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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]

Prior randomized controlled trials (RCT) comparing bladder preservation to radical cystectomy (RC) for muscle invasive bladder cancer (MIBC) closed early due to lack of accrual. Given that no future RCTs are foreseen, and in the absence of level 1 data, we aimed to provide the best evidence possible on outcomes of matched cohorts comparing trimodality therapy (TMT, maximal transurethral resection of bladder tumor followed by concurrent chemoradiation) to RC in order to guide management. This retrospective analysis included 703 patients with MIBC clinical stage T2-T3/4aN0M0 MIBC urothelial carcinoma of the bladder, 421 RC and 282 TMT who would have been eligible for both TMT or RC, treated at three tertiary referral academic institutions between 2005-2017. To compare homogeneous cohorts, all patients included in this analysis had solitary tumors <7 cm, no or unilateral hydronephrosis, and no extensive carcinoma in situ. Treatment propensity scores were estimated using logistic regression, and patients were matched 3:1 with replacement. Covariates included age, sex, clinical T stage, hydronephrosis, (neo)adjuvant chemotherapy, body mass index, smoking history, and ECOG status. Overall survival (OS) was estimated with adjusted Cox models; cancer-specific survival (CSS), distant failure-free survival, pelvic nodal failure-free survival and metastasis-free survival (combined distant and pelvic nodal failure) were estimated with adjusted competing risk models. Our primary endpoint of interest was metastasis-free survival. The analysis was performed as intent-to-treat. The 3:1 matched cohort comprised of 1,116 patients (834 RC vs 282 TMT). After matching, age (71.3 vs 71.6), cT2 clinical stage (88 vs 90%), presence of hydronephrosis (12 vs 10%), and use of (neo)adjuvant chemotherapy (60 vs 65%) was similar between RC and TMT cohorts. Salvage cystectomy was performed in 38 patients (13%) treated by TMT. At 5 years, metastasis-free (73 vs 78%, p=0.07), distant failure-free (78 vs 82%, p=0.14), and pelvic nodal failure-free (96 vs 94%, p=0.33) survival were not statistically different between RC and TMT, whereas CSS and OS favored TMT (78 vs 85%, p=0.02; 66 vs 78%, p<0.001). Outcomes for RC and TMT were not different among centers. Final pT stage in the RC patients was: pT0 14%, pT1 7%, pT2 29%, pT3/4 42% and N+ 24%. Peri RC mortality was 2.1% and median number of nodes removed was 40. NMIBC recurrence occurred in 57/282 (20.2%) TMT patients. This large multi-institutional contemporary study provides the best evidence to date, in the absence of randomized trials, supporting TMT for select patients with MIBC. Oncologic outcomes seem to be equivalent between TMT and RC, affirming the position that TMT should be offered as an effective alternative. [ABSTRACT FROM AUTHOR]

Advances in the field of cancer biology and molecular techniques have led to a better understanding of the molecular underpinnings driving cancer development and outcomes. Simultaneously, advances in imaging have allowed for improved sensitivity in initial staging, radiotherapy planning and follow-up of numerous cancers. These two phenomena have led to the development of biomarkers that can guide therapy in multiple malignancies. In bladder cancer, there is extensive ongoing research into the identification of biomarkers that can help tailor personalised approaches for treatment based on the intrinsic tumour biology. However, the delivery of bladder cancer radiotherapy as part of trimodality therapy currently has a paucity of biomarkers to guide treatment. Here we summarise the existing literature and ongoing investigations into potential predictive and prognostic molecular and imaging biomarkers that may one day guide selection for utilisation of radiotherapy as part of trimodality therapy, guide selection of the radiosensitising agent, guide radiation dose and target, and guide surveillance for recurrence after trimodality therapy. • Historically, there have been no validated biomarkers to guide the use of radiotherapy as part of trimodality therapy (TMT) for bladder cancer. • Emerging data suggest several candidate predictive and prognostic molecular biomarkers, such as MRE11, DNA damage response (DDR) mutations and gene expression profiles, that may help to identify patients who are optimal candidates for radiotherapy as part of TMT. • Ongoing investigations are studying biomarkers such as the radiation sensitivity index, which may help to guide the optimal radiation dose to maximise the therapeutic ratio. • The 24-gene hypoxia signature, DDR mutations and markers of immune activation are potential biomarkers that may help to guide the use of radiosensitising systemic therapy and immunotherapy and are undergoing active investigation. • Liquid, tumour and imaging biomarkers are being studied to determine if they can improve upon initial staging and surveillance for recurrence after TMT. [ABSTRACT FROM AUTHOR]

To evaluate the feasibility and safety of creating radiation treatment plans based on a convolutional neural network auto-contouring (AC) model for patients receiving radiation for localized prostate cancer with a radio-opaque rectal spacer hydrogel. The deep learning model produces ACs for target volumes (prostate, proximal seminal vesicle), OARs (rectum, bladder, penile bulb, femoral heads), and rectal hydrogel spacers. ACs were compared to manual contours (MC) by MDs for clinical use. Individual volumes and overall performance (composite score) were previously evaluated and reported, qualitatively using a 1 (minor discrepancy), 2 (moderate discrepancy), 3 (significant discrepancy), and 4 (rejected, gross error) scale and quantitatively using Dice Similarity Coefficient (DSC) and mean distance to agreement. VMAT treatment plans were created on unedited AC volumes from five composite 1 (C1) cases and five composite 2 (C2) cases and dose volume metrics were computed for the final MCs. Dosimetry comparison was performed to assess the safety of delivering a treatment plan created from unedited ACs. Cases were planned to 50.4 Gy in 28 fractions to the SVs, with a SIB of 70 Gy the prostate. PTV expansions were CTV+5 mm (CTV+4 mm posteriorly). Of 62 initial cases evaluated, 11 were scored as a C1, 28 were scored as a C2, and 23 received a C3. 10 cases were randomly selected for treatment planning. For prostate (CTV P) in selected C1 and C2 cases, mean score was 1 and 1.8 and mean DSC was 0.919 and 0.876, respectively. Clinical goals for planning and dosimetric data from treatment plans are shown in Table 1. The mean V70 Gy for prostate CTV/PTV was 99.83%/90.05% for C1 cases and 99.46%/89.15% for C2 cases. All clinical goals for OARs were met in both cohorts. 63% of all cases evaluated received a C1 or C2 score. Our results indicate the treatment plans generated from unedited ACs on these cases respected all clinical goals for OARs. Although C1 plans produced better PTV coverage than C2, almost all plans had sub-optimal PTV coverage, indicating the need for MDs to edit target volumes before treatment planning. [ABSTRACT FROM AUTHOR]

High-grade cT1 (HGT1) urothelial carcinoma of the bladder (UC) is an aggressive disease with a 4-year cancer-specific mortality of 36% in a large cystectomy series. NCCN guidelines recommend radical cystectomy as the preferred treatment for patients with (1) BCG-naive HGT1 with high-risk features or (2) for HGT1 disease that is BCG unresponsive or intolerant. Definitive concurrent chemoradiotherapy (CRT) has emerged as a promising bladder-sparing alternative treatment for HGT1 with the recent presentation of the single-arm RTOG 0926 trial. However, while there is level 1 evidence that CRT is superior to radiotherapy (RT) alone for muscle-invasive bladder cancer (MIBC), there is limited data on the comparative effectiveness of RT vs. CRT for HGT1 non-MIBC. We hypothesized that CRT would be associated with improved overall survival (OS) vs. RT for patients with HGT1 bladder cancer. Patients with cT1N0M0, high-grade urothelial carcinoma diagnosed between 2004-2017 and treated with transurethral resection of the bladder tumor followed by RT alone or concurrent CRT were identified in the National Cancer Database (NCDB). All patient received a cumulative RT dose ≥ 50 Gy. Patients with a Charlson-Deyo comorbidity index (CDCI) score > 1 or missing key information were excluded. Propensity-weighted multivariable analysis (MVA) using Cox regression modeling was used to compare overall survival (OS) between groups. Covariables included age, race, ethnicity, gender, year of diagnosis, CDCI score, insurance status, educational and socioeconomic metrics, and treatment at an academic center. A total of 192 patients with HGT1 UC were treated with: (i) RT alone (n = 78) or (ii) CRT (n = 114). Median age was 81 (range: 50-90), and 70% were male. The median tumor size was 4.0 cm (range: 0.4-10.5 cm). The median follow-up time was 46 months (range: 10-168 months). The mean radiation dose was 62.4 Gy (SD: ±5 Gy) and 63.2 Gy (SD: ±12 Gy) in the RT and CRT cohorts, respectively. Propensity-weighted MVA showed that combined modality treatment with CRT was associated with improved OS relative to radiation alone [Hazard Ratio (HR): 0.56, 95% Confidence Interval (95% CI): 0.36-0.89, p = 0.012]. Female gender was associated with worse OS (HR: 1.75, 95% CI 1.16-2.66, p =.008). 4-year OS for the RT alone versus CRT arm was 22% and 38%, respectively. For patients with HGT1 bladder cancer, concurrent CRT was associated with improved OS compared with radiation alone. These results complement the findings of RTOG 0926 showing the promise of CRT for the treatment of HGT1 disease and support the decision by NRG Oncology investigators to omit RT alone as a treatment arm in the successor trial to RTOG 0926 for HGT1 disease. [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]

Radiation therapy to the para-aortic and iliac lymph nodes is an effective treatment for stage IIA and appropriately selected stage IIB seminoma patients. However, there are concerns for serious late complications, particularly an increased risk of secondary cancers due to the large areas of normal tissue irradiated. The purpose of this study was to quantify the expected differences in secondary cancer risk for stage II seminomas when evaluating proton pencil-beam scanning (PBS) and volumetric modulated arc therapy (VMAT) compared to conventional AP-PA photon (3D) treatment plans. Five seminoma patients (four stage IIA receiving 30 Gy and one stage IIB receiving 36 Gy) ranging in age from 38 to 48 (mean 41.2) treated at our institution with PBS had two additional plans generated for comparison— one photon VMAT and one photon 3D. Dose differences to critical organs were examined and the risks of second primary cancers in those organs were calculated as the Excess Absolute Risk (EAR), reported in cancers per 10,000 person years, and Lifetime Attributable Risk (LAR), reported in percentage increase in risk, both projected to age 70. PBS reduced the mean organ dose compared to photons, on average by 60% but ranging from 30%-95% for different organs, except for the spinal cord which received the lowest mean dose with VMAT. PBS also reduced the EAR for all organs, with the greatest reduction for large and small bowel, liver, and stomach. Table 1 shows the average ratio of LAR between PBS, 3D, and VMAT for critical organs in five patients, and this ratio is greater than 1 for all organs for 3D compared to PBS. VMAT plans provide a mean dose reduction to some critical organs compared to 3D, particularly the spinal cord and pancreas, where VMAT also reduces the LAR compared to PBS. However, VMAT increases the low dose bath through other organs, leading to slightly increased LAR for the bladder, liver, and rectum compared to 3D. The use of protons in stage IIA/B seminoma provides a favorable dose distribution with an expectation that this will transfer into decreased toxicity and reduced secondary cancer risk compared to conventional 3D photons. VMAT is another alternative to conventional 3D photons that provides a reduction in dose to some critical organs and comparable or reduced secondary cancer risk predictions for most organs. [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]

To analyze the prospective use of a deep learning auto contouring model for patients with localized prostate cancer with or without insertion of a radiopaque hydrogel spacer. The model was initially trained with patients from an academic center. It was implemented for prospective clinical use at a satellite center by three experienced radiation oncologists. The model auto contours prostate, proximal seminal vesicles (SVs), bladder, rectum, femurs, penile bulb and spacer (when existing). The auto contours (ACs) were reviewed and edited by treating physician. The ACs were compared to the approved planning contours (PCs) for the initial 23 patients to evaluate the extent of physician editing required. Each AC was compared to the final PC by one physician using a qualitative 4-point system: 1 (minor discrepancy with significant efficiency gain), 2 (moderate discrepancy with substantial gain), 3 (significant discrepancy with meaningful gain), and 4 (rejected for gross error or no efficiency gain). A composite score was calculated by averaging the score of each structure. A Turing test was performed to see if the physician can differentiate AC vs. PC. Quantitatively, the geometric differences between each AC and PC were analyzed using Dice similarity coefficient (DSC) and mean distance to agreement (MDA). As shown in Table 1, the mean score was ≤1.4 for all structures except for SVs, and 1.26 for the composite, indicating overall significant efficiency gain. In 97.8% of cases, the ACs led to an efficiency gain. While the passing rate of the Turing test was not high, the failure was frequently due to very minor differences. The DSC was close to 1 for femurs, bladder and spacer, and >0.9 for prostate and rectum. The MDA was <2 mm for all structures except SVs. All quantitative measures except for the SVs were within the tolerance recommended by AAPM TG 132 (DSC ≥ 0.8, MDA ≤ 3 mm). On average, treating physicians estimated 17 minutes were saved for each patient. Overall, the model can accurately auto contour targets, organs, and spacer with significant efficiency gain. A majority of ACs qualitatively evaluated by a physician had only mild discrepancies. Quantitative analysis demonstrated ACs for most organs had only minor geometric differences, unlikely to result in any significant dose-volume impact. [ABSTRACT FROM AUTHOR]

Bladder-sparing chemoradiation therapy (CRT) is a definitive first-line treatment option for muscle-invasive bladder cancer (MIBC). There is considerable variability in radiotherapy target volumes in the United States, and ongoing cooperative trials support either bladder only or bladder plus pelvic nodal treatment. Whether the addition of pelvic lymph node treatment impacts outcomes is unknown. We identified 2,566 patients in the National Cancer Database with cT2-4N0M0 urothelial cell carcinoma of the bladder treated with definitive-intent CRT following maximal transurethral resection of bladder tumor from 2004 to 2016. Patients were included if total radiation dose was ≥40 Gy and chemotherapy was initiated within 30 days of radiation. We excluded those who were post-cystectomy, node-positive, or metastatic; who had variant histology, history of prior malignancy, or received palliative-intent therapy. The exposure of interest was bladder only (BO) versus bladder plus pelvic lymph node (BPN) radiation. Annual use from 2004 to 2016 was compared using Cochran-Armitage test for trend. Overall survival (OS), defined from the date of diagnosis, was compared using Kaplan-Meier, log-rank test, and multivariable Cox proportional hazard analysis. Final multivariable model, developed via backward selection with an alpha level of 0.1 for removal, included age, race, diagnosis year, comorbidity score, insurance provider, education level, geographic region, and T stage. Sensitivity analysis tested an interaction term for T stage. We identified 719 patients treated with BO and 1,847 patients treated with BPN CRT. Median (IQR) dose to pelvic nodes was 45 Gy (39.6-50); median (IQR) dose to bladder (in both groups) was 64.8 Gy (59.4-64.8). There was a significant increase in use of pelvic nodal treatment from 2004 to 2016 (65.4 to 76.8%, p <.0001 for trend). With a median follow up of 6.2 years, there was no difference in survival between groups: 5-year and 10-year OS 28.4% (95% CI 24.8-32.1%) in the BO group versus 31.9% (95% CI 29.5-34.3%) in the BPN group, and 11.5% (95% CI 8.4-15.2%) in the BO group versus 14.0% (95% CI 11.7-16.6%) in the BPN group, respectively (log-rank p=.19). On multivariable analysis, there was no significant association between pelvic nodal coverage and OS (adjusted HR 0.93, 95% CI 0.84-1.03, p=.17). No differential effect by T stage was observed (T3-4 versus T2, interaction p=.41). These hypothesis-generating results suggest that routine inclusion of pelvic nodal coverage is not needed for patients undergoing definitive CRT for node-negative MIBC. Use of pelvic nodal treatment, however, has continued to increase in the United States. Prospective investigation with adverse event, quality of life, and cancer-specific endpoints is warranted. [ABSTRACT FROM AUTHOR]

RTOG 1115 was a randomized phase III trial evaluating the addition of orteronel (TAK-700), a novel CYP17A1 inhibitor, to dose escalated radiation plus ADT in men with high risk, localized prostate cancer. Originally designed to evaluate overall survival, the trial was halted early due to discontinuation of orteronel development in prostate cancer. We report here the initial primary endpoint analysis. The study was designed to enroll 900 men with high-risk prostate cancer (Gleason 9-10, PSA > 20, or clinical stage T2 or higher with Gleason ≥ 8). Ultimately, 238 patients were enrolled (May 2012-Sept 2014), and randomized 1:1 to receive standard therapy (Arm A), or standard therapy plus two years of twice daily orteronel (Arm B). Radiation therapy entailed dose-escalated external beam radiation (EBRT) to the prostate and pelvis to 45 Gy in 25 fractions, followed by a boost to 79.2 Gy using EBRT or either HDR or LDR. The analysis plan was reframed around detecting a reduction in rate of a composite biochemical failure endpoint (Phoenix biochemical failure, local/regional or distant disease, or salvage ADT). With 238 patients enrolled and followed, the study would have 70% power to detect a 40% decrease in the composite failure primary endpoint after 70 events had occurred. 231 patients were evaluable for efficacy and toxicity, 115 in Arm A and 116 in Arm B, and median follow up was 6.2 years. Grade 3 adverse events were observed in 35% and 60% of men in Arm A and B, respectively, with most common being urinary or gastrointestinal disturbance. Time to grade 3 adverse event was significantly faster in Arm B (log rank P value < 0.001). There were four deaths due to adverse events, three of which were in Arm A, and all were deemed unlikely related to treatment. Notably, only 29% of men in Arm B received 80% or more of the planned dose of orteronel due to a variety of factors that impacted drug tolerability. With respect to the primary outcome, patients did well overall with 6-year failure rates of 22.5% and 16.1%, respectively, in Arms A and B (hazard ratio [HR] 0.83, 95% CI 0.47-1.48). By Phoenix definition, PSA failure was only 18.4% and 12.1% in Arms A and B through 6 years. Distant failure occurred in 10.0% and 4.0% of patients (HR 0.71, 95% CI 0.29-1.75). Quality of life outcomes will be reported separately. While all efficacy trends favored the experimental arm, due to the small number of patients and events none of the differences between arms achieved statistical significance. The addition of orteronel to dose escalated RT and ADT did not result in statistically significant improvement in efficacy outcomes, although results were limited by early termination of accrual and impaired drug tolerability. Intensification of hormonal therapy with better tolerated novel agents remains an appealing strategy for the treatment of high-risk localized prostate cancer. [ABSTRACT FROM AUTHOR]

For men with intermediate- and high-risk prostate cancer receiving definitive radiotherapy, the ideal duration of ADT to improve overall survival (OS) is unclear. Additionally, actual treatment duration received, given the low and variable patient compliance with long-term ADT, has not been compared with intention-to-treat (ITT) duration. Recent retrospective data suggest that the optimal ADT duration may exert a continuous non-linear benefit (Kishan et al., JAMA Onc 2022), and herein we aim to assess this in the MARCAP consortium of randomized trials. A meta-analytic framework was generated to determine the optimal duration of ADT. An IPD meta-analysis performed by the MARCAP consortium using 13 randomized trials (EORTC 22863 and 22961, GICOR/DART, ICORG 9701, PCS III and IV, TROG 96.01 and RADAR, and NRG/RTOG 8610, 9202, 9408 and 9910). Both ITT and treatment received ADT durations were analyzed. Inverse probability of treatment weighting (IPTW) was performed to assess the effect of ADT duration with adjustments for age, PSA, Gleason score, cT-stage, radiotherapy dose, pelvic nodal radiotherapy use, and mid-trial enrollment year. Multivariable additive Cox models were then used to model the association between the primary endpoint of OS and ADT duration. Secondary endpoints included prostate cancer-specific survival (PCSM) and other-cause mortality (OCM). A pre-specified sensitivity network meta-analysis (NMA) of EORTC 22961 (6 vs 36 months), PCS IV (18 vs 36 months), and TROG RADAR (6 vs 18 months) was also performed. There were 10,266 patients included with a median follow-up of 11.3 (IQR: 9.5-14.5) years. On ITT meta-analysis, there were significant improvements in OS from extending ADT from 9 to 18 months (HR 0.77, 95%CI 0.68-0.86, p< 0.0001) and from 18 to 28-36 months (HR 0.78, 95%CI 0.68-0.89, p=0.0002). The optimal duration of ADT for OS on ITT analysis was 28 months, which was not impacted by RT dose (p=1.0). ADT duration based on compliance data demonstrated the optimal ADT duration was actually 21 months for OS. These findings were consistent on the sensitivity NMA. Optimal ADT durations based on PCSM was ≥36 months, while 0 months was optimal for OCM with a 0.5% increase in OCM HR per month (HR 1.005 95%CI 1.002 - 1.008), and HR = 1.19 (95% CI 1.06 - 1.33) for 36 vs 0 months. For men enrolled in the context of randomized trials, after accounting for much of the non-compliance with durations of ADT beyond 18 months, we demonstrate that 21 months is optimal for OS in men with intermediate- and high-risk prostate cancer. While longer durations of ADT provide incremental benefit on PCSM, this must be balanced against potential worsening of OCM, cost, and quality of life. [ABSTRACT FROM AUTHOR]

Clinical stage II (CS2) testicular seminoma has been historically treated with chemotherapy or radiation (RT). Limited data exists reporting outcomes with contemporary RT dose and fields, and between de novo CS2 vs. relapsed stage I seminoma. We investigated recurrences in CS2 seminoma patients treated in the modern era across two institutions. A retrospective review was performed of 71 patients who received RT for CS2 seminoma between 2001-2021. Recurrence-free survival (RFS) was determined using the Kaplan-Meier method. Univariate analysis for recurrence was calculated using Cox proportional hazard regression. Recurrence was defined as a new lymph node or mass, biopsy-proven to be seminoma, after RT completion. Covariates tested included: CS2 at orchiectomy (de novo) or CS2 diagnosed on surveillance after orchiectomy (relapsed), lymphovascular invasion (LVI), lymph node (LN) size at CS2 diagnosis, AJCC staging, RT modality, and treatment decade (2000s vs 2010s). Second malignancies were recorded as a biopsy-proven malignancy originating in the prior RT field. The median age at diagnosis was 39 years (IQR: 34, 46). Thirty-six (51%) patients presented with de novo CS2 while 35 (49%) patients had relapsed CS2. Staging was: IIA = 38, IIB = 33. Patients were treated with AP/PA (n = 45), or other (3D/conformal, VMAT or protons (n = 20)). Median follow-up time was 4.3 years (IQR: 1.9 – 7.1). Overall RFS was 91% at 1 year, 89% at 2 years, and 82% at 5 years. All recurrences were outside the RT field. De novo CS2 and patients treated in the second decade (2012-2021) exhibited a trend towards decreased recurrence (Table 1). RFS of the de novo cohort was 86%, 83%, and 74% at 1, 2, and 5 years, respectively. RFS of the relapsed cohort was 97%, 97%, and 91%, at 1, 2, and 5 years, respectively. Nine of the recurrences were salvaged with chemotherapy and one was salvaged with RT. There were no deaths due to seminoma. Two second malignancies occurred, a prostate cancer and a colorectal cancer (from which the patient died). In this contemporary cohort of patients with stage II seminoma treated with modern RT, recurrence was uncommon, particularly for patients with relapsed CS2 and those treated in most recent decade, and exclusively occurred outside the RT field. All patients were successfully salvaged, and disease-specific survival was 100%. De novo CS2 approached statistical significance as a negative prognostic factor and may portend more aggressive or already metastatic disease. [ABSTRACT FROM AUTHOR]

The use of radiation therapy (RT) and androgen deprivation therapy (ADT) following radical prostatectomy (RP) has been recently addressed by the NRG/RTOG 0534 phase III trial, which compared prostate bed RT alone (arm 1), prostate bed RT + short term (st-ADT) (arm 2), and prostate bed RT + st-ADT + pelvic lymph node (LN) RT (arm 3). A wide range of LN volumes were removed at RP prior to enrollment. We sought to study the influence of LN dissection volumes on clinical outcomes. Our hypothesis was that the number of LNs resected at RP on NRG/RTOG 0534 influences the benefit of pelvic LN RT (arm 3). Outcomes of interest included freedom from progression (FFP), time to distant metastasis (DM) and toxicity. Pretreatment characteristics were compared across quartiles of number of LNs dissected using the Kruskal Wallis test for categorical variables and the f-test from analysis of variance for continuous variables. Adjusted multivariable (MV) Cox proportional hazards models (cause-specific in the presence of competing risks) were used to assess the interaction between treatment arm and LNs dissected (0-1 vs. 2+ and as a continuous variable) with FFP and time to DM. 1,626 eligible patients had data on number of LNs dissected, 538 in arm 1 , 543 in arm 2 , and 545 in arm 3. 606 patients had 0 LNs removed, 228 had 1-2, 414 had 3-7, and 378 had over 7 LNs removed (max of 54). A higher number of LNs removed was associated with more adverse Gleason grade (p< 0.01), T-stage (p< 0.01), seminal vesicle invasion (p < 0.01), and academic medical center enrollment (p < 0.01). Controlling for differences in patient characteristics and continuous LN dissected, patients on arm 3 (vs. arm 2) did not demonstrate improvement in FFP (HR 1.19, 95% CI: 0.93-1.51, p = 0.2) nor was the interaction between treatment and LN dissected significant. Upon MV analysis for DM, there was a significant interaction between continuous number of LNs dissected and treatment arm. Specifically, patients with 0 LNs removed on arm 3 had a significant improvement in DM when compared with arms 1 and 2 (vs. arm 1 HR 2.49, 95% CI: 1.46-4.26; vs. arm 2 HR 1.75, 95% CI: 1.02-3.01). Patients with 1 node removed and on arm 3 had a significant improvement in DM when compared with arms 1 and 2 (vs. arm 1 HR 2.34, 95% CI: 1.42-3.85; vs. arm 2 HR 1.67, 95% CI: 1.00-2.77). The benefit of arm 3 vs. arm 2 was no longer significant in patients with 2+ LNs removed as the 95% CIs crossed 1.0. 2+ vs. 0-1 pelvic LNs removed and treatment on arm 3 vs. 1 exhibited higher rates of any grade renal/genitourinary toxicity (HR=1.16, 95% CI:1.02-1.31; HR=0.86, 95% CI: 0.75-0.99, respectively). The extent of surgical pelvic LN dissections influences the benefit of post-operative pelvic LN RT on FFP and DM. Patients with 0-1 LNs removed, and randomized to pelvic LN RT and st-ADT, benefitted significantly from the addition of pelvic LN RT. Although no improvements with pelvic LN RT were seen in patients with 2+ nodes removed, these analyses had low statistical power. [ABSTRACT FROM AUTHOR]

Trimodality therapy (TMT), which consists of transurethral resection of bladder tumor (TURBT) followed by chemoradiation, is an alternative to radical cystectomy for muscle-invasive bladder cancer (MIBC), but molecular determinants of response are poorly understood. We characterized the genomic and transcriptomic landscape associated with response to TMT through whole exome sequencing (WES) and expression profiling. MIBC patients treated with TMT at a single institution were identified. DNA and RNA were extracted from available FFPE pre-treatment TURBT samples, and WES and transcriptome-wide expression profiling were performed. WES data were analyzed by standard mutation analysis pipelines with a common variant filter to account for lack of matched germline samples. Somatic mutations, insertion/deletions, and copy number variations were identified. Molecular subtypes and DNA damage response (DDR) pathway scores were derived from expression profiles. Responders (R) were defined as patients with complete response at post-treatment cystoscopy and no recurrence. Nonresponders (NR) were defined as patients with incomplete response at post-treatment cystoscopy, those who underwent salvage cystectomy, or those with regional/distant disease progression. Pre-treatment TURBT FFPE samples from 77 selected TMT patients were successfully sequenced and passed quality control metrics, 68 of which had matched transcriptomic profiling. The median age of the cohort was 72.7 years; 23% were female. All patients had MIBC (87% T2, 13% T3/T4) and the majority were treated with concurrent cisplatin-based chemotherapy. Median follow-up was 42 months in alive patients. Thirty-nine patients were classified as NR, while 38 were R. Mean somatic tumor mutational burden among R and NR was 13.5 (range, 4.2-31.5) and 11.3 (range, 3.4-26.8) mutations/megabase, respectively (p=0.08). Exploratory analyses of DDR pathways revealed more patients classified as R had mutations in ERCC2 (n=7) as compared to NR (n=1), p=0.023. Six of these 8 patients with ERCC2 mutations received cisplatin-based chemotherapy; of the 2 that did not, 1 was NR. Samples with ERCC2 mutations had higher hallmark DNA repair scores (median 0.110 versus -0.310, p=0.02), suggesting dysregulation of DDR. ERCC2 mutant tumors were also enriched for GSC luminal subtype compared to ERCC2 wildtype (83% vs. 37% luminal; p=0.03). Patients with ERCC2 mutations had improved disease-specific survival (HR 0.17 (95%CI: 0.064-0.41), p=0.04). Consistent with these results, in vitro studies showed ERCC2 mutant bladder cancer cell lines are significantly more sensitive to cisplatin and radiation than isogenic ERCC2 wildtype cells. Our data demonstrate that alterations in ERCC2, a crucial DDR gene, may be associated with improved response to TMT. These findings require validation in larger cohorts. [ABSTRACT FROM AUTHOR]

Purpose/objective(s): Recurrent T1 bladder cancer has a substantial rate of progression and is usually treated with radical cystectomy. Bladder preservation therapy is a well-established approach for the treatment of muscle invasive urothelial cancer of the bladder. RTOG 0926 was a single arm, phase II trial investigating the use of trimodality bladder preservation therapy for recurrent, high-grade non-muscle invasive urothelial cancer.Materials/methods: Eligible patients had pathologically confirmed urothelial cancer of the bladder with AJCC stage T1, Nx or N0, M0. Eligible patients had recurrence of cancer following standard therapy with transurethral resection and intravesicular biological or chemotherapy. The primary endpoint of the study was three-year rate of freedom from radical cystectomy. The sample size was 37 patients, with the hypothesis that the observed rate would be at least 75%, thereby producing a lower, one-sided 97.5% confidence limit of at least 60%. Secondary endpoints included distant disease progression at 3 and 5 years, progression to muscle invasion, disease specific and overall survival, and safety. Protocol therapy consisted of maximal transurethral resection followed by chemoradiation with 61.2 Gy in 34 daily fractions along with either cisplatin or mitomycin/5-fluorouracil for radiosensitization.Results: A total of 37 patients were enrolled between 2009-2017 in this single arm study, and 34 were evaluable. Median follow up is 4.2 years, and more than 5 years in surviving patients. The three-year freedom from cystectomy rate was 88% (lower one-sided confidence limit of 70%), meeting the primary goal of the study. Overall survival at 3 and 5 years was 69% (95% CI: 53%, 85%) and 53% (95% CI: 35%, 72%), respectively. The rate of distant metastatic disease at 3 and 5 years was 12% (95% CI: 4%, 26%) and 20% (95% CI: 8%, 37%), respectively. 8 patients died of urothelial cancer. Eleven patients had local recurrence at three years (33%; 95% CI: 17%, 49%). Twenty patients (59%) had grade 3 adverse events, most commonly anemia, gastrointestinal events, UTI, lymphopenia, metabolism and nutrition disorders, or hematuria. Two grade 4 AEs were reported, one of which (neutropenia) attributed to protocol therapy. There were no deaths due to treatment. The mean AUA score was 9.8 at baseline and 12.0 at 3 years.Conclusion: Trimodality bladder preservation therapy is an effective treatment option for patients with recurrent high grade, non-muscle invasive urothelial cancer of the bladder. At three years, nearly 90% of patients remained free of cystectomy, although the overall survival was only 69% likely reflecting the age and comorbidities of this population. Bladder preservation is an effective bladder cancer treatment strategy yet remains underutilized. [ABSTRACT FROM AUTHOR]