Sherry, Alexander D.

Abstract In phase 3 oncology clinical trials, identifying and understanding potential sources of differential censoring (DC), which describes censoring imbalance between treatment arms, in overall survival (OS) endpoints is vital to reduce bias and misinterpretation of OS benefit. Among 322 trials, 34 (11%) trials exhibited DC overrepresented in the control arm (DCC). Compared to trials without DC or those with DC overrepresented in the experimental arm (DCE), trials with DCC showed higher rates of OS benefit (56% vs. 32%; odds ratio [OR] = 2.26, 95% CI = 1.04 to 4.90; P = .04) and were associated with patient withdrawal (median 8.0% vs. 3.8%; P = .0002), lack of double blinding (15% vs. 48%, OR = 0.19, 95% CI = 0.06 to 0.56; P = .003), and better global quality of life in the experimental arm (32% vs. 13%, OR = 3.01, 95% CI = 1.26 to 7.19; P = .01). OS DCC is a prominent challenge that requires rigorous trial design and comprehensive patient and mortality follow-up to reduce bias in interpreting OS benefit.

ABSTRACT Background Blinding mitigates bias in randomized trials and may be especially crucial for surrogate endpoints, such as progression‐free survival (PFS). Here, we characterize utilization of and factors associated with blinding in Phase III oncology trials with PFS primary endpoints. Methods Two‐arm, superiority‐design trials investigating systemic therapy were identified in May 2024 from ClinicalTrials.gov with no date limitation. Trials were required to have a PFS primary endpoint. The study outcomes were the presence of double‐blind designs and blinded independent central review (BICR) for the primary endpoint. Ninety‐five percent credible intervals for binary outcomes were estimated from beta distributions, and multivariable logistic regressions explored associations with trial‐level features. Results After screening, 237 trials were included, enrolling 127,518 patients. A double‐blind design was used in 105 trials (44%, 95% CrI 38%–51%). BICR was used in 111 trials (47%, 95% CrI 41%–53%), including 39 double‐blind trials (16%, 95% CrI 12%–22%). Trials with BICR had higher odds of meeting the primary endpoint (OR 1.84; 95% CI 1.06–3.18; p = 0.03). The PFS assessor identity (central vs. local) or blinding status was not reported in 50 trials (26%, 95% CrI 16%–27%). Trials that met prespecified significance criteria for PFS were more likely to report whether PFS assessors were blinded/unblinded and central/local (OR, 3.05; 95% Cl: 1.60–5.81; p = 0.0007). Conclusions Despite the importance of double blinding in combination with BICR for reducing bias, only a few trials blinded physicians, patients, and primary endpoint assessors. This meta‐epidemiological study illuminates the prevalence of potential assessment biases affecting PFS in Phase III oncology and secondarily emphasizes the need for improved methodology reporting.

PURPOSE Randomized clinical trials (RCTs) have shown progression-free survival (PFS) benefits of metastasis-directed therapy (MDT) without androgen deprivation therapy for oligometastatic castration-sensitive prostate cancer (omCSPC). Most patients with bone metastatic (BM) omCSPC recur with additional bone disease after MDT. We hypothesized the BM-targeting alpha-emitter radium-223 dichloride (Ra223) could target subclinical bone disease and delay progression. METHODS This is an investigator-initiated, multicenter, open-label phase II RCT. Eligible men with recurrent omCSPC with ≥one bone metastasis (≤three on conventional imaging and/or ≤five on molecular imaging) were randomly assigned (1:1) to stereotactic ablative radiation (SABR) MDT alone or SABR MDT with Ra223 (six cycles). Primary end point was composite PFS. RESULTS From August 9, 2019, to March 2, 2023, 64 patients were randomly assigned, 33 to SABR MDT and 31 to SABR MDT/Ra223 balancing for key covariates. Most SABR MDT/Ra223 patients (87%) received six cycles of Ra223. The median PFS was 11.8 months with SABR MDT and 10.5 months with SABR MDT/Ra223 (adjusted hazard ratio [aHR], 1.42 [95% CI, 0.79 to 2.56]; P = .24). Seven patients (11%) experienced grade 3 treatment-related adverse events (no grade 4 or 5), 2 of 33 (6%) with SABR and 5 of 30 (17%) with SABR MDT/Ra223. Patients with high-risk (HiRi) pathogenic mutations in ATM , BRCA1/2 , RB1 , or TP53 had worse PFS (HR, 5.95 [95% CI, 1.83 to 19.3]; P = .003). Greater T-cell receptor (TCR) unique productive rearrangements were prognostic for improved PFS independent of the treatment arm (aHR, 0.45 [95% CI, 0.21 to 0.96]; P = .04). CONCLUSION Adding Ra223 to SABR MDT in BM omCSPC does not delay progression of disease. We provide evidence for an HiRi mutational signature and TCR repertoire as prognostic biomarkers in omCSPC treated with SABR MDT, highlighting the importance of collecting biological correlates in RCTs for omCSPC.

140 Background: In the phase II EXTEND iADT omPC basket, MDT+iADT improved progression-free survival (PFS) vs iADT. Here we present the primary results of the EXTEND cADT omPC basket. We further report a pre-specified combined analysis with updated results from the iADT basket and examine the effects of MDT on immunity. Methods: Patients with 1 to 5 omPC metastases were randomized 1:1 to MDT+cADT vs cADT (NCT03599765). MDT consisted of definitive local therapy. cADT consisted of ADT +/- second-generation anti-androgens. The primary endpoint was per-protocol PFS, defined by biochemical criteria (Prostate Cancer Working Group 3), radiologic measures (RECIST v1.1), clinical progression, or death. 87 patients were needed to show superiority at a one-sided P of 0.10 by log-rank test. CDR3 regions in rearranged T cell receptor (TCR) β-chains from pre- and post-enrollment peripheral blood were sequenced with immunoSEQ (Adaptive Biotech). TCR repertoire modulation was defined as having TCR expansion plus contraction using a false-discovery-corrected betabinomial model. TCR sequencing from the ORIOLE trial (NCT02680587) was assessed for external validation. Results: From 2018 to 2022, 87 randomized patients were treated per protocol (MDT+cADT: 45; cADT: 42). 39% had castrate resistant omPC. MDT was definitive radiotherapy in all cases. With median follow-up of 31 mo, median PFS was 47 mo after MDT+cADT vs 22 mo after cADT (HR 0.50; 95% CI 0.23 to 1.08; one-sided P = 0.036). In the combined analysis (N=174) with median follow-up of 42 mo, MDT+ADT improved PFS (HR 0.45; 95% CI 0.30 to 0.69; P < 0.001), radiologic PFS (HR 0.63; 95% CI 0.40 to 0.97; P = 0.038), and castration-resistance free-survival (HR 0.40; 95% CI 0.19 to 0.82; P = 0.013). MDT+ADT had higher odds of TCR repertoire modulation vs ADT (55% vs 15%, P < 0.001). This finding was validated in the ORIOLE trial (MDT: 57% vs observation: 19%, P = 0.03). Among the subset of patients with extreme responses, random forest modeling of 37 clinical/immune variables identified TCR repertoire modulation as the variable with highest importance; further, MDT+ADT induced TCR repertoire modulation in all patients with favorable responses (i.e. PFS > 4 years) and none with unfavorable responses (i.e. PFS < 1 year). Among all patients randomized to MDT+ADT, TCR repertoire modulation was associated with longer PFS (HR 0.21; 95% CI 0.06 to 0.76; P = 0.02). Conclusions: MDT+cADT met the PFS primary endpoint of the phase II EXTEND trial, warranting phase III testing. From the combined analysis, MDT+ADT may also improve longer term outcomes including radiologic PFS and castration-resistance-free survival. Improved outcomes may result from MDT-induced immunomodulation, with implications for future trial design. Clinical trial information: NCT03599765 .

Abstract Purpose: Metastatic castration-resistant prostate cancer (mCRPC) resistant to androgen receptor signaling inhibitors (ARSI) is often lethal. Liquid biopsy biomarkers for this deadly form of disease remain under investigation, and underpinning mechanisms remain ill-understood. Experimental Design: We applied targeted cell-free DNA (cfDNA) sequencing to 126 patients with mCRPC from three academic cancer centers and separately performed genome-wide cfDNA methylation sequencing on 43 plasma samples collected prior to the initiation of first-line ARSI treatment. To analyze the genome-wide sequencing data, we performed nucleosome positioning and differential methylated region analysis. We additionally analyzed single-cell and bulk RNA sequencing data from 14 and 80 patients with mCRPC, respectively, to develop and validate a stem-like signature, which we inferred from cfDNA. Results: Targeted cfDNA sequencing detected AR/enhancer alterations prior to first-line ARSIs that correlated with significantly worse progression-free survival (P = 0.01; HR = 2.12) and overall survival (P = 0.02; HR = 2.48). Plasma methylome analysis revealed that AR/enhancer lethal mCRPC patients have significantly higher promoter-level hypomethylation than AR/enhancer wild-type mCRPC patients (P &lt; 0.0001). Moreover, gene ontology and CytoTRACE analysis of nucleosomally more accessible transcription factors in cfDNA revealed enrichment for stemness-associated transcription factors in patients with lethal mCRPC. The resulting stemness signature was then validated in a completely held-out cohort of 80 patients with mCRPC profiled by tumor RNA sequencing. Conclusions: We analyzed a total of 220 patients with mCRPC, validated the importance of cell-free AR/enhancer alterations as a prognostic biomarker in lethal mCRPC, and showed that the underlying mechanism for lethality involves reprogramming developmental states toward increased stemness. See related commentary by Nawfal et al., p. 7

Objective: To evaluate the predictors of remnant tumor regrowth and need for salvage therapy after less than gross total resection (GTR) of vestibular schwannoma (VS). Study Design: Retrospective chart review. Setting: Tertiary neurotologic referral center. Patients: Patients who underwent VS resection between 2008 and 2019 either with GTR, near total resection (NTR), and subtotal resection (STR). Interventions: Microsurgical resection, salvage radiosurgery. Main Outcome Measures: Regrowth free interval, salvage free interval, tumor doubling rate. Results: Three hundred eighty five cases (GTR = 236, NTR = 77, and STR = 71) from 2008 to 2019 were included. STR cohort had much larger and complex tumors with significant differences in tumor volume, ventral extension and brainstem compression (p < 0.001). On single predictor analysis, tumor volume, ventral extension, brainstem compression as well as STR strategy was associated with significant increased risk of regrowth and need for salvage therapy. Multivariate analysis revealed STR strategy as significant predictor of regrowth (hazard ratio 3.79, p < 0.0005). Absolute remnant volume and extent of resection (EOR) did not predict regrowth. A small proportion of cases (NTR = 4%, STR = 15%) eventually needed salvage radiosurgery with excellent ultimate local tumor control with no known recurrence to date. Conclusions: Conservative surgical strategy employing NTR or STR can be employed safely in large and complex VS. While there is increased risk of regrowth in the STR cohort, excellent local control can be achieved with appropriate use of salvage radiosurgery. No disceret radiologic or operative predictors of regrowth were identified.

Objective: To report and discuss the effectiveness of stereotactic radiosurgery (SRS) or fractionated radiotherapy (FRT) for tumor control following surgical resection of endolymphatic sac tumors (ELST). Study Design: Retrospective case series. Setting: Multi-institutional academic referral centers. Patients: Patients undergoing surgical resection for ELST followed by SRS or FRT. Intervention(s): Surgical resection followed by radiotherapy. Main Outcome Measures: Local tumor control. Results: Two of the five patients experienced tumor recurrence after gross total microsurgical at 78 and 11 months, respectively. The former patient received salvage 3D conformal radiotherapy (3D-CRT) and while the latter patient underwent three courses of salvage SRS for recurrence, two of which were in-field and was disease-free at last follow up. Two additional patients underwent subtotal tumor resection (STR) followed by intensity-modulated radiation therapy (IMRT) and are currently without disease. One patient underwent STR followed by proton-beam therapy (PBT) and was free of disease at most recent follow-up. Conclusion: SRS/FRT remains a useful adjuvant for treatment of residual or recurrent ELSTs, where the risk of revision microsurgical resection is high.