Siva, Shankar

Background Stereotactic body radiotherapy (SBRT) is increasingly used for patients with oligometastatic prostate cancer, yet the optimal target definition, dose, and toxicity profile for rib metastases remain uncertain. Objectives We assessed local control (LC), toxicity, and the risk of radiation-induced rib fracture (RF) after SBRT for rib metastases. Design Retrospective multicenter cohort study. Methods We analyzed prostate cancer patients with radiologically diagnosed rib metastases treated with SBRT and >=12 months of follow-up. Outcomes were descriptively compared between gross tumor volume (GTV)-only and GTV plus an intraosseous clinical target volume (CTV) margin. Analyses included Kaplan-Meier survival estimates, cumulative incidence functions, and exploratory univariable Cox and logistic regression; no formal equivalence testing or multivariable validation was attempted because event numbers were very low. Results We included 102 patients with a median follow-up of 20 months. The 1- and 2-year LC rates were 97.9% and 96.3%, respectively. At 3 years, local progression was 2.1% in the GTV-only group, absent in patients treated with >=10 mm margins, and numerically highest with 3-5 mm CTV margins (13.5%, p=0.022). Among 13 symptomatic patients, pain control was excellent, with complete or partial response in all patients within 6 months. No grade >=3 toxicities occurred. RFs were rare (n=3, 2.9%), comprising one symptomatic Grade 2 event (0.9%) and two asymptomatic Grade 1 events (2.0%). Baseline symptoms and extraosseous infiltration were associated with RF in exploratory univariable analysis, but confidence intervals were wide. Higher PTV dose exposure, particularly PTV D50% (36.9 vs. 31.1 Gy, p=0.041), was also observed among RF cases. Conclusions SBRT for rib metastases from prostate cancer was associated with high LC, pain relief, and low observed toxicity in this retrospective real-world cohort. GTV-only contouring may be feasible in carefully selected patients staged and planned with PSMA-PET/CT, but the non-randomized design, baseline imbalances, short follow-up, and very low event count preclude drawing conclusions about equivalence or independent validation. RF predictor analyses should be considered exploratory and hypothesis-generating.

498 Background: Radiotherapy-based metastasis-directed therapy (MDT) has emerged as a viable treatment paradigm for oligometastatic clear cell renal cell carcinoma (ccRCC). However, the optimal integration of MDT with frontline immune checkpoint inhibition (ICI) is unclear, especially in light of the M1 NED subgroup analysis of KEYNOTE-564 suggestive of a larger benefit from adjuvant pembrolizumab. Here, we sought to compare the effects of MDT with or without pembrolizumab on clinical and translational outcomes among patients with oligometastatic ccRCC enrolled on two prospective phase II trials. Methods: We undertook an exploratory cohort study of two prospective, single-arm, investigator-initiated phase II trials. The RAPPORT trial (NCT02855203) assigned 30 patients to radiotherapy-based MDT followed by pembrolizumab 200 mg Q3W for eight cycles (MDT+ICI cohort). The MD Anderson trial (NCT03575611) assigned 121 patients to serial MDT (which was almost exclusively radiotherapy-based) without systemic therapy (MDT cohort). For both trials, eligibility criteria consisted of 1 to 5 ccRCC metastatic lesions amenable to MDT. For the present analysis, the primary endpoint was progression-free survival (PFS), prospectively defined by RECIST v1.1 and analyzed using Cox regression. Peripheral blood flow cytometry obtained at baseline, end of MDT in both cohorts (after 1 cycle of ICI in the MDT+ICI cohort), and after completion of all treatment in both cohorts (3 months in the MDT alone cohort and 12 months in the MDT+ICI cohort) was compared using adjusted linear mixed effect models. Results: A total of 150 patients were included for analysis (MDT+ICI: 30; MDT: 120). Median follow-up time was 34 months (MDT+ICI: 28; MDT: 36). At enrollment, the MDT+ICI cohort had a larger number of metastases (median 3 vs 1). Adjusted for prognostic factors, median PFS was 28 months after MDT+ICI and 17 months after MDT (HR, 0.57; 95% CI: 0.31 to 0.998; P = 0.049). Induction of activated systemic CD8 + T cells (ICOS + ) was observed in both cohorts following MDT; however, this increase was greater in the MDT+ICI cohort. Moreover, there was evidence of decreased systemic CD8 + T cell immunosuppression (CD73 + ) following treatment cessation in the MDT+ICI group. Conclusions: To our knowledge, this is the largest prospective analysis of MDT for ccRCC in the ICI era. The addition of maintenance ICI to MDT may improve clinical outcomes in patients with oligometastatic ccRCC. Greater immunomodulatory signals were observed with MDT+ICI, providing a mechanistic link to the clinical benefits. The ASTROs trial (NCT06004336) randomizing patients with oligometastatic ccRCC to MDT with or without pembrolizumab has been initiated to test the hypotheses generated by the present study. Clinical trial information: NCT02855203 and NCT03575611 .

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co‐primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. The initial STOMP and ORIOLE trial reports suggested that metastasis-directed therapy (MDT) in oligometastatic castration-sensitive prostate cancer (omCSPC) was associated with improved treatment outcomes. Here, we present long-term outcomes of MDT in omCSPC by pooling STOMP and ORIOLE and assess the ability of a high-risk mutational signature to risk stratify outcomes after MDT. The primary end point was progression-free survival (PFS) calculated using the Kaplan-Meier method. High-risk mutations were defined as pathogenic somatic mutations within ATM, BRCA1/ 2, Rb1, or TP53. The median follow-up for the whole group was 52.5 months. Median PFS was prolonged with MDT compared with observation (pooled hazard ratio [HR], 0.44; 95% CI, 0.29 to 0.66; P value < .001), with the largest benefit of MDT in patients with a high-risk mutation (HR high-risk, 0.05; HR no high-risk, 0.42; P value for interaction: .12). Within the MDT cohort, the PFS was 13.4 months in those without a high-risk mutation, compared with 7.5 months in those with a high-risk mutation (HR, 0.53; 95% CI, 0.25 to 1.11; P = .09). Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained clinical benefit to MDT over observation. A high-risk mutational signature may help risk stratify treatment outcomes after MDT.

5025 Background: Prospective reports suggest metastasis directed therapy (MDT) in oligometastatic castration sensitive prostate cancer (omCSPC) is associated with improved treatment outcomes. Here we present long term outcomes of the phase II STOMP and ORIOLE trials and assess the ability of a high-risk (HiRi) mutational signature to provide prognostic and predictive information regarding MDT response. Methods: Patients with omCSPC (< 3 lesions) enrolled on STOMP (n = 62) and ORIOLE (n = 54) randomized to MDT or observation were pooled. The primary endpoint was progression-free survival (PFS) defined as either PSA or radiographic progression, initiation of androgen deprivation, or death. Secondary endpoint was radiographic PFS (rPFS) defined as radiographic progression or death. Both were calculated using the Kaplan-Meier method and stratified by treatment group. Next generation sequencing (NGS) was performed to identify a HiRi mutational signature defined as pathogenic mutations within ATM, BRCA1/2, Rb1, or TP53. Cox proportional hazards regressions were fit to calculate hazard ratios (HR) and assess the prognostic and predictive values of HiRi mutational status. Results: Median follow-up was 52.5 months. Median PFS was prolonged with MDT (11.9 months) compared to observation (5.9 months) with a pooled HR of 0.44 (95% CI, 0.29 – 0.66, p-value < 0.001). MDT was associated with PSA decrease in a majority of patients (84%) as compared to the observation group (41%). On NGS, the incidence of a pathogenic mutation in a HiRi gene was 24.3%. HiRi mutation was prognostic for PFS -- in those without a HiRi mutation median PFS was 11.9 months compared to 5.9 months in those with a HiRi mutation (HR of 1.74, p = 0.06). HiRi mutation was also prognostic for rPFS -- those without a high-risk mutation experienced median rPFS of 22.6 months compared to 10.0 months in those with a high-risk mutation (HR 2.62, p < 0.01). Tumors without a HiRi mutation treated with MDT experienced the longest PFS (13.4 months) while those with a HiRi randomized to observation experienced the shortest PFS (2.8 months). Stratifying by both treatment arms and HiRi status appeared to show a differential benefit to MDT, with those with HiRi mutations experiencing a larger relative magnitude of benefit to treatment: (HiRi mutation: HR of 0.05, p < 0.01; no HiRi mutation: HR of 0.42, p = 0.01; p interaction, 0.12) suggesting a HiRi mutational status can provide information regarding differential response to treatment. Conclusions: Long-term outcomes from the only two randomized trials in omCSPC suggest a sustained benefit to MDT over observation. A HiRi mutational signature appears prognostic for outcomes in omCSPC and those with HiRi might have a relatively larger magnitude of response to MDT. Future studies are needed to optimize patient selection. Clinical trial information: NCT02680587.

Objectives: Metastatic cancer has historically been considered fatal; however, there is a paucity of evidence characterizing the epidemiology of incidence, treatment, and outcomes in these patients. Materials and Methods: Incidence rates, annual percent change (APC), descriptive epidemiological statistics, and odds ratios for survival were calculated using registry data from the Surveillance, Epidemiology, and End Results (SEER) and the National Cancer Database (NCDB), 1998 to 2015. Results: There were a total of 1,055,860 patients with metastatic cancer. The most frequent primary cancers were lung (42.6%), colorectal (9.5%), and ovarian (5.5%). Metastatic lung and colorectal cancer incidence decreased, APC: −1.57 (P<0.001) and APC: −1.48 (P<0.001), respectively; metastatic pancreatic cancer incidence increased, APC: 0.62 (P=0.001). The use of local therapies decreased for almost all sites, and the use of systemic therapies increased across multiple sites: single-agent chemotherapy in kidney (2.54% increase/year), female breast (1.14% increase/year), and prostate cancer (1.08% increase/year); multiagent chemotherapy, most notably in pancreas (2.23% increase/year), uterus (1.81% increase/year), and colorectal cancer (1.54% increase/year). Increased utilization of immunotherapy was observed across the majority of sites, most notably in melanoma (2.14% increase/year). Patients diagnosed from 2006 to 2010 had 17.4% higher odds of surviving at least 60 months compared with 1998 to 2002. Conclusions: In this study, metastatic disease has been shown to have unique epidemiological patterns, and survival has improved. Continued research on metastatic disease is important in understanding and addressing the distinct health concerns of this population.