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366 Background: The kinetics of testosterone recovery (TR) vary following cessation of androgen deprivation therapy (ADT) of various durations when given in combination with radiotherapy for prostate cancer. Time to TR will impact on quality of life. We aim to identify factors affecting the time to TR following ADT use. Methods: We included trials of prostate radiotherapy and ADT in the Meta-Analysis of Randomized trials in Cancer of the Prostate (MARCAP) consortium for which prospectively collected serial testosterone data is available. Time to non-hypogonadal TR (NHTR) (>8.0nmol/L) and time to full TR (FTR) (>10.5nmol/L) were estimated from the date of first available testosterone at trial enrolment to the date of TR using the Kaplan-Meier method. The effect of interactions between duration of ADT and patients’ age on TR was evaluated. Results: There were 1439 men with non-castrate testosterone at baseline (>1.7nmol/L) who met the inclusion criteria for analysis, of which 220, 765 and 454 men had 3-, 6-, and 18-months of ADT. There were 959 (67%) men who had FTR at last follow-up. For men who had 3-, 6-, and 18-months of ADT, the median time (range) to NHTR were 5.5 (1.6-76.3), 12.2 (0.8-53.6), and 30.1 (2.8-90.4) months respectively, while the median time (range) to FTR were 6.2 (1.8-75.7), 15.2 (0.8-86.0), and 36.0 (18.1-85.5) months respectively. In the subset of 1160 men who had normal testosterone at baseline (>10.5nmol/L), 851 (69%) men had FTR, with a median time (range) to FTR of 5.5 (1.8-75.7), 12.7 (1.8-86.0), and 30.8 (18.1-84.1) months for men who had 3-, 6- and 18-months ADT, respectively. For any given duration of ADT, men aged above 65 years were less likely to have FTR compared to those aged under 65 years – HR=0.67 (95%CI=0.46-0.99), HR=0.80 (95%CI=0.67-0.96), HR=0.64 (95%CI=0.51-0.81) for men who had 3-, 6-, and 18-months ADT respectively. There was no evidence of interaction between the effect of ADT duration on time to FTR and age (interaction P=0.3 for entire cohort). Conclusions: This is the largest pooled analysis of prospectively collected serial testosterone data from randomized trials, indicating substantial delay in FTR in men receiving longer durations of ADT. Approximately one-third of the men did not achieve FTR, which may have life-long impact on quality of life.

136 Background: rPFS is often used as an intermediate clinical endpoint (ICE) for overall survival (OS) in randomized trials in mCRPC. However, the current literature shows conflicting results on the surrogacy of rPFS for OS. Moreover, it remains unknown if TTrP, which does not consider death as an event, is an ICE for OS. We performed a combined analysis of COU-AA-302 and ACIS to determine if TTrP and rPFS can be used as ICE. Methods: In COU trial, docetaxel-naïve mCRPC patients were randomized to abiraterone (abi) versus placebo. In ACIS, a similar patient population was randomized to abi alone or abi with apalutamide (abi+apa). We applied weighted Cox regression models to evaluate the effect of treatment on TTrP and OS and used landmark analyses to determine the if the treatment effect on OS is mediated by that on radiographic progression. We estimated a semiparametric Spearman correlation between the ICE and OS at the patient level. We determined the trial level correlation of treatment effect on the ICE and OS in the 2 trials where each of them was subdivided into 9 pseudo-trial centers and then calculating the adjusted R2 between center level estimates of treatment effect for ICE and OS. The procedure of creating pseudo-trial centers was repeated 500 times and the presented R2 is the average across 500 repetitions after excluding those with negative association. Results: Overall, 2016 patients were eligible for this study – 1053 from COU and 963 from ACIS. Abi was associated with superior TTrP (HR 0.55 [95%CI 0.45-0.66]) and OS (HR 0.80 [0.70-0.92]). Similar results were seen with abi+apa (0.51 [0.41-0.64], 0.77 [0.65-0.91]). Radiographic progression was associated with significantly higher hazard of death in the state arrival extended Markov proportional hazard model (3.64 [1.54-8.62]) while longer TTrP was associated with reduced hazard of death (0.94 [0.93-0.95]). At the patient level, the correlation between TTrP & OS and rPFS & OS was 0.58 [0.54-0.63] and 0.68 [0.65-0.71], in the overall cohort. In the abi and abi+apa group, the correlation between TTrP and OS was 0.60 [0.53-0.66] and 0.73 [0.66-0.79] and that for rPFS and OS was 0.72 [0.67-0.75] and 0.79 [0.74-0.83], respectively. At the trial level, the treatment effect on rPFS & OS and TTrP & OS were correlated with average R2 of 0.84, 0.84, 0.85, and 0.86, respectively. The mean surrogate threshold effect over 500 permutations for HRrPFS and HRTTrP was 0.78 and 0.70 in ACIS and 0.54 and 0.45 in the COU-AA-302 trials, respectively. Conclusions: TTrP and rPFS were found to have significant association with OS in chemo-naïve mCRPC patients. We noted a modest to strong correlation between the treatment effect on both the ICE and OS at the trial level. Larger meta-analytic studies are needed to validate these findings.

391 Background: Event-free survival, a PSA-driven endpoint, was shown to not be surrogate endpoint for overall survival (OS) in the ICECAP two-stage meta-analytic approach. However, time to biochemical recurrence (TTBCR) in NRG/RTOG 9202 met Prentice criteria for surrogacy. We performed an individual patient data (IPD) meta-analysis of 11 randomized controlled trials evaluating RT dose escalation, ADT use, and adjuvant ADT prolongation to evaluate the surrogacy of time to BCR (TTBCR), censoring for non-prostate cancer deaths, using both approaches to evaluate surrogacy. Methods: This individual patient level meta-analysis was performed using data from the MARCAP consortium, and 11 radiotherapy trials were included. TTBCR was defined as time to developing a BCR or experiencing prostate cancer-specific mortality (PCSM), with censoring at time of other-cause death or loss to follow-up. Landmark analyses were used to test the Prentice criteria for surrogacy. For patient level correlation between TTBCR and OS, we applied a bivariate Copula model to estimate the Kendall’s τ. For trial level correlation of the treatment effect on TTBCR and true endpoints, a weighted linear regression model was applied between the effects of treatment (natural log of hazard ratio [log-HR]) on OS versus TTBCR using a weightage that was inverse variance of BCR log-HR estimate. Results: Based on Prentice criteria, BCR at the landmark time point of 48 months was associated with increased risk of mortality in trials that compared treatment intensification with adjuvant ADT prolongation (HR 2.18 [95% CI 1.95-2.42]), the addition of ADT (HR 1.38 [1.25-1.54]), and RT dose escalation (HR 2.12 [1.83-2.46]) on uni- and multi-variable analyses. At the patient level, there was a low to moderate level correlation between BCR and OS with Kendall’s τ of 0.34 and a R2 of 0.55 for correlation of treatment effect on TTBCR and OS. At the trial level, there was a poor correlation between treatment effect on TTBCR and OS (R2=0.16). Conclusions: This IPD meta-analysis demonstrates that while BCR is prognostic, it is not a surrogate endpoint for OS in localized prostate cancer for patients treated with a diverse array of radiotherapeutic strategies. This highlights the importance of other cause mortality in prostate cancer. Our results highlight the differences in interpretability of Prentice criteria and the two-stage meta-analytic approach and suitability of endpoints for clinical trial design.

5039 Background: The Intermediate Clinical Endpoints (ICEs) in Cancer of the Prostate (ICECaP) working group identified metastasis-free survival as a valid surrogate endpoint for overall survival (OS) for patients with localized prostate cancer. No comparably validated surrogate endpoints for OS exist in advanced prostate cancer. Methods: In this meta-analysis, PubMed was searched for trials in advanced prostate cancer, defined as node positive (N1M0), metastatic castration-sensitive (mCSPC), non-metastatic (M0CRPC), or metastatic castration-resistant prostate cancer (mCRPC). Eligible randomized trials were required to report OS and ≥1 intermediate clinical endpoint (ICE). ICEs included biochemical-failure (BF), clinical failure (CF), BF-free survival (BFS), progression-free survival (PFS), radiographic PFS (radiographic +/- other study defined endpoints). Candidacy for surrogacy was assessed using the second condition of the meta-analytic approach, correlation of the treatment effect of the ICE and OS, using R2 weighted by the inverse variance of the log ICE hazard ratio and defined as an R2 > 0.70. Results: A total of 143 randomized trials (n = 75,601 patients) were included. No candidate endpoints met criteria for surrogacy; R2 BF (n = 28,922) 0.42 (95%CI 0.18-0.64), BFS (n = 25,741) 0.57 (95%CI 0.37-0.73), CF (n = 22,616) 0.31 (95%CI 0.0075-0.56), PFS (n = 52,639) 0.50 (95%CI 0.35-0.63), and radiographic PFS (n = 52,548) 0.50 (95%CI 0.35-0.63). Within preplanned subgroups by castration sensitive or resistant disease, or by treatment type, neither BFS nor PFS met criteria for surrogacy. When assessing radiographically-defined progression (exclusive or with clinical progression), PFS for the overall group and by castration status did not meet criteria for surrogacy. Sensitivity analyses demonstrated that candidacy for surrogacy of all endpoints tested did not change over time. Conclusions: Our aggregate screening method for surrogate endpoints in advanced prostate cancer demonstrated commonly used clinical endpoints are not valid surrogate endpoints for OS, and further composite endpoint construction is necessary.

e17006 Background: In 2021, national data between the Decipher 22-gene prognostic gene expression classifier (GC) for men with prostate cancer and the Surveillance, Epidemiology, and End Results (SEER) cancer registries were linked. The purpose of the work is to report on the linkage by characterizing national GC usage and its association with treatment decisions for men with prostate cancer. Methods: Patients in the SEER registries with primary prostate cancer diagnosis from 2010 to 2018 were included and linked to data from GC testing conducted between 2014 to 2020 (Veracyte, San Diego, CA). GC scores (range 0-1) and GC risk groups (low, intermediate, and high) were used for continuous and categorical analyses. Multivariable logistic regression was used to quantify the association between GC and active surveillance and watchful waiting (AS/WW) use and adverse pathology at radical prostatectomy (RP). Adverse pathology was defined as pathological grade group ≥3, pathological stage ≥pT3b, or lymph node invasion. Results: A total of 575,363 patients were eligible for analysis, of which 10,528 patients underwent GC testing (5,015 GC biopsy test, and 5,513 GC RP test). The median age was 67 for both tested and untested, but more white patients underwent testing (82% vs 76%, p < 0.001). For GC biopsy tested patients, AS/WW was highest for those with GC low risk results (41%) as compared to those with intermediate (32%) or high (17%) GC risk (p < 0.001). RP rates were lower in the tested compared to untested (25% vs. 36%, p < 0.001), and among the tested patients, RP use increased by GC risk group (19% of low, 25% of intermediate, and 34% of high GC risk, p < 0.001). A similar trend by GC risk group in management for radiation therapy was observed (13% of low, 19% of intermediate, and 29% of high GC risk, p < 0.001). In a multivariable logistic regression adjusted for age, race, NCCN risk group, and year of diagnosis, GC tested patients were more likely to undergo AS/WW compared to untested (OR 2.9 [95% CI, 2.8-3.1], p < 0.001). Within the subset of patients classified as NCCN low/favorable intermediate risk at biopsy and who were subsequently treated with RP (n = 594), GC high risk (> 0.6) was associated with more than 3 times the odds of harboring adverse pathology (OR 3.2 [95% CI 1.6-6.4], p < 0.001). Conclusions: Using the first ever linked SEER-Decipher data, we demonstrate that population-based treatment patterns are independently associated with GC test results. Patients with lower GC scores are independently more likely to undergo AS/WW; those with higher scores are more likely to have adverse pathology at time of RP.

223 Background: The current standard of care for men with intermediate- and high-risk localized prostate cancer treated with radiotherapy (RT) is the addition of androgen deprivation therapy (ADT). Presently, there are no validated predictive biomarkers to guide ADT use or duration in such men. Herein, we train and validate the first predictive biomarker for ADT use in prostate cancer using multiple phase III NRG Oncology randomized trials. Methods: Pre-treatment biopsy slides were digitized from five phase III NRG Oncology randomized trials of men receiving RT with or without ADT. The training set to develop the artificial intelligence (AI)-derived predictive biomarker included NRG/RTOG 9202, 9413, 9910, and 0126, and was trained to predict distant metastasis (DM). A multimodal deep learning architecture was developed to learn from both clinicopathologic and digital imaging histopathology data and identify differential outcomes by treatment type. After the model was locked, an independent biostatistician performed validation on NRG/RTOG 9408, a phase III randomized trial of RT +/- 4 months of ADT. The DM rates were calculated using cumulative incidence functions in biomarker positive and negative groups, and biomarker-treatment interaction was assessed using Fine-Gray regression such that death without DM was treated as a competing event. Results: Clinical and histopathological data was available for 5,654 of 7,957 eligible patients (71.1%). The training cohort included 3,935 patients and had a median follow-up of 13.6 years (IQR [10.2, 17.7]). After the AI-derived predictive ADT classifier was trained, it was validated in NRG/RTOG 9408 (n = 1719, median follow-up 17.6 years, IQR [15.0, 19.7]). In the NRG/RTOG 9408 validation cohort that had digital histopathology data, ADT significantly improved DM (HR 0.62, 95% CI [0.44, 0.87], p = 0.006), consistent with the published trial results. The biomarker-treatment interaction was significant (p-value = 0.0021). In patients with AI-biomarker positive disease (n = 673, 39%), ADT had a greater benefit compared to RT alone (HR 0.33, 95% CI [0.19, 0.57], p < 0.001). In the biomarker negative subgroup (n = 1046, 61%), the addition of ADT did not improve outcomes over RT alone (HR 1.00, 95% CI [0.64, 1.57], p = 0.99). The 15-year DM rate difference between RT versus RT+ADT in the biomarker negative group was 0.3%, vs biomarker positive group 9.4%. Conclusions: We have successfully validated in a phase III randomized trial the first predictive biomarker of ADT benefit with RT in localized intermediate risk prostate cancer using a novel AI-derived digital pathology-based platform. This AI-derived predictive biomarker demonstrates that a majority of patients treated with RT on NRG/RTOG 9408 did not require ADT and could have avoided the associated costs and side effects of this treatment.

9549 Background: Standard combination ipilimumab/nivolumab (I/N) is given as 4 induction doses for advanced stage melanoma. While many patients receive less than 4 doses due to treatment-related toxicities, it is unclear if fewer doses of I/N may still provide long term clinical benefit. Our aim is to determine if response assessment after 1 or 2 doses of I/N can predict long-term survival and if fewer doses of I/N can achieve similar survival outcomes. Methods: We performed a single-center, retrospective analysis on a cohort of patients with metastatic or unresectable melanoma from 2012 to 2020 who were treated with standard I/N. Cox regression of progression free survival (PFS) and overall survival (OS) models were performed to assess the relationship between response assessment after 1 or 2 doses of I/N and risk of progression and/or death. Clinical benefit response (CBR) was assessed, defined as SD (stable disease) + PR (partial response) + CR (complete response) by imaging or physical examination. Among patients who achieved a CBR after 1 or 2 doses of I/N, a multivariable Cox regression of survival was used to compare 3 or 4 vs 1 or 2 doses of I/N adjusted by age, gender, pre-treatment LDH level, BRAF mutation status, primary melanoma site, time to initial assessment, brain metastasis, and liver metastasis. Results: 199 patients were identified and considered evaluable in our study. Median follow up was 28.8 months. Patients with CBR after 1 dose of I/N had improved PFS (HR: 0.23, 95% CI 0.14-0.39; p

443 Background: Enfortumab vedotin (EV) is an antibody-drug conjugate targeting Nectin-4, which is FDA approved for patients (pts) with treatment-refractory advanced urothelial cancer (aUC). The activity of EV in pt subsets of interest such as those with distinct histological variants has not been well defined. Methods: A retrospective study of pts with aUC treated with ≥1 dose of EV as standard of care (SOC) or on a clinical trial (if trial results already reported) at 12 US sites was undertaken. Objective response rate (ORR) was investigator-assessed for pts with at least one post-baseline scan or clear evidence of clinical progression. ORR was compared across subsets of interest using proportion test. Results: A total of 184 patients with aUC were included; median age at diagnosis 70, 20% women and 60% with definitive surgery. Most common primary sites included bladder (70%) and upper tract (28%). Majority of pts (72%) had pure urothelial histology (UH) per local review, but 26% had at least a component of variant histology (VH), most commonly squamous (14%), micropapillary (8%) or plasmacytoid (3%). EV was given as monotherapy in 84% and as SOC in 58%; and 81% had ≥ 1 prior treatment in the metastatic (met) setting. ECOG PS was ≥2 in 15%; 37% had baseline neuropathy, 15% diabetes and 9% had GFR≤30. At median follow-up of 37.0 (IQR: 20.5-60.2) months from initial diagnosis, median time from met diagnosis to EV start was 11.7 (IQR: 4.3 – 20.5) months. Median duration of EV was 5.5 (IQR: 1.4 – 6.7) months, and 84% of pts were evaluable for response. ORR for evaluable pts was 53% (8% CR, 45% PR); 25% had SD and 21% PD. Median PFS and OS were not yet reached. At data cutoff in 9/2020, 55% had stopped EV (36% due to PD, 19% intolerance) and 65% were alive. Comparison of ORR in subgroups of interest for 127 evaluable pts treated with EV monotherapy is shown in the table below. Notably, among 31 pts with FGFR3 alterations, 26 were evaluable and ORR was 46%. Conclusions: In a large, retrospective, multi-institutional cohort, responses to EV were observed across a broad range of aUC pts, including pts with variant histology component, FGFR3 alterations and also in populations previously excluded from clinical trials such as pts with GFR

5584 Background: The timing of systemic therapy in relation to radiotherapy (RT) is important in most malignancies. In contrast, androgen deprivation therapy (ADT) has largely been investigated in relation to its duration rather than its sequencing with RT. Herein, we conduct the first combined individual patient analysis of two phase III randomized trials to determine the optimal timing of ADT with RT in localized prostate cancer (PCa). Methods: Individual patient data was obtained from the Malone et al trial (JCO 2019), which randomized patients to receive neoadjuvant/concurrent or concurrent/adjuvant ADT for 6 months with prostate only RT. This was combined with the prostate only RT arms of RTOG 9413 that randomized patients to 4 months of neoadjuvant/concurrent or adjuvant ADT. The neoadjuvant/concurrent arms of both trials were combined into the “neoadjuvant” group, and the concurrent/adjuvant (Malone) and adjuvant arm (RTOG 9413) were combined in the “adjuvant” group. The Kaplan-Meier method was used to estimate overall survival (OS) and progression-free survival (PFS). Cumulative incidence of distant metastasis (DM), PCa-specific mortality (PCSM) and biochemical failure (BF) were calculated using the Fine-Gray method with non-PCa deaths as competing events. Late genitourinary (GU) and gastrointestinal (GI) toxicity are also reported. Results: The median follow-up was 14.9 years (yrs) and 1065 patients were included (n=531 neoadjuvant, 534 adjuvant). Groups were well balanced for all baseline characteristics. Adjuvant ADT was superior to neoadjuvant ADT in terms of BF (15yr: 33% vs 43%, HR: 1.37 (95%CI: 1.12-1.68), p=0.002), DM (15yr: 12% vs 18%, HR: 1.40 (95%CI: 1.00-1.95), p=0.04), and PFS (15yr: 36% vs 29%, HR: 1.25 (95%CI: 1.07-1.47), p=0.01). Adjuvant ADT yielded lower PCSM (15yr: 15% vs 20%, HR: 1.29 (95%CI: 0.95-1.75), p=0.10), but did not reach statistical significance. This approached statistical significance in high risk PCa (HR 1.39 (95%CI 1.00-1.93), p=0.053). OS was not significantly different between arms (15yr: 39% vs 34%, HR: 1.11 (95%CI: 0.95-1.30), p=0.20). There was no significant difference in either late grade ≥3 GI (p=0.21) or GU (p=0.98) toxicity. Conclusions: We demonstrate for the first time that sequencing of ADT with RT significantly impacts long-term oncologic outcomes in localized PCa, favoring an adjuvant rather than neoadjuvant approach, without increasing late toxicity. This data has important implications to ongoing and future clinical trial design. Clinical trial information: NCT00769548 .

e14554 Background: There is no consensus for the treatment of central nervous system lymphoma (CNSL) refractory to first line high dose methotrexate-based chemotherapy. Whole brain radiation (WBRT) has often been used but may lead to unacceptable neurocognitive dysfunction. We examined our institutional experience with treating CNSL with radiotherapy (RT) and concurrent temozolomide (TMZ) including the resultant acute and long term toxicities. Methods: This single institution IRB approved retrospective study examined treatment, toxicity, and outcome variables in adults with primary or secondary CNS lymphoma. Inclusion criteria were brain-directed RT and development of the treatment plan at our institution. Three main RT field designs were used, including low and high dose WBRT and low dose WBRT with a focal boost to residual disease (WBRT+boost). We assessed relationships between treatment approach (RT field design and concurrent TMZ use) and clinical outcomes and toxicities using multivariable logistic regression models and Kaplan-Meier methods. Toxicity was recorded using the Common Terminology Criteria for Adverse Events version 5. Results: A total of 93 patients with median age of 57 years (range 24 – 86) treated from 2004 – 2019 were included, and 26 patients received concurrent TMZ. The RT field design of low dose WBRT (median dose: 23.4Gy) plus focal boost (median dose: 21.6Gy) was associated with favorable overall survival (OS) and progression free survival (PFS) without any significant difference in Grade 3+ toxicity compared to low dose WBRT (p = 0.20) or WBRT without boost (p = 0.80). Concurrent TMZ with RT was associated with significantly improved OS (HR 0.46, p = 0.025) and CNS PFS (HR 0.49, p = 0.019). Four of nine (44%) Grade 3+ non-hematologic toxicities occurred in patients receiving concurrent TMZ (p = 0.40). The most common non-hematologic toxicities included fatigue and nausea. Long term neurocognitive dysfunction was similar whether or not patients received concurrent TMZ (21% in TMZ group vs 23% in non-TMZ group; OR 0.87, 95% CI 0.25 – 2.68, p = 0.82) and irrespective of RT field design (WBRT+boost vs low dose WBRT p = 0.25, WBRT+boost vs WBRT without boost p = 0.19). Conclusions: Our findings suggest that concurrent TMZ use with brain RT for chemo-refractory CNSL is a promising strategy, with improved survival and no major additional toxicity. Further research that includes rigorous neurocognitive assessments is needed in prospective clinical trials to guide treatment approaches using concurrent TMZ with brain RT in CNSL patients.