicalutamide to SRT+6 months of GnRH Agonist may improve PFS and MFS, particularly in the subgroup of patients with PSA>0.5 where a pre-planned subgroup analysis by stratification factors observed a statistically significant benefit for both PFS and MFS. (NCT03141671). [ABSTRACT FROM AUTHOR]

Decipher is a prognostic genomic classifier (GC) validated in several prospective NRG Oncology Phase III trials. Herein, we validate the GC in pre-treatment biopsy samples for risk stratification in a cohort of high-risk men treated with definitive radiotherapy and androgen suppression with or without docetaxel chemotherapy. As per a pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on the NRG/RTOG 0521 randomized phase III trial. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA) and GC scores were obtained. Pre-specified categorical GC scores, adjusted for archival tissue analysis, were used to define higher (>0.46) and lower (≤0.46) risk groups. The primary objective was to validate the independent prognostic ability of GC for metastasis-free survival (MFS) with Cox multivariable analyses (MVA). Samples were obtained from 283 consented, evaluable patients with tissue (50% of trial) yielding 183 (65%) GC scores that passed quality metrics, 91 from control and 92 from the interventional arm. Median age was 66 years, median PSA was 19.3 ng/uL (IQR: 8.1-41.4), 81% had clinical stage ≥T2 and 80% had Gleason score ≥8 (47% ≥9). Median GC score was 0.55 (IQR: 0.38-0.78) and overall the arms were balanced for key covariates. With a median follow-up of 9.9 years (IQR: 9.3, 10.7), 67 MFS events including 34 distant metastases (DM) were observed. On MVA, only the GC (per 0.1 unit) was independently associated with MFS (HR 1.12, 95% CI 1.01-1.25) as well as DM (sHR 1.22, 95% CI 1.06-1.41), whereas the 4 pre-defined trial risk groups used for stratification (based on Gleason score, T-stage and PSA), randomization and patient age were not. For categorical GC, on MVA, higher-risk GC patients (65%) had worse DM (sHR 2.82, 95% CI 1.1-7.3) compared to those with lower GC. Cumulative incidence of DM at 10-years was 27% for higher GC vs 9% (95% CI 7-18%) for lower GC. No biomarker-by-treatment interaction with GC and the addition of docetaxel was detected. In pre-treatment biopsy samples from a randomized Phase 3 trial cohort, GC demonstrated its ability to further risk stratify clinically high-risk men demonstrating an independent association of GC score with DM and MFS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making. NRG-GU009/PREDICT-RT (NCT04513717) aims to determine the optimal therapy based on GC score for high-risk prostate cancer. [ABSTRACT FROM AUTHOR]

The phase 3 ATLAS study (NCT02531516) is investigating if treatment intensification with apalutamide (APA) to neoadjuvant and adjuvant treatment with gonadotropin-releasing hormone agonist (GnRHa) and external beam radiation therapy (EBRT) improves metastasis-free survival (MFS) in high-risk patients (pts). To determine MFS improvement, long-term patient retention and physician engagement are critical. Here, we describe initiatives used for pt and physician participation, noting specific challenges related to pt retention during the COVID-19 pandemic, while maintaining trial integrity. Eligible HRLPC pts (Gleason score [GS] ≥ 8 or 7; if GS 7, prostate-specific antigen ≥ 20 ng/mL; stage ≥ cT2c; ECOG PS 0/1; Charlson Comorbidity Index ≤ 3) stratified to GS, pelvic nodal status, use of brachytherapy boost, and region were randomized 1:1 to APA or placebo (PBO) plus GnRHa for 30 (28 d) treatment cycles. Treatment was applied neoadjuvant/concurrent to EBRT with APA 240 mg/d vs bicalutamide 50 mg/d for 4 cycles; 26 cycles are completed adjuvantly post EBRT with APA 240 mg/d vs PBO. To maximize pt retention to MFS primary end point, especially considering impact of the COVID-19 pandemic, retention initiatives that can be chosen by sites per local regulation are: reimbursing travel expenses, arranging travel for appointments, visiting nurse appointments for treatment management, using local labs and onsite radiology to reduce travel, using third-party vendors to maintain contact information, and regular pt newsletters. To support consistent physician engagement, initiatives include materials on pt retention, site newsletters, teleconferences on reducing pt engagement barriers, and training on study updates. Pts (N = 1503) were randomized at 266 sites in 24 countries (North America, Latin America, Europe, Asia). The study is ongoing. For patient retention, most sites (95%) are participating in travel reimbursement, coordination with local labs and onsite radiology, and pt newsletters; other program participation is varied. For physician engagement, all sites are receiving materials to retain pts and site newsletters. As of January 2022, 96% of patients remaining eligible for follow-up have been retained on the study. With the retention initiatives implemented, the overall dropout rate can be maintained below the expected and statistically acceptable limits. Despite the COVID-19 pandemic, very low dropout rates have been observed. These initiatives have resulted in high levels of patient retention and physician engagement post treatment and aid in understanding how to enhance long-term clinical trial outcomes. [ABSTRACT FROM AUTHOR]

Bicalutamide, a first-generation androgen receptor antagonist, continues to be selectively used in the management of prostate cancer (PCa) in place of androgen deprivation therapy (ADT), often to avoid select ADT-specific side effects. However, none of the major American or European guidelines support the use of bicalutamide monotherapy (BICmono) without ADT for localized disease. Herein, we perform the first, to our knowledge, meta-analysis of randomized trials to assess the efficacy of BICmono in PCa. A pre-specified protocol was registered with PROSPERO. MEDLINE, Embase, and Cochrane databases were searched for randomized trials testing the use of BICmono in PCa published before January 2022. The prescribed BICmono dose was 150 mg orally daily. The primary endpoint was overall survival (OS) with progression-free survival (PFS) as a secondary endpoint. Analyses were stratified into disease states defined by the Early Prostate Cancer (EPC) definition of localized (cT1-2, N0M0) and locally advanced (cT3-4, N0-1, M0). Patients with M1 disease were excluded. Standard of care (SOC) was defined as radical prostatectomy, radiotherapy, or watchful waiting. Comparisons of SOC +/- ADT was performed through an individual patient data meta-analysis in PCa randomized trials (MARCAP) consortium (5336 patients from NRG/RTOG 8610 and 9408, EORTC 22863 and 22991, TROG 9601, and PCS III). SOC +/- BICmono was compared through a study-level meta-analysis (9125 patients from EPC 23, 24, 25, PMH 9907, and NRG/RTOG 9601). SOC+BICmono versus SOC+ADT was compared through a random-effects network meta-analysis. Sensitivity analyses were conducted for the subset of patients who received RT as SOC. For localized PCa (n=9,897 patients), the addition of ADT to SOC significantly improved OS (HR 0.83, 95%CI 0.72-0.96). Conversely, BICmono did not significantly impact OS compared to SOC alone (HR 1.06, 95%CI 0.89-1.27). Results were similar for the subset of patients treated with radiotherapy as the SOC. Likewise, PFS was significantly improved with the addition of ADT to SOC (HR 0.69, 95%CI 0.61-0.77), but not from the addition of BICmono to SOC (HR 0.89, 95%CI 0.77-1.04). The network meta-analysis demonstrated that SOC+ADT was superior to SOC+BICmono for OS (HR 0.78, 95%CI 0.62-0.98) and PFS (HR 0.77, 95%CI 0.63-0.93). Similar trends were observed in locally advanced disease (n=4284 patients). This study presents strong evidence for the superiority of ADT over BICmono for men with PCa. Furthermore, there was no improvement in outcomes from the use of BICmono compared to SOC alone without the use ADT in localized PCa. Thus, based on current randomized evidence, BICmono does not appear to have clinically meaningful activity in localized disease and SOC alone should be recommended if a patient declines ADT. [ABSTRACT FROM AUTHOR]

Emerging data suggest metastasis-directed therapy (MDT) improves outcomes in patients with oligometastatic castration-sensitive prostate cancer (omCSPC). Prostate-specific membrane antigen positron emission tomography (PSMA-PET/CT) can detect occult metastatic disease and has been proposed as a biomarker for treatment response. Herein we identify and validate a PSMA-PET biomarker for clinical outcomes following MDT in omCSPC. This was an international multi-institutional retrospective study of two independent cohorts of omCSPC, defined as ≤3 lesions, treated with metastasis-directed stereotactic ablative radiation therapy (SABR). Patients underwent PSMA-PET/CT prior to and 3-6 months after treatment. Pre- and post-SABR PSMA-PET/CT standardized uptake value (SUV) was measured for all lesions and PSMA response defined discretely using a cutpoint of ≥ 30% decrease in SUV max. PSMA-PET response was correlated with lesion local control (LLC), and metastasis-free survival (MFS), defined per ICECaP working group by a new metastasis on conventional imaging alone (not including pelvic lymph node metastases) or death. A total of 131 patients (discovery n=35, validation n=96) with 261 treated metastases were included in the analysis, with median follow-up of 29 months (IQR 18.5-41.3). Following SABR, 78.4% of lesions experienced a partial or complete PSMA response. Multivariable analysis demonstrated SUV response significantly associated with improved LLC (HR=0.10, 95%CI 0.04-0.26; p<0.01). Patients with PSMA response in all lesions experienced significantly better MFS (HR=0.37, 95%CI 0.21-0.65; p<0.01) compared to their counterparts, and this maintained significance within both the discovery (p=0.02) and validation (p<0.01) cohorts. Following SABR, PSMA-PET response is a robust and externally validated radiographic biomarker for MFS in omCSPC. This approach holds promise for guiding clinical management of omCSPC and should be validated as an early response indicator biomarker in localized and other advanced states of prostate cancer. [ABSTRACT FROM AUTHOR]

Trimodality therapy (TMT) with maximal TURBT followed by chemoradiation (CRT) is a category 1 bladder preservation treatment option for patients with non-metastatic muscle invasive bladder cancer (MIBC). Radiation therapy increases PD-L1 expression in bladder cancer. This trial evaluates the activity of atezolizumab (atezo) in MIBC in combination with TMT. This trial was designed with pre-specified safety analyses of the first 80 patients (40 in each arm). The previous analyses did not show any significant increase in toxicity and DSMC recommended to proceed with further enrollment. This is the updated safety report of 213 patients. This is a randomized phase III trial testing atezo every 3 weeks for 6 months given concurrently and adjuvantly with TMT vs. TMT alone in 432 eligible patients with MIBC (T2-T4aN0M0). Patients are stratified based on performance status; T2 vs T3 or T4; choice of chemotherapy; and radiation field (bladder only vs small pelvis). Patients undergo biopsy 3 months after finishing CRT to assess treatment response and are followed for 5 years for bladder intact event free survival. 100 patients were randomized to the TMT alone (control) arm and 113 patients to the TMT+ atezo arm. Patient characteristics for the atezo vs control arm are: Median age (75 vs 72), T2 (82% vs 81%), chemotherapy regimen: cisplatin (48% vs 50%), 5-fluorouracil/mitomycin (15% vs 13%), gemcitabine (37% vs 37%), radiation field including small pelvis (57% vs 58%), bladder only (43% vs 42%), performance status 0-1 (96% vs 95%). Two patients in each arm reported grade 3 diarrhea. Two patients had grade 3 cystitis in the atezo arm as compared to 1 patient in the control arm. Only 1 patient had treatment related grade 3 radiation cystitis confirmed by cystoscopy and biopsy and continued atezo without worsening of symptoms. Overall, 65 patients reported treatment related grade 3 or higher toxicity events in the atezo arm vs 44 in control arm (57% vs 44%). Most common toxicity was hematological (43% vs 36%) which was considered non-immune related. Other Grade 3 or higher known immune related AEs (irAE's) of atezo like pancreatitis (1), rash (1), acute kidney Injury (2), gastritis (1), transaminitis (1), & dyspnea (1) were observed in the atezo arm. Table1. Toxicities observed were numerically higher in the atezo arm. One reason could be that more eligible patient data were available from the atezo arm (113 vs100). Most of them were hematological toxicities which did not require holding atezo and were considered non-immune related by the treating provider. Known irAE's were observed in the atezo arm. The trial is expected to finish accrual in next two years and this update demonstrates no safety concerns. [ABSTRACT FROM AUTHOR]

Many tools are used to predict the probability of lymph node involvement (LNI) in patients with prostate cancer before radical prostatectomy (RP) and to select patients for lymph node dissection. Our goal was to externally validate common prediction tools and to create a machine learning model for the prediction of LNI in patients with prostate cancer referred for RP. Patients treated at two academic institutions between 1990 and 2020 with RP followed by pelvic lymph node dissection were included. We trained a gradient boosted tree on data from one institution and the model was validated on the other dataset. Variables incorporated into the model are patient's age, percentage of cores positive on biopsy, Gleason scores, preoperative PSA, and clinical T-stage (cT). The area under curve of the receiver operator characteristic curve (AUC) served as the performance metric. We further compared our model's performance to that of established nomograms, namely the Roach formula, the online Memorial Sloan Kettering Center (MSKCC) nomogram, and the 2012 Briganti nomogram. The combined dataset consisted of 19,090 patients with median age of 65, median PSA at diagnosis of 7.60 ng/mL, and median percentage of positive cores at biopsy of 44%. 14,252 patients (74.6%) had a Gleason score (GS) of 7, and 4,841 (25.4%) had a GS of ≥ 8. Most patients (18,570 or 97.3%) had cT-stage ≤cT2 disease, and 523 (2.7%) had cT3-4 disease. 3,058 patients (16%) were found to have lymph node involvement. The external validation dataset had 1,093 patients, with 10.7% having lymph node positive disease. After training and on external validation, the AUC of our model was 0.79 (CI: 0.7465-0.83), compared to 0.69 (0.64-0.7455), 0.73 (0.6813-0.7742), and 0.74 (0.6931 - 0.7914) when using the Roach formula, MSKCC nomogram, and Briganti 2012 nomogram, respectively. Furthermore, our model's improved performance was statistically significant, with p-value <0.05 when comparing its AUC to that of all other models. Our machine learning model can be used to estimate an individual patient's risk of LNI and serves as an additional tool with improved performance compared to established prediction models. [ABSTRACT FROM AUTHOR]

The SAKK 09/10 phase 3 trial showed that dose-intensified salvage radiotherapy (SRT) was not superior to conventional dose SRT for biochemically recurrent prostate cancer (PCa) after radical prostatectomy (RP). We previously reported on the validation of the 22-gene genomic classifier as prognostic in this trial but did not observe an interaction with RT dose. Herein, we examine the PORTOS classifier, an expression signature of 24 DNA damage repair and immune pathway genes, previously shown to predict benefit from postoperative radiotherapy, to test its predictive ability to SRT dose. The SAKK 09/10 trial (NCT01272050) was a multicenter, randomized phase 3 trial that included PCa patients with biochemical progression after RP (PSA > 0.1 to 2 ng/mL at randomization). Patients were randomized to 64Gy vs 70Gy to the prostate bed. No patients received concurrent androgen suppression or pelvic nodal radiotherapy. After central review, the highest-grade tumors were profiled using the Decipher whole-transcriptome assay (Veracyte, San Diego, CA) to generate PORTOS. The independent prognostic ability and interaction effects were examined for the biochemical progression, clinical progression-free survival (CPFS), receipt of salvage hormone therapy, and metastasis-free survival endpoints with Cox multivariable and interaction analyses (MVA). Categorical analyses used the published threshold for PORTOS radiotherapy response (high vs low). Of the 226 trial patients with transcriptome data, 16% had high PORTOS radiation response compared to 84% with lower PORTOS. Patients with high PORTOS were well balanced between the randomization arms. PORTOS was not prognostic for the endpoints in MVA with the trial stratification factors. A high PORTOS, however, was predictive for improved outcomes in patients receiving dose-intensified SRT. Patients with high PORTOS that received 70Gy dose had 5-year CPFS of 94% compared to 49% with the 64Gy dose (log-rank p=0.006). In interaction analysis, PORTOS had a statistically significant interaction with RT dose for multiple endpoints: freedom from biochemical progression (interaction p=0.04), clinical progression-free survival (interaction p=0.003) and metastasis-free survival (interaction p=0.037). In a phase 3 trial testing SRT dose intensification after RP, patients with high PORTOS had significantly better outcomes with dose-intensified treatment, suggesting that higher doses should be considered in this subgroup. Further studies are warranted to validate PORTOS as the first predictive biomarker to help personalize dose prescription in the postoperative setting. [ABSTRACT FROM AUTHOR]