Background and objectives The calcimimetic cinacalcet reduced the risk of death or cardiovascular (CV) events in older, but not younger, patients with moderate to severe secondary hyperparathyroidism (HPT) who were receiving hemodialysis. To determine whether the lower risk in younger patients might be due to lower baseline CV risk and more frequent use of cointerventions that reduce parathyroid hormone (kidney transplantation, parathyroidectomy, and commercial cinacalcet use), this study examined the effects of cinacalcet in older ($65 years, n=1005) and younger (,65 years, n=2878) patients.Design, setting, participants, & measurements Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events (EVOLVE) was a global, multicenter, randomized placebo-controlled trial in 3883 prevalent patients on hemodialysis, whose outcomes included death, major CV events, and development of severe unremitting HPT. The age subgroup analysis was prespecified.Results Older patients had higher baseline prevalence of diabetes mellitus and CV comorbidity. Annualized rates of kidney transplantation and parathyroidectomy were .3-fold higher in younger relative to older patients and were more frequent in patients randomized to placebo. In older patients, the adjusted relative hazard (95% confidence interval) for the primary composite (CV) end point (cinacalcet versus placebo) was 0.70 (0.60 to 0.81); in younger patients, the relative hazard was 0.97 (0.86 to 1.09). Corresponding adjusted relative hazards for mortality were 0.68 (0.51 to 0.81) and 0.99 (0.86 to 1.13). Reduction in the risk of severe unremitting HPT was similar in both groups. ConclusionsIn the EVOLVE trial, cinacalcet decreased the risk of death and of major CV events in older, but not younger, patients with moderate to severe HPT who were receiving hemodialysis. Effect modification by age may be partly explained by differences in underlying CV risk and differential application of cointerventions that reduce parathyroid hormone.

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11511 Background: CDK4/6 inhibitors showed a favorable progression-free survival (PFS) in DD LPS, a sarcoma bearing 12q 13-15 amplicon that implies CDK4 amplification. The median PFS was 4 and 7 months (m) for palbociclib and abemaciclib, respectively. Preclinical experiments in 10 sarcoma cell lines and 6 PDX models, including only one DD LPS, showed higher efficacy of anti-CDK4 in cases with high expression of CDK4 and low expression of p16. This rationale supported the design of a phase II trial exploring palbociclib in a wide range of sarcomas, excluding DD LPS. Methods: Progressing pretreated advanced soft tissue sarcoma, excluding DD LPS, or osteosarcoma adult patients (pts), whose tumors overexpressed CDK4 and underexpressed CDKN2A mRNA in a baseline mandatory biopsy, were enrolled. CDK4 and CDKN2A expression were assessed by qRT-PCR, using an external control as reference (Universal human reference RNA; Agilent Technologies). The primary endpoint was 6-m PFS rate. Minimax Simon’s two-stage with type 1 and 2 errors of 10%, and null and alternative hypothesis of H0 15%, H1 40%, 6-month PFS rates were specified. The study will warrant further investigation if 6 or more pts had a PFS > 6 m from 21 evaluable pts. Palbociclib was administered orally at 125 mg/ day 21 out of 28 days. Pre-screening intended to increase the probability of positive profile in the baseline biopsy. Results: A total of 214 pts with 236 CDK4/ CDKN2A determinations were assessed for enrolment; 141 for prescreening, in archive tumor sample, and 95 for screening, in a baseline biopsy. There were 38/141 (27%) and 28/95 (29%) pts with favorable mRNA profile from pre and screening, respectively. Twenty-two pts were enrolled with a median of previous systemic lines of 3 (1-5). There were 9 different sarcoma subtypes, including 2 osteosarcomas. With a median FU of 10 m (0.4-23.3), the median PFS was 4.2 m (95% CI 0.9-7.4), while the 6- and 12-m PFS rates were 30% (95% CI 9-51) and 18% (95% CI 12-48) respectively. From 19 evaluable pts (1 early death by COVID, 1 withdrew consent and for 1 it was too early to be assessed) 11 had stable disease (58%) and 8 progressed (42%) as the best response. Patients with CDK4 expression above the median value had significantly longer mPFS in the univariate analysis: 5.9 m (95% CI 1.4-10.4) vs 1.9 m (95% CI 0.6-3.2), p = 0.046; and longer OS: 15.5 m (95% CI 6.8-24.3) vs 10.6 m (95% CI 0-23.2), p = 0.047, respectively. The probability to find a positive profile in the screening was 29%, but this proportion increased up to 41% if in pre-screening had been positive. Conclusions: Palbociclib showed to be effective in a wide variety of sarcoma subtypes, other than DD LPS, selected by CDK4/CDKN2A biomarkers. Clinical trial information: NCT03242382.

5511 Background: Endometrial cancers (ECs) are stratified into four molecular categories: wild type TP53 with non-specific molecular profile typically with microsatellite stability (NSMP, p53wt/MSS), DNA polymerase ε exonuclease domain-mutated (POLEmut), microsatellite instability high (MSI) and TP53 abnormal (p53abn). These are associated with specific prognoses. Selinexor (SEL) is a specific XPO1 inhibitor that leads to the nuclear retention and activation of tumor suppressor proteins (TSP) including p53. SEL showed improved progression-free survival (PFS) over placebo (PLB) in the stratification adjusted results of the ENGOT-EN5/GOG-3055/SIENDO study (NCT03555422; ESMO 2022). Methods: The SIENDO study is a prospective, multicenter, double-blind, placebo-controlled, phase 3 study of SEL (80 mg once weekly) vs. PLB (2:1 randomization) as maintenance therapy in 263 patients (pts) with advanced or recurrent EC after one line of taxane-platinum therapy with partial or complete remission. TP53 mutations and MSI were assessed by centralized targeted sequencing and local immunohistochemistry. Classification was based on sequencing 648 genes on tumor samples from 172 pts (107 on SEL), assigned first by POLEmut, then MSI, then p53abn or p53wt (NSMP). Preliminary exploratory analyses based on molecular classification were prespecified in the trial. Results: The SIENDO study resulted in a median progression-free survival (PFS) of 5.7 months (SEL) vs. 3.8 months (PLB), with a stratification adjusted (eCRF) hazard ratio (HR) of 0.70 (p =.024; and a stratification non-adjusted (IRT) HR of 0.76 (p=0.063). Among the 172 patients who underwent molecular classification, those on SEL (107 pts) were classified as follows: 37 (35%) NSMP, 2 (2%) POLEmut, 18 (17%) MSI, and 50 (46%) p53abn. A similar distribution was seen in those on PLB (65 pts): 20 (31%) NSMP; 4 (6%) POLEmut; 8 (12%) MSI; 33 (51%) p53abn. Subgroup analysis of pts with TP53wt showed a PFS of 13.7 mo with SEL vs. 3.7 mo with PLB (HR 0.375; 95% CI, 0.210-0.670; nominal p =.0003) and pts with MSS/pMMR disease had a PFS of 6.9 mo with SEL vs. 5.4 with PLB (HR 0.593; 95% CI, 0.388-0.905, nominal p =.007). An analysis of patients with NSMP (p53wt, MSS) showed a substantial difference in PFS for SEL vs. PLB: medians NR and 3.71 months, respectively (HR 0.163; 95% CI, 0.060-0.444; nominal p <.0001). Analyses of the other 3 molecular categories did not show significant differences in PFS between SEL and PLB. Additional biomarker identification studies assessing tumor genetics and epigenetics are ongoing. Conclusions: SEL showed improved PFS over PLB in the SIENDO study based on the stratification adjusted analysis. As an indirect p53 activator, preliminary exploratory subgroup analyses of SEL showed improvement over PLB amongst the patients with TP53wt, MSS, and the NSMP EC comprising approximately 50% of patients with advanced/recurrent EC. Clinical trial information: NCT03555422.