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Background Hyperinsulinemia and inflammation are inter-related pathways that link diet with the risk of several chronic diseases. Evidence suggests that these pathways may also increase prostate cancer risk. Objective To determine whether hyperinsulinemic diet and inflammatory diet are associated with prostate cancer incidence and mortality. Design, setting, and participants We prospectively followed 41 209 men in the Health Professionals Follow-up Study (1986–2014). Scores for two validated dietary patterns were calculated from food frequency questionnaires at baseline and updated every 4 yr. Outcome measurements and statistical analysis Total, advanced, and lethal prostate cancer outcomes were assessed. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were determined for associations between two empirical hypothesis-oriented dietary patterns—empirical dietary index for hyperinsulinemia and empirical dietary inflammatory pattern—and prostate cancer risk estimated using Cox proportional hazard regression. Results and limitations During 28 yr of follow-up, 5929 incident cases of total prostate cancer, including 1019 advanced and 667 fatal, were documented. In multivariable-adjusted models, there was a 7% higher risk of advanced prostate cancer (HR: 1.07; 95% CI: 1.01–1.15) and a 9% higher risk of fatal prostate cancer (HR: 1.09; 95% CI: 1.00–1.18) per standard deviation (SD) increase in the hyperinsulinemic diet. When stratified by age, the hyperinsulinemic diet was associated with only earlier-onset aggressive prostate cancer (men under 65 yr), with per SD HRs of 1.20 (95% CI: 1.06–1.35) for advanced, 1.22 (1.04–1.42) for fatal, and 1.20 (1.04–1.38) for lethal. The inflammatory diet was not associated with prostate cancer risk in the overall study population, but was associated with earlier-onset lethal prostate cancer (per SD increase HR: 1.16; 95% CI: 1.00–1.35). Conclusions Hyperinsulinemia and inflammation may be potential mechanisms linking dietary patterns with the risk of aggressive prostate cancer, particularly earlier-onset disease. Patient summary Avoiding inflammatory and hyperinsulinemic dietary patterns may be beneficial for the prevention of clinically relevant prostate cancer, especially among younger men.

Objectives Immune checkpoint inhibitors (ICIs) are being increasingly used across cancer types. Emergency room (ER) and inpatient (IP) care, common in patients with cancer, remain poorly defined in this specific population, and risk factors for such care are unknown. Methods We retrospectively reviewed charts for patients with solid tumors who received >1 ICI dose at 1 of 2 sites from January 1, 2011 to April 28, 2017. Demographics, medical history, cancer diagnosis/therapy/toxicity details, and outcomes were recorded. Descriptive data detailing ER/IP care at the 2 associated hospitals during ICI therapy (from first dose to 3 mo after last dose) were collected. The Fisher exact test and multivariate regression analysis was used to study differences between patients with versus without ER/IP care during ICI treatment. Results Among 345 patients studied, 50% had at least 1 ER visit during ICI treatment and 43% had at least 1 IP admission. Six percent of ER/IP visits eventually required intensive care. A total of 12% of ER/IP visits were associated with suspected or confirmed immune-related adverse events. Predictors of ER care were African-American race (odds ratio [OR]: 3.83, P=0.001), Hispanic ethnicity (OR: 3.12, P=0.007), and coronary artery disease (OR: 2.43, P=0.006). Predictors of IP care were African-American race (OR: 2.38, P=0.024), Hispanic ethnicity (OR: 2.29, P=0.045), chronic kidney disease (OR: 3.89, P=0.006), angiotensin converting enzyme inhibitor/angiotensin receptor blocker medication use (OR: 0.44, P=0.009), and liver metastasis (OR: 2.32, P=0.003). Conclusions Understanding demographic and clinical risk factors for ER/IP care among patients on ICIs can help highlight disparities, prospectively identify high-risk patients, and inform preventive programs aimed at reducing such care.

Background It remains controversial if radical prostatectomy or definitive radiation therapy produces equivalent outcomes in high‐risk localized prostate cancer. Methods We queried The Surveillance, Epidemiology, and End Results (SEER) database for those who received upfront surgery or who were recommended for surgery but instead received radiation. Inverse probability of treatment weighing was used to adjust for covariate imbalance and the weighted Cox proportional hazards model was used to estimate the effects of treatment groups on survival. A meta‐analysis was performed to pool estimates from published studies. Results Among eligible 62 533 patients, 59 540 had upfront surgery and 2993 patients had upfront radiotherapy. EBRT + BT was associated with a superior cancer‐specific survival (CSS) compared with surgery or EBRT alone (HR, 0.55, 95% CI, 0.3‐1.0; HR, 0.49, 95% CI, 0.24‐0.98, respectively), whereas EBRT was associated with an inferior overall survival (OS) compared with surgery (HR, 1.46, 95% CI, 1.16‐1.8). Radiotherapy (EBRT ± BT) was inferior to surgery by OS (HR, 1.63, 95% CI, 1.13‐2.34) in patients ≤ 65 years, and was superior to surgery by CSS in patients > 65 years (HR, 0.69, 95% CI, 0.49‐0.97). The meta‐analysis showed consistent results. Conclusion EBRT + BT was associated with a significantly better prostate CSS compared with surgery or EBRT. EBRT alone was inferior to surgery by OS., In high‐risk localized prostate cancer, radiotherapy with brachytherapy boost was associated with a longer survival outcome, compared with surgery or radiotherapy without brachytherapy boost.

INTRODUCTION AND OBJECTIVE:The role of CN in the treatment of mRCC has been questioned with the recent approval of novel systemic therapy (ST) agents and the results of the CARMENA trial. Our objec...

INTRODUCTION AND OBJECTIVE:IO/TKI combinations are a new standard of care for the initial treatment (tx) of mRCC. Efficacy and toxicity of such combination regimens beyond the first-line (1L) setti...

Background Radiation necrosis (RN) is a potential complication after radiation therapy for brain tumors. It is hypothesized that VEGF plays an important role in the pathophysiology of RN. Bevacizumab, a monoclonal antibody against VEGF-A, is often successful in the management of RN. The objective of this study is to assess whether VEGF receptor (VEGFR) inhibitors, a group of oral tyrosine kinase inhibitors (TKIs), can prevent or reverse RN. Methods We retrospectively studied a cohort of 102 patients with renal cell carcinoma and brain metastases seen at The Ohio State University James Cancer Center between January 1, 2011 and April 30, 2019. We identified those who developed RN and analyzed the temporal relationship between the use of VEGFR TKIs and the development of RN. Results The cumulative incidence of RN is 13.7% after radiation treatments that included LINAC-based stereotactic radiosurgery, fractionated stereotactic radiotherapy, or Gamma Knife radiosurgery. There was no statistically significant difference in the cumulative incidence of RN between patients taking TKIs and patients who were off TKIs (9.9% and 11.5% respectively, P = .741). The median time to development of RN was only numerically shorter in patients taking TKIs (151 vs 315 days, P = .315). One patient developed RN after stopping cabozantinib. Eight patients developed RN while on cabozantinib, pazopanib, or sunitinib. One patient was started on axitinib during active RN without significant improvement subsequently. Conclusions VEGFR TKIs do not consistently prevent RN. The therapeutic effects of VEGFR TKIs against RN warrant further research.

Background Enzalutamide, a major antiandrogen indicated for metastatic castration-resistant prostate cancer, has worrisome toxicities in aging patients. Dose reduction might limit toxicity, but potential loss of efficacy is a concern. We compare up-front low-dose versus standard-dose enzalutamide. Patients and Methods Records of prostate cancer patients receiving enzalutamide were retrospectively retrieved. Selection criteria were: age ≥ 75, metastatic disease, surgical or medical castration, and rising prostate-specific antigen (PSA). Data were excluded of those missing follow-up PSA values. Low-dose enzalutamide (≤ 80 mg per day) was compared to standard dose (160 mg per day). Progression-free survival analyzed the time from start of enzalutamide to event, defined as ≥ 25% and ≥ 2 ng/mL PSA increase above nadir, or death from any cause. Results Fifty-nine patients were identified, of whom 16 received low-dose and 43 standard-dose therapy. Patients in the low-dose group were significantly old, with a median (range) age of 84.6 (74.9-93.8) years; median (range) PSA at start of enzalutamide was 59.2 (11.0-1058.3) ng/mL; 11 had bone metastases only, 2 metastatic lymph nodes only, and 3 bone and lymph node localizations. Pain score was > 3/10 in 4 patients (27%), Eastern Cooperative Oncology Group performance status was ≥ 2 in 9 (56%); 3 patients had received prior abiraterone and 3 bicalutamide. None received chemotherapy. PSA decrease of ≥ 50% at 12 weeks was observed in 67% patients (10/15), versus 45.0% with standard dose. Median (range) PSA at last follow-up was 1.6 (0-599.3) ng/mL. Median progression-free survival was 11.2 months, versus 11.9 months for patients receiving the standard dose (P = .612). Conclusion Low-dose enzalutamide in very old, symptomatic, poor-performance patients with metastatic disease was associated with high response rate and survival comparable to standard dose.

Background Some cancer patients who are diagnosed with thromboembolism may require dual treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and factor Xa inhibitors (low-molecular-weight heparin [LMWH] or direct oral anticoagulants [DOACs]). However, to the authors' knowledge, the safety of such combinations has not been well characterized. Methods Patients with advanced cancer who were treated with concurrent VEGFR TKIs and factor Xa inhibitors between 2010 and 2018 at The Ohio State University Comprehensive Cancer Center were included. Charts were reviewed retrospectively for clinically significant bleeding events occurring during concurrent treatment compared with those occurring during factor Xa inhibitor therapy alone, using each patient as their own control. The Fisher exact test was used to compare distribution of bleeding severities. The Cox proportional hazards model was used to compare bleeding risk between groups. Results Among 86 patients, there were 29 clinically significant bleeding events (including 8 major bleeding events) reported during concurrent treatment and 17 events (including 4 major bleeding events) reported during factor Xa inhibitor therapy alone over a median follow-up of 63 days. Concurrent treatment was associated with significantly higher risks of overall bleeding (hazard ratio, 2.45; 95% confidence interval, 1.28-4.69 [P = .007]) and first-onset bleeding (hazard ratio, 2.23; 95% confidence interval, 1.13-4.42 [P = .02]). Analysis of 6-month bleeding risk and the subgroups of patients treated with concurrent TKIs and LMWH versus LMWH alone demonstrated a similar trend. The sample size was inadequate for comparisons between treatment with concurrent TKIs and DOACs versus DOACs alone. Conclusions Concurrent treatment with VEGFR TKIs and LMWH was found to be associated with a significantly increased risk of bleeding events when compared with LMWH therapy alone.

Background DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. Materials and Methods We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. Results DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03–4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31–0.8; p = .003). Conclusions Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. Implications for Practice Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.

Prostate cancer is common in countries with affluent dietary patterns and represents a heterogeneous collection of subtypes with varying behavior. Reductionist strategies focusing on individual nutrients or foods have not clearly defined risk factors. We have developed mechanisms-based dietary patterns focusing upon inflammation and chronic insulin hypersecretion, processes that are hypothesized to impact prostate carcinogenesis. In the Prostate, Lung, Colorectal, and Ovarian cancer cohort, we calculated the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores from food frequency questionnaire data among 3,517 men and women who provided a blood sample at enrollment. We used these scores in multivariable-adjusted linear regression to validate EDIH and EDIP against relevant circulating biomarkers. In a separate sample of 49,317 men, we used multivariable-adjusted Cox regression to evaluate associations of EDIH and EDIP with prostate cancer (total and subtypes) risk. Participants consuming the most hyperinsulinemic diets (EDIH quintile 5) had significantly higher concentrations of C-peptide, insulin, c-reactive protein, TNFα-R2, and lower adiponectin, than those in quintile 1. Similarly, participants consuming the most proinflammatory diets had significantly higher concentrations of IL6, TNFα-R2, C-peptide, insulin, and lower adiponectin. Men consuming hyperinsulinemic diets were at higher total prostate cancer risk: HRquintile5vs1, 1.11; 95% confidence interval (CI), 1.01–1.23; P trend = 0.03, especially high-grade cancer: HRquintile5vs1, 1.18; 95% CI, 1.02–1.37; P trend = 0.06. The EDIP was not associated with prostate cancer risk. In summary, EDIH and EDIP predicted concentrations of known insulinemic and inflammatory biomarkers, and EDIH further predicted risk of future prostate cancer. Interventions to reduce the adverse role of hyperinsulinemic diets may be a means of prostate cancer prevention.

Background: Older adults with hematologic malignancies have inferior survival outcomes due to multiple factors including under-treatment, drug toxicity, treatment discontinuation and concerns of frailty. However, aging is heterogeneous and chronological age is a poor indicator of underlying health. Standardizing the approach to identify frailty is an unmet need in malignant hematology. We have established a multi-disciplinary clinical model designed to identify frailty and develop personalized treatment based on objective measures of health. We have standardized a geriatric assessment (GA) model to identify vulnerability, frailty and geriatric syndromes. Here we report, the largest cohort to date, of older adults with hematologic malignancies (HM) depicting geriatric deficits and interventions with long-term clinical outcomes. Methods: From Feb 2016 to October 2019, 311 older adults with HM were evaluated in our multi-disciplinary Cancer and Aging Resiliency (CARE) clinic. The CARE clinic is a 7-member team prescriptively evaluating the following domains: pharmacy, audiology, psychosocial needs, nutrition, physical functioning, and cognition. Geriatric syndromes were documented by CARE physician. Referral to CARE clinic is recommended for patients 60 years of age or older but all referrals are accepted independent of age. Data was abstracted by retrospective chart review. Descriptive statistics for patient characteristics, frailty measures, and prescribed interventions in each of the GA domains were provided. Univariable and multivariable Cox models were fit to associate clinical factors with OS. OS by Rockwood Clinical Frailty Scale and deficits in activities of daily living (ADLs) was evaluated by Kaplan-Meier method. Correlation between number of geriatric syndromes, clinical frailty score, and deficits in ADLs and instrumental ADLs (IADLs) was also assessed. Results: Over the 42-month study period, 311 older adults with HM with a median age of 75.9 years were evaluated in CARE clinic. Key demographic features and the frequency of specific frailty measures are outlined in table 1.Geriatric interventions were common with 59% requiring 1-2 interventions and 34% requiring 3+ interventions. In univariable analysis, any degree of frailty by Clinical Frailty Scale (Hazard Ratio [HR]: 2.63, 95% Confidence Interval [CI]: 1.43-4.82, p Discussion: The Clinical Frailty Scale is predictive of OS among older adults with HM. GA-directed intervention is warranted in the vast majority of older adults with HM. In univariable analysis, Clinical Frailty Scale, increasing age, anemia, high risk HM, and increasing geriatric syndromes are associated with inferior OS. In multivariable analysis, age, anemia, and high risk HM remain significant. Nutrition and physical function are key modifiable risk factors predictive of inferior OS. Prospective studies focusing on geriatric interventions are warranted in this population with an emphasis on modifiable risk factors. This demonstrated prognostic significance of both geriatric assessments and interventions in older adults with HM should give way to future improvements in OS, quality of life, and treatment tolerability through GA-directed intervention. Disclosures No relevant conflicts of interest to declare.

e16567 Background: ICI/TKI combinations are a new standard of care for the initial treatment (tx) of mRCC. Efficacy and toxicity of such combination regimens beyond the first-line (1L) setting remain unknown. Methods: We retrospectively reviewed charts for adult patients (pts) receiving an ICI/TKI combination in any line of tx for mRCC of any histology at one of two academic centers as of May 1, 2020. ICIs included pembrolizumab (Pm), nivolumab (Ni), ipilimumab (Ip), or avelumab (Av); TKIs included sunitinib (Su), axitinib (Ax), pazopanib (Pz), lenvatinib (Ln), or cabozantinib (Ca). Clinical data including pt demographics, histology, International mRCC Database Consortium (IMDC) risk group, tx history, and ICI/TKI tx and toxicity details were recorded. Outcomes included objective response rate (ORR), median progression-free survival (mPFS), and safety, analyzed via descriptive statistics and the Kaplan-Meier method. Results: Of 85 pts, 69 (81%) were male and 67 (79%) had clear cell histology. IMDC risk was favorable (24%), intermediate (54%), poor (20%), and unknown (2%). 39% had ICI/TKI tx in the 1L setting. ICI/TKI regimens included Pm/Ax (33%), Ni/Ca (25%), Ni/Ax (20%), Av/Ax (11%), Ni/Ip/Ca (8%), Ni/Su (2%), and Ni/Ln (1%). ORR and mPFS stratified by line of tx and prior tx are shown in the table. Of 52 pts who received ICI/TKI tx as salvage (after 1L), 52% had a grade 3 or higher (≥G3) adverse event (AE), of which the most common were anorexia (13.5%), diarrhea and hypertension (11.5% each), and fatigue (9.6%). 65% of pts on salvage ICI/TKI tx stopped tx for progression/death, while 16% stopped tx for ≥G3 AE. ≥G3 AE rates by line of tx were 62.5% (2L), 50% (3L), and 45% (≥4L). Conclusions: ICI/TKI combination therapy is effective and safe beyond the 1L setting. Prior tx history appears to impact efficacy but has less of an effect on safety/tolerability. These observations will need to be confirmed in prospective studies.[Table: see text]

e17020 Background: Radium-223 is an α-emitting radioisotope that induces DNA double-stranded breaks leading to cell death and has improved survival in mCRPC. In preclinical models, PARP inhibitors have shown efficacy as radiosensitizing agents. We designed a phase 1/2 trial to test the hypothesis that radium-223 + olaparib will demonstrate anti-tumor activity in mCRPC irrespective of homologous recombination repair deficiency (HRD) status. Methods: This is an open label, multi-center, phase 1/2 study (NCT03317392) evaluating the dosing, safety and efficacy of radium-223 + olaparib. Eligible patients (pts) had mCRPC with ≥2 bone metastases without visceral metastases or lymphadenopathy > 4 cm. There was no limit on prior therapy. All pts had a baseline biopsy. The phase 1 used a 3+3 dose escalation design with fixed dose radium-223 (55 kBq/kg IV every 4 weeks x 6). Dose level 1 (DL1) was olaparib 200 mg PO BID; DL2 was olaparib 300 mg PO BID. The primary objective was to determine the recommended phase 2 dose (RP2D) and safety. The dose limiting toxicities (DLT) evaluation period was 2 cycles (1 cycle=28 days). Secondary endpoints included radiographic progression-free survival (rPFS) defined by PCWG3 criteria, PSA response (50% decline from baseline), and alkaline phosphatase response (30% decline from baseline). Results: 12 pts were enrolled on the phase 1. Median age was 68 (range 59-81) years. Median prior lines of CRPC therapies was 2 (1-5), including 3 (25%) who had received prior chemotherapy and 100% a prior novel hormone therapy. 6 pts were enrolled at DL1. 1 patient experienced a DLT outside the DLT evaluation period. 3 pts had grade (G) 3-4 treatment-related adverse events (TrAE) including G3 anemia (n=2) and G3 thrombocytopenia (n=1). No patient underwent dose reductions at DL1. 6 pts were enrolled at DL2. 1 patient experienced a DLT outside the DLT evaluation period. 2 pts had G3-4 TrAE including G3 anemia and G4 lymphocytopenia (n=1) and G3 stroke (n=1). 5 underwent dose reductions at DL2. There were no G5 events. Reason for treatment discontinuation is in the table below. After review of safety data, the safety monitoring committee deemed the RP2D of olaparib at 200 mg BID when combined with radium-223. Overall, PSA response and alkaline phosphatase response were 16.7% (n=2, 1 at DL1, 1 at DL2) and 67% (n=8, 3 at DL1, 5 at DL2), respectively. Median follow-up was 6.5 (range 2.8, 11.8) months, and 6-month rPFS was 57% (95% CI: 25%, 80%). Conclusions: We demonstrate that olaparib can be safety combined with radium-223 with RP2 dose of 200 mg BID. The phase 2 study of radium-223 +/- olaparib is accruing (target 120 pts). Outcomes by HRD status will be presented. Clinical trial information: NCT03317392. [Table: see text]

The combination of personalized therapy with immunotherapy might lead to rapid complete remission in patients who are too sick to be eligible for clinical trials. We report 2 such extraordinary responders. A discussion on the use and purpose of clinical trials in this new era of very active anticancer drug discovery concludes that a paradigm shift is urgently needed.

Background Evidence-based practice in geriatric oncology is growing, and national initiatives have focused on expanding cancer care and research to improve health outcomes for older adults. However, there are still gaps between knowledge and practice for older adults with cancer. Main text Here we provide a detailed methodology of geriatric oncology care delivery within a single institution. The Cancer and Aging Resiliency (CARE) clinic is a multidisciplinary approach for implementing geriatric-driven health care for older adults with cancer. The CARE clinic was developed as a direct response to recommendations targeting key multifactorial geriatric health conditions (e.g. falls, nutritional deficits, sensory loss, cognitive impairment, frailty, multiple chronic conditions, and functional status). The multidisciplinary team assesses and delivers a comprehensive set of recommendations, all in one clinic visit, to minimize burden on the patient and the caregiver. The CARE clinic consultative model is a novel approach integrating cancer subspecialties with geriatric oncology healthcare delivery. Conclusions Older adults with cancer have unique needs that are independent of routine oncology care. The CARE clinic model provides specific assessments and interventions to improve health outcomes among older adults with cancer.

TPS175 Background: Disease progression following highly-active androgen-axis therapy (HAAT) in CRPC remains bone-dominant and docetaxel-responsive. Combination bone-homing Ra223 isotope therapy with docetaxel would be a logical combination therapy to follow but myelosuppression is dose-limiting. With 3-weekly bolus schedules of docetaxel (D), dose-reduction to 60mg/m2 Q3wkly and Ra223 to every 6 weeks has been required representing a reduction in the dose-intensity of both agents. Fractionated schedules of docetaxel Q2wkly (DQ2) have comparable activity to D 75mg/m2 Q3wkly (DQ3) with mitigated myelosuppression. We hypothesize that a fractionated dose-schedule of DQ2 in combination with standard Ra223 dosing will be feasible without reduction in dose-intensity of Ra-223 or D. Methods: Outcomes: The primary objective is to determine the feasibility and maximal tolerated dose (MTD) of the combination. Secondary objectives include PSA kinetics, objective response, bone marker outcomes, progression free and overall survival, and description of toxicity and quality of life. Eligibility: Progressive bone-metastatic CRPC, ECOG PS 0-2 with no prior Ra223, no prior docetaxel for CRPC, and no bulky visceral disease. Design: Phase I (6+6) design; 4 week lead-in with DQ2. Dose-level 1a: 40mg/m2; 2a: 50mg/m2, both with PEGylated G-CSF on Day 16. If tolerated (≤ Grade 2 toxicity, ANC ≥ 1500, Platelets ≥ 100,000), lead-in is followed by C1D1 of DQ2 plus Ra223 Q4wkly x 6 doses. Dose level 1a has accrued 6 subjects without DLT. Enrollment to Dose Level 2a began in August, 2020. An expansion cohort of 25 subjects is planned after the MTD is determined. Clinical trial information: NCT03737370.

TPS182 Background: Radium-223 is an α-emitting radioisotope that induces DNA double-stranded breaks leading to cell death and has demonstrated improvement in overall survival in men with metastatic castration-resistant prostate cancer (mCRPC) with bone metastases. PARP inhibitors, including olaparib and rucaparib, inhibit repair of DNA single-stranded beaks and have demonstrated clinical efficacy in mCRPC patients harboring alterations in the homologous recombination repair (HRR) pathway. In extensive preclinical cancer models, PARP inhibitors have shown efficacy as radiosensitizing agents. We designed a phase 1/2 trial to test the clinical hypothesis that the combination of radium-223 with olaparib will demonstrate anti-tumor activity in patients with mCRPC irrespective of underlying HRR deficiency status. Methods: This is an open label, multi-center, phase 1/2 study (NCT03317392) evaluating the dosing, safety and efficacy of olaparib in combination with radium-223 in men with mCRPC with bone metastases. Patient must have 2 or more bone metastases and at least 1 bone metastasis that has not been treated with prior radiation therapy. Key exclusion criteria include the presence of visceral metastases or malignant lymphadenopathy exceeding 4 cm and prior therapy with radium-223 and/or PARP inhibitors. The phase 1 component of the study uses a 3+3 dose escalation design to determine the recommended phase 2 dose of olaparib in combination with standard of care dosing of Radium-223. The primary endpoint of the phase 1 component is safety. The phase 2 component of the study is an open-label, randomized study evaluating the combination of olaparib and radium-223 compared to radium-223 alone. The primary endpoint of the phase 2 component is radiographic progression-free survival as defined by Prostate Cancer Working Group 3 guidelines for bone metastases and RECIST v1.1 for non-bone metastases. Secondary endpoints include time to PSA progression, PSA response, time to subsequent therapy, time to first skeletal event, overall survival, and safety. Exploratory endpoints include stratification of response based on HRR alterations, whole exome sequencing of plasma cell free DNA both at baseline, on treatment, and at progression, and evaluation of changes in the tumor immune microenvironment with therapy. As of October 1, 2020, the phase 1 component has completed accrual and we anticipate opening the phase 2 component by December 2020. Clinical trial information: NCT03317392.

Older adults with cancer have comorbidities that require medical management and confounders of chemotherapy and supportive medications exacerbate polypharmacy. A multidisciplinary team model was created to address these needs within the Cancer Aging and Resiliency (CARE) clinic. To reconcile medications for accuracy, compliance, side effects, and effectiveness, a pharmacist-led audit includes identification of potential therapeutic duplications, drug-drug interactions, or potential medication inappropriateness identified using Beers criteria. A pharmacist led review of patient’s prescriptions can identify drug therapy problems (DTP) and result in safer medication management. METHODS: A retrospective review of pharmacy specific interventions was conducted using CARE Clinic patient data from February 2016 to October 2019 evaluating data from n=259 patients. RESULTS: A preliminary analysis of n=137 patients who had received medication reconciliation were included. The mean number of medications per patient was 13.1 ± 5.7 and 457 DTP were identified leading to 523 medication related interventions. There was an average of 3.3 DTP per patient. The most common types of DTP included medication reconciliation (n=137, 30.0%), potentially inappropriate medication (PIM) (n=74, 16.2%), administration/technique (n=35, 7.7%), and drug-drug interaction (n=28, 6.1%). The most frequent types of interventions involved education to the patient (n=166, 31.7%), medication reconciliation (n=137, 26.2%), medication discontinuation (n=84, 16.1%), patient to discuss further with physician (n=39, 7.5%), and medication initiated (n=35, 6.7%). Updated results involving approximately 259 patients will be presented. CONCLUSION: Comprehensive medication review within a multidisciplinary setting for the management of older adults with cancer can reduce polypharmacy and inappropriate medication use.

INTRODUCTION Radiation necrosis (RN) is a potential complication after radiation therapy to primary brain tumors and brain metastases. The pathophysiology of RN is not well understood but it is hypothesized that vascular endothelial growth factor (VEGF) plays an important role. Bevacizumab, a monoclonal antibody against VEGF-A, is often successful in the management of RN. The objective of this study is to assess whether VEGF receptor (VEGFR) inhibitors, a group of oral tyrosine kinase inhibitors (TKIs), can prevent or reverse cerebral radiation necrosis METHODS We retrospectively studied a cohort of 102 patients with renal cell carcinoma (RCC) and brain metastases seen at The Ohio State University James Cancer Center between 01/01/2011 and 04/30/2019. We identified those who developed RN and analyzed the temporal relationship between the use of VEGFR TKIs and the development of RN. RESULTS The cumulative incidence of RN in our cohort is 13.7% after radiation treatments that included LINAC-based stereotactic radiosurgery, fractionated stereotactic radiotherapy, or Gamma Knife radiosurgery. There was no statistically significant difference in the cumulative incidence of RN between patients taking TKIs and patients who were off TKIs (9.9% and 11.5% respectively, p= 0.741). The median time to development of RN was only numerically shorter in patients taking TKIs (151 versus 315 days, p=0.315). One patient developed RN after stopping cabozantinib. Three other patients developed RN while on cabozantinib. Two patients developed RN while on pazopanib, and 3 patients developed RN while on sunitinib. One patient was started on axitinib during active RN without significant improvement subsequently. CONCLUSIONS VEGFR TKIs do not consistently prevent or reverse cerebral radiation necrosis and do not seem to have the efficacy that bevacizumab has against RN.

1543 Background: Genomic testing, useful for treatment planning and identification of patients for clinical trials, may indicate the presence of a germline mutation. We sought to evaluate the incidence of potentially actionable germline mutations detected via genomic testing and determined rates of germline testing among patients with potential germline mutations. Methods: This was a retrospective review of patients undergoing genomic testing at The University of Vermont Cancer Center (UVMCC) between 03/02-11/19. Testing was reviewed for mutations in 60 genes associated with hereditary cancer and recognized as clinically actionable by the American College of Medical Genetics. Records were reviewed for clinical follow-up. Positive (pathogenic or likely pathogenic) genomic test results were evaluated with descriptive analyses. Proportions with 95% confidence intervals are presented and comparisons made using a χ2 test. Results: 342 patients underwent genomic testing at UVMCC over the study period, with a median age of 61. Common tumor types include: CNS (19%), NSCLCA (17%), ovarian (8%), and sarcoma (7%). 59% (203/342) had a mutation in ≥ 1 gene associated with hereditary cancer. Most common tumor types with potential germline mutations include: NSCLCA (25%), CNS (18%), ovarian (8%), sarcoma (8%), and endometrial (7%). Potential germline mutations were most commonly identified in TP53, CDKN2A, PTEN, and RB1 (each with mutations in >6% of patients). 58 patients in the cohort have undergone germline testing, of which 19% were positive for germline mutations. Of patients with mutations in the highly penetrant BRCA, PALB2, and Lynch genes, 71% were positive for germline mutations. Young age ( < 50) did not enrich for germline mutations (p > 0.05). Only 18% (36/203) of patients with potential germline results were referred for genetic counseling. Conclusions: Genomic testing can reveal hereditary cancer syndromes. While the majority of patients with tumor mutations in genes associated with hereditary cancer will not have germline mutations, genetic testing is the only way to confirm this. 19% of patients who underwent genetic testing in this cohort had a pathogenic germline mutation. This was enriched to 71% when considering genes rarely mutated in tumors (BRCA, PALB2, and Lynch genes). Only 17% of this cohort underwent genetic testing, representing a significant missed opportunity given the implications of these findings for both patients and families. Patients and their providers should be aware of the potential for germline findings when genomic testing is performed.

e19305 Background: Tyrosine kinase inhibitors (TKIs) of vascular endothelial growth factor receptor (VEGFR) may interfere with the coagulation system making patients susceptible to both hemorrhage and thromboembolism. Some cancer patients require dual treatment with VEGFR TKIs and factor Xa inhibitors. However, the safety of such combination treatment (e.g. bleeding risk) has not been well characterized in the literature. Methods: This retrospective study identified metastatic cancer patients who received VEGFR TKIs (pazopanib, sunitinib, sorafenib, axitinib, regorafenib, vandetanib, lenvatinib, cabozantinib, tivozanib) and Xa inhibitors (low-molecular weight heparin [LMWH] or direct oral anticoagulants [DOACs]- rivaroxaban or apixaban) from 2001 to 2018 at the Ohio State University. We assessed bleeding risks of dual therapy vs factor Xa inhibitors alone, using the same patients as self-controls. We defined bleeding based on criteria from the International Society on Thrombosis and Haemostasis. Fisher’s exact test was used to compare distribution of bleeding severities and the Cox model was used to analyze bleeding risk. Results: A total of 86 patients were included for analysis, with a median age of 56 (range, 34-88). The patient population was predominantly of male gender (69.7%), Caucasian race (89.3%) and renal cell cancer type (48.9%). As some patients had been on both LMWH and DOAC at different time periods, we found that 81 patients received concurrent TKI and LMWH; 19 patients had concurrent TKI and DOAC. Overall, 25 patients developed 29 clinically significant bleeding events (including 8 major bleeding) during concurrent treatment, and 15 patients developed 17 clinically significant bleeding events (4 major bleeding) during factor Xa inhibitor alone over a median follow up of 63 days. We found a statistically higher bleeding risk with concurrent treatment (HR = 2.23, 95% CI, 1.13–4.42, p = 0.02) compared with Xa inhibitor alone. In a stratified analysis, concurrent VEGFR TKI plus LMWH or DOAC both showed a strong trend for elevated bleeding risk. Although there were increased bleeding events with concurrent treatment, there was no significant difference in the proportion of major bleeding (27.6% vs 23.5%, p = 0.76). Median time to first bleeding event was 56 days for concurrent therapy and 72 days for Xa inhibitor alone. Conclusions: Concurrent treatment of VEGFR TKI and factor Xa inhibitors is associated with significantly increased bleeding risk when compared with factor Xa inhibitors alone in metastatic cancer patients.

5007 Background: The immuno-oncology (I-O) combination nivolumab + ipilimumab (NIVO+IPI) is approved for first-line (1L) and NIVO is approved for second-line treatment post TKI therapy in aRCC. The open-label, randomized, phase 2 Fast Real-Time Assessment of Combination Therapies in Immuno-Oncology (FRACTION-RCC; NCT02996110) platform study has an adaptive design allowing rapid evaluation of I-O therapies, including NIVO+IPI or other investigational combinations. This FRACTION analysis reports preliminary outcomes with NIVO+IPI in aRCC pts after progression on checkpoint inhibitor therapy. Methods: All pts, except 1, had previously received and progressed on checkpoint inhibitor treatment. Pts received NIVO+IPI (NIVO 3 mg/kg + IPI 1 mg/kg Q3W ×4, then after 6 weeks, NIVO 480 mg Q4W), up to 2 years or until progression, toxicity, or protocol-specified discontinuation. Primary endpoints were confirmed objective response rate (ORR; per investigator using RECIST v1.1), duration of response (DOR), and progression-free survival probability at week 24. Safety outcomes were reported. Results: 46 pts were randomized to NIVO+IPI. Pts had 0 (n = 1), 1 (n = 10), 2 (n = 12), 3 (n = 10), or ≥4 (n = 13) prior lines of therapy. All pretreated pts had prior anti-PD-(L)1-, none had prior anti-CTLA-4- therapy, and 37 had prior TKI-based therapy; 45 pts progressed on anti-PD-(L)1 as the most recent therapy. Most pts had clear cell aRCC (n = 44). After a median study follow-up of 8.9 months, ORR was 15.2%; no pts achieved complete response and 7 achieved partial response. DOR ranged from 2–19+ months (n = 7); 5 pts had ongoing response. Six of 7 responders had received ≥2 prior lines of therapy. Any-grade treatment-related adverse events (AEs) were reported in 36 pts (78.3%; fatigue, rash [both 19.6%], and diarrhea [17.4%] were most common). Grade 3–4 treatment-related AEs were reported in 13 pts (28.3%; diarrhea [8.7%], ↑amylase and ↑lipase [both 6.5%] were most common). Treatment-related immune-mediated AEs of any grade were reported in 22 pts (47.8%; rash [19.6%], diarrhea [17.4%], and ↑alanine aminotransferase [8.7%]). No treatment-related deaths were reported. Updated and expanded results with an additional 3 months of follow-up will be presented. Conclusions: These results suggest that NIVO+IPI may provide durable partial response in some pts with prior progression on checkpoint inhibitors, including some heavily pretreated pts. The safety profile of NIVO+IPI in FRACTION pts was similar to historic data in aRCC with this combination. Clinical trial information: NCT02996110 .

e15142 Background: Immune checkpoint inhibitors (ICIs) are increasingly utilized across cancer types. Risk factors for emergency room (ER) and inpatient (IP) care in this patient (pt) population remain poorly defined. Methods: We retrospectively reviewed charts for pts with (w/) advanced solid tumors who received more than 1 ICI dose at Mount Sinai from 1/1/11 – 4/28/17. Demographics, medical history, cancer diagnosis and therapy (tx) details, and outcomes were recorded. Descriptive data detailing ER/IP care during ICI tx (from first dose to 3 months after last dose) were collected. Fisher’s exact test and multivariable regression analyses were used to study differences between pts w/ versus w/out ER/IP care during ICI tx. Significance level was set at 0.05 for all tests. Results: 345 patients met the inclusion criteria for this study. Mean age was 64 years. Common tumor types were non-small cell lung cancer (n = 87), melanoma (n = 78), hepatocellular carcinoma (n = 53), and urothelial carcinoma (n = 38). 83% of patients had metastatic disease. Median duration of ICI tx was 2 months. During ICI tx, 50% received ER care and 43% received IP care, resulting in 369 total episodes of ER and/or IP care. 12% of episodes were attributed to ICI toxicity; 6% required intensive care. Median time to ER/IP care was 111 days. Median IP length of stay was 2 days. Several factors were found to be significant predictors of risk for ER or IP care on multivariable analysis (Table). African-American race and Hispanic ethnicity were each predictive of increased risk for both ER and IP care. Conclusions: ER/IP care is common among pts w/ advanced solid tumors on ICI tx. Understanding demographic and clinical risk factors can help prospectively identify higher-risk pts to inform preventive programs aimed at reducing such care. [Table: see text]

e17561 Background: Prostate cancer (PCa) is common in countries with affluent dietary patterns and represents a heterogeneous collection of subtypes with varying behavior. Reductionist strategies focusing on individual nutrients or foods have not clearly defined risk factors. We have developed mechanisms-based dietary patterns focusing upon inflammation and chronic insulin hypersecretion, processes that are hypothesized to impact prostate carcinogenesis. Methods: First, we examined associations of the empirical dietary index for hyperinsulinemia (EDIH) and empirical dietary inflammatory pattern (EDIP) scores with circulating concentrations of relevant biomarkers, to assess the validity of these two dietary patterns. Secondly, we investigated associations of the EDIH and EDIP with risk of PCa (total, low-grade, high-grade, advanced and lethal). EDIH and EDIP dietary scores calculated from food frequency questionnaire data for 3,517 men and women who provided a blood sample at enrollment, were used to validate dietary patterns against known relevant biomarkers. A separate sample of 49,317 men was used to evaluate the associations of EDIH and EDIP with prostate cancer risk. We used multivariable-adjusted linear regression to compute the percent change and 95% confidence intervals (95%CI) in biomarker concentrations, and Cox regression to estimate hazard ratios (HR) and 95%CI for PCa risk; in dietary score quintiles, using the lowest quintile as reference. Results: Compared to the lowest quintile, participants in the highest EDIH quintile (most hyperinsulinemic diets) had significantly higher concentrations of C-peptide, insulin, CRP, and TNF-R2 and lower adiponectin. Those consuming the most pro-inflammatory diets (EDIP) had significantly higher concentrations of IL-6, TNF-R2, C-peptide and insulin with lower adiponectin. Men classified in EDIH quintile 5 compared to 1, were also at higher total PCa risk: HR, 1.11; 95%CI, 1.01, 1.23; P-trend = 0.03, especially high-grade cancer: HR, 1.18; 95%CI, 1.02, 1.37; P-trend = 0.06; whereas the EDIP was not associated with risk. Conclusions: EDIH and EDIP predicted concentrations of biomarkers relevant to the insulinemic and inflammatory potential of diet in PLCO. EDIH predicted future PCa risk and may suggest a dietary pattern for PCa prevention.

Background: Some cancer patients with thromboembolism require dual treatment of VEGFR TKIs and factor Xa inhibitors (direct or indirect), which may contribute to increased bleeding risks. However, the safety of such combination treatment has not been well characterized in the literature or national guidelines. Methods: This is a single center retrospective study, where we identified metastatic cancer patients (renal cancer, colorectal cancer, sarcoma, etc) who received concurrent VEGFR TKIs (pazopanib, sunitinib, sorafenib, axitinib, regorafenib, vandetanib, lenvatinib or cabozantinib) and Xa inhibitors (low-molecular weight heparin [LMWH] or direct oral anticoagulants [DOACs] including rivaroxaban or apixaban) at the Ohio State University Medical Center. We assessed bleeding risks of dual therapies vs. factor Xa inhibitors alone, using the same patients as self controls. We reviewed medical charts of all identified patients for clinically significant bleeding events (defined as combined major bleeding and clinically relevant non-major bleeding by the International Society of Thrombosis and Haemostasis criteria). The Cox proportional hazard model was used to compare the differences of time to first clinically significant bleeding event between the groups of concurrent use and anticoagulant use only. Results: A total of 86 patients (26 females and 60 males) were included: 78 Caucasians, 6 African Americans, and 2 others. 81 patients had concurrent TKI and LMWH treatment; 20 patients had concurrent TKI and DOACs; and 85 patients have had been on factor Xa inhibitor alone (LMWH or DOACs) at some point. Some patients had been on both LMWH and DOACs at different time periods. Overall, there were 29 clinically significant bleeding events (including 8 major bleeding) during concurrent treatment and 17 events (4 major bleeding) during factor Xa inhibitor alone over a median follow up of 63 days (52 days for concurrent treatment and 99 days for Xa inhibitor alone). In this self-control study, concurrent treatment was associated with a statistically higher risk of clinically significant bleeding events (HR, 2.84; 95% CI, 1.43-5.64, P < 0.01), which reached 37% patient population in the first 3 months, while the bleeding associated with factor Xa inhibitor alone seemed spaced out at the entire length of anticoagulation (8% by 6 months). Similar trend was found in the analysis of patient group of concurrent TKI and LMWH vs. LMWH alone (HR, 1.96; 95% CI, 0.95-4.02, P = 0.067), although significance was not reached likely due to insufficient power. Sample size was inadequate for meaningful comparison between concurrent VEGFR TKI and DOAC vs. DOAC alone. Conclusions: Concurrent treatment of VEGFR TKI and factor Xa inhibitors is associated with a significantly increased bleeding risks when compared with factor Xa inhibitors alone in patients with metastatic cancer. Disclosures No relevant conflicts of interest to declare.

e16602 Background: Radical prostatectomy (RP) and definitive radiation with androgen deprivation therapy (ADT) are both standard of care options for intermediate and high-risk localized prostate cancer (PCa). It remains controversial if the two modalities produce equivalent outcomes because the PROTECT trial (2016) and three recent retrospective studies (2018) drew inconsistent conclusions. Methods: The Surveillance, Epidemiology and End Results (SEER) database was queried from 2004 to 2015 for localized PCa (TxN0M0) who received upfront surgery or who were recommended for surgery but instead received external beam radiation (EBRT) with or without brachytherapy boost to control selection bias. The Kaplan-Meier method was used to generate overall survival (OS) curves and the Cox regression analysis was performed to compare survival outcomes. Results: A total of 175,349 patients were eligible with a median age of 62 years old (age range: 26 to 99). 167,234 patients had upfront surgery and 8,115 patients had upfront radiotherapy, including 7,099 EBRT and 1,016 EBRT with brachytherapy. Overall, upfront surgery was associated with a better OS, compared with patients who received radiotherapy (all patients: adjusted HR [adjHR], 0.79; 95% CI, 0.74–0.83, P < 0.001). The survival benefit is more pronounced in patients of intermediate-risk group (adjHR, 0.61; 95% CI, 0.57–0.66, P < 0.001; N = 112,816), and remains significant in patients of high-risk group (adjHR, 0.91; 95% CI, 0.84–0.98, P = 0.02; N = 62,533). However, in elderly high-risk PCa patients (age ≥ 70), surgery was associated with a significantly inferior OS, compared with radiotherapy (adjHR, 1.16; 95% CI, 1.06–1.28, P = 0.002). Conclusions: Compared with upfront radiation therapy, definitive surgery was associated with overall survival benefit in intermediate- and high-risk localized PCa, except patients with old age and high-risk features, who should be considered for radiation therapy.

e18201 Background: Neutrophil to Lymphocyte Ratio (NLR) is prognostic for cancer patients treated with immune checkpoint inhibitors (ICI). We showed the change in NLR early during treatment to be a stronger, curvilinear predictor, i.e. patients with an intermediate change in NLR performed better than those with large decreases or increases. This led us to re-examine whether NLR is an optimal predictor of overall survival (OS). Methods: A retrospective review of 467 patients with advanced cancer who received ICIs from 2011 to 2017 at the Ohio State University was performed with IRB approval. NLR was collected at the initiation of ICI and on-treatment (median 21, IQR 8 days) and calculated as ratio of absolute neutrophil to lymphocyte counts. Variable selection machine-learning algorithms included fast and frugal decision trees and random forest, performed in R. Results: The machine-learning algorithm fast and frugal decision trees identified the ratio of NLR on treatment to baseline NLR, the NLR on treatment, the change in NLR and the cubic change in NLR to be the most informative predictors of survival at 12 months. A random forest algorithm identified the same four variables as the most important for prediction accuracy. Age, sex and cancer type were the least informative predictors in the model, suggesting the on-treatment NLR variables are of value across wide range of demographics. Conclusions: NLR measured during treatment, and its derivative values of the ratio to baseline, change from baseline, and the cubic change from baseline, hold more predictive value than NLR measured at baseline. Common control variables such as age, and sex showed little effect on the model, suggesting on-treatment NLR is useful across wide demographic space. [Table: see text]

e13037 Background: Genomic testing, useful for treatment planning, may indicate the presence of a germline mutation. We evaluate the incidence of potentially actionable germline mutations detected via genomic testing and determined rates of follow-up referrals for genetic counseling and germline testing among patients with potential germline mutations. Methods: This was a retrospective chart review of patients who underwent genomic testing at The University of Vermont Cancer Center (UVMCC). Test reports were reviewed for mutations in 24 genes associated with hereditary cancer and recognized as clinically actionable by the American College of Medical Genetics. Medical record review was performed to identify patients referred for genetic counseling and results of germline testing. Results: Between 8/2009 and 9/2016 157 patients underwent genomic testing at UVMCC. Eighty-one percent (127/157) had a mutation in ≥ 1 gene associated with hereditary cancer (range 0-4 mutations per patient), and 46% (73/157) had mutations in more than one gene. Potential germline mutations were most commonly identified in TP53, CDKN2A, RB1, PTEN, STK11 and APC (each with mutations in > 10% of patients). To date only 12% (15/127) of patients with potential germline mutations have been referred for genetic counseling. Two were referred for evaluation of findings seen on genomic testing others being referred for personal or family history of cancer. The majority (11/15) of referred patients have undergone genetic testing with 27% (3/11) having germline mutations identified; 2/3 of which were also identified on genomic testing. Conclusions: Genomic testing can be an important tool for identifying hereditary cancer syndromes. While the majority (81%) of patient’s undergoing genomic testing had mutations genes associated with hereditary cancer, the low rate of referral (12%) for genetic counseling to determine if these are truly germline represents a significant missed opportunity. Identification of germline mutations has implications for both the patient (for treatment and risk of second cancers) and their family. Patients and their providers should be aware of the potential for germline findings when genomic testing is performed.

427 Background: DDR defects play an important role in tumorigenesis, progression, treatment response and outcomes of BCa. We previously showed DDR mutations were associated with better prognosis in relapsed/advanced (TxN2-3M0-1) BCa. In this study, we aimed to update and validate our findings in 3 independent datasets. Methods: 81 BCa patients (pts) who had FoundationOne tumor tissue genomic sequencing (315 cancer-related genes) were used as discovery dataset. Validation dataset 1 consisted of additional 91 pts with FoundationOne test. Validation dataset 2 consisted of 129 relapsed/advanced pts from TCGA BCa cohort. Overall survival (OS) was measured from time of initial BCa diagnosis to death or last follow-up. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI). Logistic regression analysis was performed to calculate odds ratio (OR) and 95% CI. A panel of 32 DDR genes (excluding ATM) were used for analyses because ATM mutation was a negative prognostic factor in our prior study. Results: DDR mutations were present in 76.5% (62/81), 40.7% (37/91) and 51.2% (66/129) pts of the 3 datasets. They were associated with longer OS (adjHR = 0.39, 95% CI 0.21–0.73, p = 0.003) in the discovery dataset, which were confirmed in two validation datasets (Validation 1: adjHR = 0.51, 95% CI 0.26–1.03, p = 0.059; Validation 2: adjHR = 0.62, 95% CI 0.39–0.97, p = 0.038). There was a trend for longer OS with increased number of DDR mutations in individual pts. Pts carrying ≥3 DDR mutations had the best prognosis (data not shown). In 144 cisplatin or carboplatin-treated pts pooled from the 3 cohorts, pts with DDR mutations were more likely to have objective response (OR = 1.81, 95% CI 0.85–3.92 for any DDR mutations; OR = 3.65, 95% CI 0.91–14.7 for ≥3 DDR mutations) and longer overall survival (HR = 0.61, 95% CI 0.38–0.98 for any DDR mutations; HR = 0.49, 95% CI 0.19–1.27 for ≥3 DDR mutations). Conclusions: DDR mutations (excluding ATM gene and especially ≥3) correlated with better outcomes in relapsed/advanced BCa. Further exploration of the deleterious nature and functional impact of alterations is critical along with prospective validation in ongoing trials.