Shah, Amit B.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. NRG Oncology RTOG 0415 is a randomized phase III noninferiority (NI) clinical trial comparing conventional fractionation (73.8 Gy in 41 fractions) radiotherapy (C-RT) with hypofractionation (H-RT; 70 Gy in 28) in patients with low-risk prostate cancer. The study included 1,092 protocol-eligible patients initially reported in 2016 with a median follow-up of 5.8 years. Updated results with median follow-up of 12.8 years are now presented. The estimated 12-year disease-free survival (DFS) is 56.1% (95% CI, 51.5 to 60.5) for C-RT and 61.8% (95% CI, 57.2 to 66.0) for H-RT. The DFS hazard ratio (H-RT/C-RT) is 0.85 (95% CI, 0.71 to 1.03), confirming NI ( P < .001). Twelve-year cumulative incidence of biochemical failure (BF) was 17.0% (95% CI, 13.8 to 20.5) for C-RT and 9.9% (95% CI, 7.5 to 12.6) for H-RT. The HR (H-RT/C-RT) comparing biochemical recurrence between the two arms was 0.55 (95% CI, 0.39 to 0.78). Late grade ≥3 GI adverse event (AE) incidence is 3.2% (C-RT) versus 4.4% (H-RT), with relative risk (RR) for H-RT versus C-RT 1.39 (95% CI, 0.75 to 2.55). Late grade ≥3 genitourinary (GU) AE incidence is 3.4% (C-RT) versus 4.2% (H-RT), RR 1.26 (95% CI, 0.69 to 2.30). Long-term DFS is noninferior with H-RT compared with C-RT. BF is less with H-RT. No significant differences in late grade ≥3 GI/GU AEs were observed between assignments (ClinicalTrials.gov identifier: NCT00331773 ).

5094 Background: In prior studies, basal vs. luminal differentiation portends differential response to a) androgen suppression (AS) duration for high-risk prostate cancer (PCa) (NRG-GU-TS006) and b) docetaxel chemotherapy (CT) and AS for metastatic hormone-sensitive disease (CHAARTED). In NRG-GU-TS006, basal tumors appeared to benefit the most from longer duration of AS while those with luminal subtype did not whereas, in CHAARTED, luminal subtype had greater benefit from addition of CT. Herein, we examined basal-luminal subtyping to predict differential response to the addition of CT in the setting of high-risk PCa treated with AS and definitive radiotherapy (AS + RT) in NRG/RTOG 0521. Methods: Per pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available NRG biobank biopsy specimens from patients enrolled on the NRG/RTOG 0521 phase III trial, which randomized patients to AS + RT +/- CT. The highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA). Basal-luminal subtypes were generated using a 215-gene PCa subtyping classifier (PSC), a second generation PAM50 basal-luminal model. Treatment effects in Luminal Proliferating (LP) and non-LP subtypes were examined with Cox (for overall survival, OS, and metastasis-free survival, MFS) and Fine & Gray (for distant metastasis, DM) multivariable (MVA) models adjusted for age and trial risk stratification, as well as with restricted mean survival times (RMST). Results: Of 183 samples available for analysis (91 from control and 92 from the CT arm), 52 (28%) were classified as LP subtype. Median follow-up for OS was 9.9 years. No significant differences in clinical or pathological variables were observed between LP and non-LP subtypes. In MVA, we did not detect any significant LP subtype-by-CT treatment interaction but observed evidence of non-proportional hazards (Grambsch-Therneau test, p<0.05). In unselected patients, 5- and 10-year RMST difference between the arms was 0.9 (95% CI [-1.5, 3.4], p=0.46) and 5.7 (95% CI [-2.5, 13.9], p=0.17) months of OS. Stratifying by tumor subtype, at 5 years the RMST difference in months was 3.8 (95% CI [0.3, 7.2], p=0.03) for LP and -0.2 ([-3.4, 2.9], p=0.89) for non-LP. The RMST difference in months at 10-years was 13.7 (95% CI [-0.2, 27.5], p=0.053) for LP and 2.5 ([-7.6, 12.5], p=0.63) for non-LP. Conclusions: In pre-treatment biopsy samples from a Phase 3 trial cohort of localized high-risk men, luminal-basal subtyping of tumors demonstrated differential response to docetaxel CT. Similar to results from the CHAARTED trial of metastatic disease, LP tumors may derive greater benefit from addition of CT. Validation of these findings may enable effective earlier use of CT in men with PCa.

PURPOSE To compare the predictive ability of mapping algorithms derived using cross-sectional and longitudinal data. METHODS This methodological assessment used data from a randomized controlled noninferiority trial of patients with low-risk prostate cancer, conducted by NRG Oncology (ClinicalTrials.gov identifier: NCT00331773 ), which examined the efficacy of conventional schedule versus hypofractionated radiation therapy (three-dimensional conformal external beam radiation therapy/IMRT). Health-related quality-of-life data were collected using the Expanded Prostate Cancer Index Composite (EPIC), and health utilities were obtained using EuroQOL-5D-3L (EQ-5D) at baseline and 6, 12, 24, and 60 months postintervention. Mapping algorithms were estimated using ordinary least squares regression models through five-fold cross-validation in baseline cross-sectional data and combined longitudinal data from all assessment periods; random effects specifications were also estimated in longitudinal data. Predictive performance was compared using root mean square error. Longitudinal predictive ability of models obtained using baseline data was examined using mean absolute differences in the reported and predicted utilities. RESULTS A total of 267 (and 199) patients in the estimation sample had complete EQ-5D and EPIC domain (and subdomain) data at baseline and at all subsequent assessments. Ordinary least squares models using combined data showed better predictive ability (lowest root mean square error) in the validation phase for algorithms with EPIC domain/subdomain data alone, whereas models using baseline data outperformed other specifications in the validation phase when patient covariates were also modeled. The mean absolute differences were lower for models using EPIC subdomain data compared with EPIC domain data and generally decreased as the time of assessment increased. CONCLUSION Overall, mapping algorithms obtained using baseline cross-sectional data showed the best predictive performance. Furthermore, these models demonstrated satisfactory longitudinal predictive ability.

Abstract Background: Prostate cancer is the most common cancer among men. Monitoring of patient-reported outcomes (PROs) can enhance provider-patient communication, promote better decision-making, and improve survival. Geospatial factors, namely rurality and neighborhood socioeconomic deprivation, could influence the experience across cancer treatment, thus impacting PROs and survival. This study examined associations of rurality, neighborhood socioeconomic deprivation (Area Deprivation Index [ADI]) with cancer treatment-related PROs and survival in men with prostate cancer. Methods: Data from men with prostate cancer in the trial NRG Oncology/RTOG 0415 were analyzed. In this trial, 1092 men were randomized to receive conventional radiotherapy (RT) or hypofractionated RT. Patients had Gleason scores of 2-6 and prostate-specific antigen of &lt;10 ng/mL. Rurality was categorized as urban vs rural using Rural-Urban Continuum Codes via patient zip codes. Neighborhood socioeconomic deprivation was assessed by the ADI calculated via the American Community Survey by patient zip codes. The Expanded Prostate Cancer Index Composite (EPIC) measures cancer-specific quality of life (QOL); Hopkins Symptom Checklist measures anxiety and depression; EuroQoL-5 Dimension (EQ-5D) VAS and Index scores assess general health. All PROs were measured at baseline before and 6, 12, 24 and 60 months after RT. Overall survival (OS) and disease-free survival (DFS) were assessed using Cox proportional hazards models. Mixed effects models and generalized estimating equations were used to analyze PROs. Results: We analyzed 751 patients with complete data. Patients from the ADI 25% most deprived neighborhoods (vs. the other 75% of neighborhoods) were more likely to be non-white, unmarried and from rural areas. At baseline, patients from the most deprived areas had worse EPIC bowel score (P=0.011), worse sexual score (P=0.042) and worse hormonal score (P=0.015); patients from the most deprived areas had worse self-care (P=0.04) and more pain (P=0.047). Patients from rural areas had worse EPIC urinary score (P=0.03) and sexual score (P=0.003). Longitudinal analyses showed that ADI 25% most deprived areas (β=4.05, P=0.001) and rural areas (β=-5.70, P=0.003) were associated with worse EQ-5D VAS score. Compared to the 75% less deprived neighborhoods and urban, the ADI 25% most deprived neighborhoods and rural areas respectively had 47% (HR=1.466, P=0.033) and 93% (HR=1.925, P=0.026) relative increase in risk of recurrence or death (DFS). No differences were seen in OS. Conclusions: Patients with prostate cancer from the most deprived neighborhoods and rural areas had low QOL at baseline, poor general health and DFS. Interventions should target populations from socioeconomic deprived neighborhoods and rural areas to improve patient access to supportive care services and DFS. Citation Format: Jinbing Bai, Stephanie L. Pugh, Ronald Eldridge, Katherine Yeager, Qi Zhang, W Robert Lee, Amit B. Shah, Ian S. Dayes, David P. D'Souza, Jeff M. Michalski, Jason A. Efstathiou, John M. Longo, Thomas M. Pisansky, Jordan M. Maier, Sergio L. Faria, Anand B. Desai, Samantha A. Seaward, Howard M. Sandler, Mary E. Cooley, Deborah W. Bruner. Rurality and neighborhood socioeconomic deprivation associated with patient-reported outcomes andsurvivalin men with prostate cancer in NRG RTOG 0415 [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 2528.

60 Background: Mapping algorithms informing economic evaluations are often derived using baseline data from clinical trials. It is unclear if these algorithms can predict health utilities accurately in post-intervention data. Thus, this study examines the longitudinal predictive ability of mapping algorithms derived from baseline trial data and explores the factors associated with prediction errors. Methods: This methodological study utilized data from an international, multicenter, randomized controlled trial of patients with low-risk prostate cancer (PC), conducted by NRG Oncology (NCT00331773). In addition to patient demographic and clinical data, this study utilized PRO data collected at baseline and 6, 12 and 24 months post-intervention. The Expanded Prostate Cancer Index Composite (EPIC) questionnaire measures health-related quality-of-life (HRQoL) and has four domains (urinary, sexual, hormonal, and bowel) and two subdomains per domain (function and bother); EuroQOL-5D-3L (EQ5D) captures health utilities. Ordinary Least Squares (OLS) regression models were used to map EPIC scores to EQ5D utilities in the baseline data through 5-fold cross-validation. Predictive performance was tested in the post-intervention data; predicted and reported utilities were compared using t-tests, and the absolute prediction error was modeled using fixed effects, as a function of baseline demographic and clinical covariates, as well as observed and predicted EQ5D utilities. Results: A total of 267 (199) patients had complete EQ5D and EPIC domain (or subdomain) data at baseline and all subsequent assessments. In the EPIC domain sample, mean ± standard deviation observed EQ5D utility was 0.90±0.13 at baseline, 0.92±0.11 at 6 months, 0.90±0.13 at 12 months and 0.89±0.14 at 24 months. Mean absolute differences (MDs) between reported and predicted were lower for models using EPIC subdomain data compared to EPIC domain data, and generally decreased as the time of assessment increased. The mapping functions over-predicted utilities for patients in perfect health while the prediction errors were increasingly negative for lower reported EQ5D scores. According to the fixed effects model for EPIC domain data, lower observed and predicted baseline EQ5D scores, and time of assessment were significant predictors of the absolute prediction error; for EPIC subdomain data, lower observed and predicted baseline EQ5D scores, hormonal bother and function, and bowel function significantly predicted the absolute prediction error. Conclusions: This study is the first to demonstrate the longitudinal validity of EPIC questionnaire, and builds upon existing research on longitudinal validity of mapping functions. The low MDs in prediction errors in post-intervention data indicate that the mapping functions are sensitive to treatment effect, thereby increasing confidence in their use in economic evaluations in PC.

1 Background: To determine whether the efficacy of a hypofractionated (H) schedule is no worse than a conventional (C) schedule in men with low-risk prostate cancer. Methods: From April 2006 to December 2009, one thousand one hundred fifteen men with low-risk prostate cancer (clinical stage T1-2a, Gleason ≤ 6, PSA < 10) were randomly assigned 1:1 to a conventional (C) schedule (73.8 Gy in 41 fractions over 8.2 weeks) or to a hypofractionated (H) schedule (70 Gy in 28 fractions over 5.6 weeks). The trial was designed to establish with 90% power and alpha = 0.05 that (H) results in 5-year disease-free survival (DFS) that is not lower than (C) by more than 7% (hazard ratio (HR) < 1.52). Secondary endpoints include freedom from biochemical recurrence (FFBR) and overall survival. At the third planned interim analysis (July 2015), the NRG Oncology Data Monitoring Committee recommended that the results of the trial be reported. Results: One thousand one hundred and one protocol eligible men were randomized: 547 to C and 554 to H. Median follow-up is 5.9 years. Baseline characteristics are not different according to treatment arm. At the time of analysis 185 DFS events have been observed; 99 in the C arm and 86 in the H arm. The estimated 7-year disease-free survival is 75.6% (95% CI 70.3, 80.1) in the C arm and 81.8% (77.5, 85.3) in the H arm. The DFS HR (C/H) is 0.85 (0.64, 1.14). Comparison of biochemical recurrence (HR = 0.77, (0.51, 1.17)) and overall survival (HR = 0.95, (0.65, 1.41)) also met protocol non-inferiority criteria. Grade ≥ 3 GI toxicity is 3.0% (C) vs. 4.6% (H), Relative risk (RR) for H vs. C 1.53, (95% CI 0.86, 2.83); grade ≥ 3 GU toxicity is 4.5% (C) vs. 6.4% (H), RR = 1.43 (0.86,2.37). Conclusions: In men with low-risk prostate cancer, 70 Gy in 28 fractions over 5.6 weeks is non-inferior to 73.8 Gy in 41 fractions over 8.2 weeks. Clinical trial information: NCT00331773.