Rosenthal, Seth A.

PURPOSE Precision medicine has revolutionized oncology; however, tumor biomarkers are not reflective of the heterogeneous cancer population. We evaluated NRG Oncology prostate cancer (PCa) clinical trials for demographic differences among patients with optional biospecimen collection (BC) consent and biospecimen submission (BSub). METHODS Data from 19 NRG PCa clinical trials closed before 2015 were analyzed. Patients who consented to BC and completed BSub were evaluated by race, ethnicity, median income, area deprivation index (ADI; categorized as highest v lowest three quartiles), age at enrollment, site, and year of enrollment. T/chi-square tests were used for continuous/categorical variables, respectively, followed by logistic regression. RESULTS Of the 15,648 randomized patients eligible for BC, 11,796 (75%) had specimens submitted. In all, 4,598 (82.2%) of 5,597 eligible patients consented for optional BC in nine clinical trials with a separate BC consent process (consent rates by race/ethnicity: 74.1% Black, 72.8% Hispanic/Latino, 83.8% White). A smaller proportion of Black and Hispanic/Latino patients consented to optional BC compared with those who did not (12.1% v 19.5% Black, P < .0001; 3.5% v 5.8% Hispanic, P = .0006). In univariable logistic regression models, high ADI (more socioeconomic disadvantage) was associated with a decreased likelihood for optional BC consent (odds ratio [OR], 0.67 [95% CI, 0.55 to 0.82]; P = .02), but not a decreased likelihood for BSub (OR, 0.74 [95% CI, 0.53 to 1.04]; P = .08). Multivariable models demonstrated that Black/Hispanic/Latino patients were less likely to consent to optional BC, and Black patients were less likely to have BSub ( P < .05 for all). CONCLUSION White/non-Hispanic patients and those with less socioeconomic disadvantage were more likely to consent to optional BC, whereas Black patients were less likely to have BSub. Targeted solutions are needed to improve biorepository representation so that precision medicine approaches better reflect the cancer population.

ABSTRACTBackgroundWe aim to evaluate whether increased lymph node yield at prostatectomy (RP) is associated with improved outcomes in NRG/RTOG 9601, a randomized clinical trial of men who underwent either radiation (RT) alone or RT + bicalutamide for PSA elevation following RP for pT2/T3 prostate cancer.MethodsWe reviewed available pathology reports for patients in NRG/RTOG 9601 to determine the nodal count at RP. Cox proportional hazards models were used to assess effect of lymph nodes yield, arm (RT alone or RT + bicalutamide), Gleason score, positive margins, and seminal vesicle invasion on the following endpoints: times to local and distant failure and overall and disease‐specific survival.ResultsOf 760 patients, 552 (73%, 276 in each arm) had complete data available. Median node count in the entire cohort was 6 (range: 0–33, IQR: 3–9). There were no significant differences between arms in terms of patient demographic or clinical characteristics, including total lymph nodes removed in either arm. There was no significant association between total lymph nodes and overall or disease‐specific survival with both arms combined and when adjusting for arm. Notably, interaction analysis revealed that in seminal vesicle invasion, there was a significant association between lymph node yield and OS and DSS (HR = 0.91, 95% CI: 0.83–0.99, p = 0.034; HR = 0.87, 95% CI: 0.77–0.99, p = 0.029, respectively).ConclusionsAlthough lymph node yield in NRG/RTOG 9601 did not show association with adverse outcomes in the entire cohort or either arm alone, there was significant association between lymph node yield and adverse outcomes when seminal vesicle invasion was present. The therapeutic benefit of extensive lymph node dissection remains uncertain but could be more relevant in higher risk patients.

309 Background: Standard of care (SOC) treatment options for HR-PCa include RT with long-term androgen deprivation (LT-ADT) or RP with selective use of post-operative RT +/- androgen deprivation therapy (ADT). The optimal treatment approach has been assessed in retrospective population-based and multi-center comparisons, which have yielded mixed results with substantial bias. Therefore, we conducted an emulated randomized comparison of RT vs RP in HR-PCa leveraging patients enrolled in RCTs. Methods: We searched Medline for RCTs in HR-PCa with a SOC arm of an RT- or RP-based regimen. Inclusion required similar experimental treatment and contemporaneous enrollment in the same country to reduce bias. This identified 2 trials, NRG/RTOG 0521 (RT+LT-ADT +/- 6 cycles docetaxel [doce]), and CALGB 90203 (RP +/- neoadjuvant 6 cycles doce and ADT). Due to inherent difference in the biochemical recurrence criteria after RT vs RP, we chose inverse probability of treatment weighted (IPTW) cumulative incidence of distant metastasis (DM) as the primary endpoint, considering deaths as competing events. Death after DM was measured to create a harmonized metric of deaths likely attributed to PCa. To assess potential residual selection bias, death without DM to capture non-cancer associated deaths was analyzed. Results: Overall, 1290 patients (RT n=557, RP n=733) were included, with similar median follow-up of 6.4 years. Prior to IPTW, RP patients were significantly younger with lower baseline PSA compared to RT patients. Adjuvant (18%) and salvage therapy (44%) was used in RP cohort. Cumulative incidence of DM was significantly lower in patients who underwent RT compared to RP (8-year DM: 16% vs 23%; p=0.01; subdistribution hazard ratio [sHR] 0.48 [95%CI 0.34-0.69], p<0.001). 8-year rates of death after DM were 10% vs 8% (p=0.72) in the RP and RT patients, respectively. RT patients had significantly greater risk of death without DM (HR 2.09 [1.01-4.34], p=0.048) with early differences measured. On a cross-arm comparison, 8-year cumulative incidence of DM when comparing SOC RT+LT-ADT group versus the doce+ADT+RP group was 18% vs 21%, respectively (sHR 0.75 [0.45-1.24], p=0.26). Conclusions: HR-PCa patients enrolled on RCTs had significantly lower incidence of DM with an RT-based strategy compared to an RP-based approach. Longer follow-up is needed to assess deaths attributed to PCa. Despite the strengths of the comparison (use of cooperative group RCT data, contemporaneous enrollment in the same country, patients fit enough for chemotherapy, and IPTW adjustments) there appears to be residual unmeasured bias, as expected, based on greater early deaths without DM in the RT arm. Utilization of post-operative radiotherapy and ADT+Doce may mitigate differences between RP and SOC RT+LT-ADT.

320 Background: sRT is used in men with prostate cancer (PC) recurrence following radical prostatectomy (RP) signaled by a persistent or delayed elevation in PSA. It was previously reported that the use of AAT with RT improved cancer control and overall survival (OS). Long-term follow-up (FU) results are presented here. Methods: From 1998to 2003, 760 eligible post-RP patients with Stage pT3N0 or with pT2N0 and positive margins and PSA from 0.2 to 4.0 ng/mL were randomly assigned on a double-blinded, placebo-controlled trial of RT + placebo vs. RT + anti-androgen therapy (AAT) (24 months of bicalutamide, 150mg daily) during and after RT (64.8 Gy in 36 fractions prostate bed). The primary endpoint was OS estimated using Kaplan-Meier method. Time to PC death and metastatic PC (competing risk of death without an event) was estimated using cumulative incidence. The hazard ratio (HR) was obtained using Cox models (OS) and subdistribution HRs (sHRs) used the Fine-Gray model (time to PC death and metastatic PC). All tests are one-sided based on study design. Results: Median FU for surviving patients was 19 years. OS at 18 years was 53% [95% confidence interval (CI): 47-58%] for RT + AAT and 43% [95% CI: 38-48%] for RT + placebo (adjusted HR 0.82 [95% CI: 0.67-1.00], p = 0.025). The 18-year incidence of centrally reviewed PC deaths were 18% [95% CI: 14-22%] RT + AAT and 28% [95% CI: 23-32%] RT + placebo (adjusted sHR = 0.57 [95% CI: 0.42-0.78], p<0.001). The 18-year incidence of metastatic PC was 22% [95% CI: 18-26%] and 31% [95% CI: 26-35%] for AAT and placebo arms respectively with adjusted sHR = 0.59 [95% CI: 0.44-0.80, p<0.001]. Subgroup analyses is shown in the Table. Conclusions: Long term results of 24-month duration AAT during and after sRT are consistent with the primary report with significantly improved long-term OS, reduced incidence of metastatic PC and PC death for RT+AAT. Statistically significant metastatic PC was noted for Gleason score 8-10, study entry PSA>1.5 and margin positive patients and borderline significance was observed in patients with study entry PSA 0.7-1.5. Clinical trial information: NCT00002874 . [Table: see text]

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.

265 Background: A recent study ( Fossati et al, 2018) found that higher lymph node count at radical prostatectomy was associated with improved outcomes in patients treated with salvage radiation for elevated prostate-specific antigen (PSA) after surgery. We sought to validate these results in NRG/RTOG 9601, a randomized controlled trial of men with pT2/T3 disease who underwent either radiation (RT) alone or RT+antiandrogen (bicalutamide) therapy for PSA elevation following radical prostatectomy from 1998-2003. Methods: We reviewed available pathology reports for all patients in NRG/RTOG 9601 to determine the nodal count at radical prostatectomy. Clinical data was as of 11/5/2015, same as the primary endpoint for the trial. Cox proportional hazards models were used to assess the effect of number of positive lymph nodes, treatment arm (RT alone or RT+bicalutamide), Gleason score, positive margins, and seminal vesicle invasion on the following endpoints: times to local and distant failure and overall and disease specific survival. Results: Out of the 760 patients originally eligible in the trial, 552 (73%, 276 in each arm) had complete data available. Median node count in the entire cohort was 6 (range 0-33, Q1-Q3 3-9). There were no significant differences between treatment arms in terms of patient demographic or clinical characteristics, including total lymph nodes removed in either arm (RT alone vs RT+bicalutamide median 5 vs 6, p = 0.11). There was no significant association between total lymph nodes and overall survival with both arms combined (HR = 1.00, 95% CI:0.97-1.03, p = 0.87) or in the individual arms alone (RT+Casodex: HR = 1.01, 95% CI:0.97-1.05, p = 0.65; RT+Placebo: HR = 0.98, 95% CI: 0.94-1.03, p = 0.45). There was also no significant association between total lymph nodes and disease-specific survival with both arms combined (HR = 1.00, 95% CI:0.95-1.04, p = 0.84) and in the arms alone (RT+Casodex: HR = 1.00, 95% CI:0.95-1.05, p = 0.92; RT+Placebo: HR = 0.99, 95% CI: 0.92-1.07, p = 0.86). In multivariable analysis performed on the two arms, Gleason score was the only feature associated with worse overall and disease-specific survival, seen only in the RT alone arm. Similar findings were seen when evaluating times to local and distant failure. Conclusions: Lymph node yield in NRG/RTOG 9601 did not show any association with adverse outcomes in the entire cohort, or in either treatment arm alone. The therapeutic benefit of an extensive lymph node dissection in this population remains uncertain. Clinical trial information: NCT00002874.

9525 Background: Determine if prophylactic tadalafil maintains spontaneous (off-drug) erectile function (EF) compared to placebo in patients (pts) treated with radiotherapy (RT) for prostate cancer. Methods: Double-blind 1:1 randomization to tadalafil 5mg daily for 6 mos vs placebo starting with RT. Primary outcomes measured by International Index of Erectile Function (IIEF). Eligibility included pre-RT IIEF Question [Q] 1 response “sometimes/most times/always” able to get an erection. Ps treated with hormones were excluded. Primary outcome was response to IIEF Q1 at 30 wks (6 wks off drug). Pts were stratified by RT modality (external vs. brachytherapy) and age (≤65 vs. >65 years). 182 pts were needed in an intent-to-treat analysis to show a difference from 20% responders with placebo to 40% with tadalafil based on a 2-sided Fishers exact test with α=0.05 and 80% power. Results: We report on 155/222 analyzable/eligible pts. Median age was 63 years, white (73%), and external RT (63%). Mean total dose for external RT was 77.23 Gy and 136.74 Gy for brachytherapy with penile bulb D50 of 24.46 Gy and 31.24 Gy respectively. Most pts completed treatment per protocol (84% tadalafil, 70% placebo). Spontaneous EF at 30 wks from drug start was not different (p=0.99) between arms based on IIEF Q1 response, total IIEF score (52.5 drug vs 52.8 placebo), or score change from baseline (-8.0 drug vs -8.8 placebo). No difference in these outcomes was noted at 1 year. Non-responders at 30 wks were likely to be older (age≥65; p=0.432), but there were no significant predictors at 1 year. About 80% of pts maintained spontaneous EF in both arms. Conclusions: Low-dose daily tadalafil did not preserve EF within the first year of RT for prostate cancer. If tadalafil positively influences delayed RT-induced vasogenic injury, additional time may be needed to observe a benefit to tadalafil as a preventive agent. Alternatively, tadalafil dose modification or altered dosing schedules may be needed to demonstrate a protective effect of this agent when used with RT. Clinical trial information: NCT00951184.

327 Background: Though Black men with prostate cancer are more likely to have aggressive disease features than White men, race-specific differences in initial treatment responses in localized disease remains unknown. Methods: Individual patient data were obtained for 9259 patients (including 1674 [18.1%] Black men and 7585 [81.9%] White men) enrolled on eight randomized controlled trials evaluating definitive radiotherapy (RT) ± short-term or long-term androgen deprivation therapy (STADT and LTADT). The primary endpoints were biochemical recurrence (BCR), distant metastasis (DM), and prostate cancer-specific mortality (PCSM). Fine-Gray subdistribution HR (sHR) models were developed to evaluate the cumulative incidences of all endpoints after stratification by National Comprehensive Cancer Network risk grouping. A meta-analysis was done to estimate pair-wise comparisons of treatments within and between Black and White men, after adjusting for age, Gleason score, clinical T stage, and initial PSA. Results: Black men were more likely to have NCCN high-risk disease at enrollment (656/1674 [39.2%] vs 2506/7585 [33%], p<0.001). However, within the high-risk stratum Black men had lower 10-year rates of BCR (46.1% vs. 50.4%, p=0.02), DM (14% vs. 21.6%, p<0.001), and PCSM (4.9% vs. 9.8%, p<0.001). After adjusting for age and disease characteristics, Black men with high-risk prostate receiving RT+STADT had lower rates of BCR (sHR 0.73, 95% CI 0.62-0.86, p<0.001), DM (sHR 0.64, 95% CI 0.49-0.84, p=0.001) and PCSM (sHR 0.49, 95% CI 0.25-0.95, p=0.04). There were no differences in BCR, DM, or PCSM among men receiving RT+LTADT. The interaction between race and the impact of adding STADT to RT alone on BCR was statistically significant (p=0.003). Conclusions: Black men enrolled on randomized trials with long-term follow-up have higher risk disease at enrollment, but have better BCR, DM, and PCSM outcomes with RT-based therapy compared with White men, particularly with the addition of STADT.