OBJECTIVE To evaluate a multimodal strategy aimed at treating all sites of disease that provides a rapid readout of success or failure in men presenting with non-castrate metastatic prostate cancers that are incurable with single modality therapy. MATERIALS AND METHODS Twenty selected men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis were treated using a multimodal approach that included androgen deprivation, radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease or the primary site. Outcomes of each treatment were assessed sequentially. Androgen deprivation was discontinued in responding patients. The primary end point was an undetectable prostate-specific antigen (PSA) after testosterone recovery. The goal was to eliminate all detectable disease. RESULTS Each treatment modality contributed to the outcome: 95% of the cohort achieved an undetectable PSA with multimodal treatment, including 25% of patients after androgen deprivation alone and an additional 50% and 20% after surgery and radiotherapy, respectively. Overall, 20% of patients (95% confidence interval: 3%–38%) achieved the primary end point, which persisted for 5, 6, 27+, and 46+ months. All patients meeting the primary end point had been classified with M1b disease at presentation. CONCLUSION A sequentially applied multimodal treatment strategy can eliminate detectable disease in selected patients with metastatic spread at diagnosis. The end point of undetectable PSA after testosterone recovery should be considered when evaluating new approaches to rapidly set priorities for large-scale testing in early metastatic disease states and to shift the paradigm from palliation to cure.

Electronic health record (EHR)-derived real-world data (RWD) can be sourced to create external comparator cohorts to oncology clinical trials. This exploratory study assessed whether EHR-derived patient cohorts could emulate select clinical trial control arms across multiple tumor types. The impact of analytic decisions on emulation results was also evaluated. By digitizing Kaplan-Meier curves, we reconstructed published control arm results from 15 trials that supported drug approvals from January 1, 2016, to April 30, 2018. RWD cohorts were constructed using a nationwide EHR-derived de-identified database by aligning eligibility criteria and weighting to trial baseline characteristics. Trial data and RWD cohorts were compared using Kaplan-Meier and Cox proportional hazards regression models for progression-free survival (PFS) and overall survival (OS; individual cohorts) and multitumor random effects models of hazard ratios (HRs) for median endpoint correlations (across cohorts). Post hoc, the impact of specific analytic decisions on endpoints was assessed using a case study. Comparing trial data and weighted RWD cohorts, PFS results were more similar (HR range = 0.63-1.18, pooled HR = 0.84, correlation of median = 0.91) compared to OS (HR range = 0.36-1.09, pooled HR = 0.76, correlation of median = 0.85). OS HRs were more variable and trended toward worse for RWD cohorts. The post hoc case study had OS HR ranging from 0.67 (95% confidence interval (CI): 0.56-0.79) to 0.92 (95% CI: 0.78-1.09) depending on specific analytic decisions. EHR-derived RWD can emulate oncology clinical trial control arm results, although with variability. Visibility into clinical trial cohort characteristics may shape and refine analytic approaches.Contextualizing drug efficacy data from single-arm and small randomized clinical trials (RCTs) using robust external data sources and analytical methodologies is critical, especially in the regulatory approval setting for treatment of diseases that are rare or have high unmet medical need.

Introduction Effectiveness metrics for real-word research, analogous to clinical trial ones, are needed. This study aimed to develop a real-world response (rwR) variable applicable to solid tumors and to evaluate its clinical relevance and meaningfulness. Methods This retrospective study used patient cohorts with advanced non-small cell lung cancer from a nationwide, de-identified electronic health record (EHR)-derived database. Disease burden information abstracted manually was classified into response categories anchored to discrete therapy lines (per patient-line). In part 1, we quantified the feasibility and reliability of data capture, and estimated the association between rwR status and real-world progression-free survival (rwPFS) and real-world overall survival (rwOS). In part 2, we investigated the correlation between published clinical trial overall response rates (ORRs) and real-world response rates (rwRRs) from corresponding real-world patient cohorts. Results In part 1, 85.4% of patients ( N = 3248) had  at least one radiographic assessment documented. Median abstraction time per patient-line was 15.0 min (IQR 7.8–28.1). Inter-abstractor agreement on presence/absence of at least one assessment was 0.94 (95% CI 0.92–0.96; n = 503 patient-lines abstracted in duplicate); inter-abstractor agreement on best confirmed response category was 0.82 (95% CI 0.78–0.86; n = 384 with at least one captured assessment). Confirmed responders at a 3-month landmark showed significantly lower risk of death and progression in rwOS and rwPFS analyses across all line settings. In part 2, rwRRs (from 12 rw cohorts) showed a high correlation with trial ORRs (Spearman’s ρ = 0.99). Conclusions We developed a rwR variable generated from clinician assessments documented in EHRs following radiographic evaluations. This variable provides clinically meaningful information and may provide a real-world measure of treatment effectiveness. Supplementary Information The online version contains supplementary material available at 10.1007/s12325-021-01659-0.

No abstract

IMPORTANCEIn observational oncology studies of solid tumors, response to treatment can be evaluated based on electronic health record (EHR) documentation (clinician-assessed response [CAR]), an approach different from standardized radiologist-measured response (Response Evaluation Criteria in Solid Tumours [RECIST] 1.1). OBJECTIVE To evaluate the feasibility of an imaging response based on RECIST (IRb-RECIST) and the concordance between CAR and imaging response based on RECIST assessments, and investigate discordance causes. DESIGN, SETTING, AND PARTICIPANTS This cohort study used an EHR-derived, deidentified database that included patients with stage IV non-small cell lung cancer (NSCLC) diagnosed between January 1, 2011, to June 30, 2019, selected from 3 study sites. Data analysis was conducted in August, 2020.EXPOSURES Undergoing first-line therapy and imaging assessments of response to treatment. MAIN OUTCOMES AND MEASURESIn this study, CAR assessments (referred to in prior publications as "real-world response" [rwR]) were defined as clinician-documented changes in disease burden at radiologic evaluation time points; they were abstracted manually and assigned to response categories. The RECIST-based assessments accommodated routine practice patterns by using a modified version of RECIST 1.1 (IRb-RECIST), with independent radiology reads. Concordance was calculated as the percent agreement across all response categories and across a dichotomous stratification (response [complete or partial] vs no response), unconfirmed or confirmed. RESULTSThis study found that, in 100 patients evaluated for concordance, agreement between CAR and IRb-RECIST was 71% (95% CI, 61%-80%), and 74% (95% CI, 64%-82%) for confirmed and unconfirmed response, respectively. There were more responders using CAR than IRb-RECIST (40 vs 29 with confirmation; 64 vs 43 without confirmation). The main sources of discordance were the different use of thresholds for tumor size changes by RECIST vs routine care, and unavailable baseline or follow-up scans resulting in inconsistent anatomic coverage over time. CONCLUSIONS AND RELEVANCEIn this cohort study of patients with stage IV NSCLC, we collected routine-care imaging, showing the feasibility of response evaluation using IRb-RECIST criteria with independent centralized review. Concordance between CAR and centralized IRb-RECIST was moderate. Future work is needed to evaluate the generalizability of these results to broader populations, and investigate concordance in other clinical settings.

203 Background: Androgen deprivation therapy (ADT) does not completely eliminate disease in mNCPC or BRPC. We explored a multimodality treatment (tx) approach combining ADT with ipilimumab (ipi) with the aim of achieving no evidence of disease or complete elimination of disease, given the potential for cure seen with immunotherapy. Methods: Cohort A (Coh A) enrolled men with ≤ 10 bone metastases treated with induction of degarelix (deg) and ipi prior to RP and subsequent ipi q3 weeks x 3 and 8 months (mos) total of deg. Cohort B (Coh B) opened later and enrolled men with BRNCPC after RP with a doubling time ≤ 12 mos, and received ipi q3 weeks x 4 and 8 mos of deg. The primary endpoint was an undetectable PSA (<0.05) at 12 and 20 mos with non-castrate testosterone. Results: 16 pts (7 Coh A; 9 Coh B) were treated. No Coh A pts experienced immune related toxicities (irAE) that delayed surgery. 4/7 (57%) Coh A pts came off study for irAE, 1 (14%) for insurance reasons, and 2 (29%) completed all protocol requirements. In Coh B 6/9 (67%) pts have completed tx and entered follow-up. Conclusions: A combined modality approach with ipi 10mg/kg, ADT, and RP in mNCPC was associated with limiting toxicities, however 3mg/kg was better tolerated and more feasible in a BRNCPC cohort. One pt in Coh A (14%) had an undetectable PSA with testosterone recovery while evaluation of efficacy for Coh B is ongoing. The role for RP and other immunotherapeutic approaches in NCPC remain viable interests to the field. Clinical trial information: NCT02020070. [Table: see text]

No abstract

187 Background: The paradigm of first testing systemic treatments in advanced disease followed by development in earlier disease states and finally large-scale trials evaluating whether the approach, in combination with local therapy, can prevent or delay the time-to-event measures of disease progression or death in patients with “high-risk” tumors is no longer practical now that 6 life-prolonging systemic therapies in metastatic castration-resistant prostate cancer are available. New strategies are needed to rapidly evaluate and prioritize regimens for large-scale phase 3 testing. Methods: We conducted a pilot study of twenty men with oligometastatic M1a (extrapelvic nodal disease) or M1b (bone disease) at diagnosis. All sites of disease were treated using a multimodal approach that included androgen deprivation (ADT), radical prostatectomy plus pelvic lymphadenectomy (retroperitoneal lymphadenectomy in the presence of clinically positive retroperitoneal nodes), and stereotactic body radiotherapy to osseous disease and/or the primary site. ADT was discontinued in responding patients. Outcomes of each treatment were assessed sequentially. The primary endpoint of “no evidence of disease” (NED) was defined by an undetectable PSA with noncastrate levels of testosterone at 20 months. Results: Each treatment modality contributed to the outcome: 95% of the cohort achieved an undetectable PSA with multimodal treatment, including 25% of patients after ADT alone and an additional 50% and 20% after surgery and radiotherapy, respectively. Overall, 20% of patients (95% confidence interval 3-38%) achieved the primary endpoint, which persisted for 5, 6, 27+, and 46+ months. All patients meeting the primary endpoint had been classified with M1b disease at presentation. Conclusions: Treatment directed at all sites can eliminate detectable disease in selected patients with metastatic prostate cancer. A multimodal treatment strategy inclusive of the NED endpoint for patients who present with disease that is beyond the limits of curability by any single modality should be considered to enable the evaluation of new approaches in order to prioritize large-scale testing in early stages of advanced disease.