Publications

<p>Supplementary Methods, Figures, and Tables</p>

Current randomized controlled data ([1][1] , [2][2]) demonstrate the safety and efficacy of 6 cycles of [177Lu]Lu-PSMA-617 therapy in men with metastatic castration-resistant prostate cancer. In our first phase 2 trial ([3][3]), 15 of 30 patients received additional cycles; 11 (73%) had a subsequent

Abstract Despite patients with stage II melanoma being relatively high risk, contributing to 30% of melanoma-associated deaths, there remains a relatively low individual chance of melanoma recurrence. Therefore, strategies are required to better select those patients at highest risk of recurrence. We have developed assays using circulating tumour DNA (ctDNA) to detect minimal residual disease (MRD) or molecular recurrence of melanoma. Originally, the DETECTION trial was designed to perform ctDNA sampling in addition to clinical follow-up in patients with stage IIB/C melanoma. Those with ctDNA detected were randomized 1 : 1 in a double-blind fashion to continue routine follow-up with the investigators’ choice of treatment if they developed disease recurrence or were unblinded and treated with nivolumab. Since its opening, adjuvant therapy has been licensed, with trials showing approximately 6% absolute reduction in distant metastasis in stage IIB/C melanoma with 1 year of antiprogrammed cell death protein 1 therapy; however, grade 3 or 4 toxicity was observed in 16% of patients, with 25% experiencing lifelong endocrine disorders. Better enrichment of patients at high risk of recurrence, and avoiding treatment toxicity in those who do not require it, therefore remains highly relevant. As DETECTION had only started recruitment, there was opportunity to redesign it, which we present here. We have designed tumour-informed assays targeting BRAF (V600E/K/R), NRAS (G12D, Q61K/L/R) and the H-TERT promoter region (−124 and −146) mutations for ctDNA detection using droplet digital polymerase chain reaction. DETECTION has been redesigned as a phase III trial with the primary objectives of elucidating (i) whether MRD/molecular relapse following curative intent surgery can be identified earlier than clinical relapse and (ii) whether early treatment of molecular recurrence based on ctDNA detection is noninferior to adjuvant therapy in preventing distant metastasis. Patients (n = 1000) with stage IIB/C/III/IV resected BRAF/NRAS/TERT promoter mutant cutaneous melanoma, ECOG 0/1 and adequate organ function, with complete resection performed within 12 weeks and radiological/clinical disease-free status confirmed and no prior immune/targeted therapy will be included. Patients will be randomized 1 : 1 to either 1 year of adjuvant therapy (arm A) or longitudinal ctDNA monitoring (arm B) and treatment only if a local recurrence (surgery followed by 1 year of adjuvant therapy with ongoing ctDNA monitoring) or ctDNA detection (2 years of the investigators’ choice of therapy). The primary endpoint is distant metastasis-free survival. CtDNA is a useful tool to monitor for MRD/molecular relapse. The DETECTION trial will assess whether it can be used to safely monitor patients and systemically treat only those at highest risk of melanoma progression.

22 Background: We characterised the immune response in human prostate cancer (PC) to high dose rate brachytherapy (HDRBT) using serial pre- and post-HDRBT biopsies. Methods: Prostate biopsies and peripheral blood samples were obtained from 9 men with clinically localised PC at baseline and again 14 days following a 10 Gy fraction of HDRBT. Immune infiltrates were characterised using multiplex immunohistology (T cell and pan-immune panels) and targeted gene expression profiling (Nanostring pan-cancer immune panel). T cell repertoire was assessed using T cell receptor (TCR) Vbeta CDR3 deep sequencing. Results: HDRBT induced profound but heterogenous immune responses. At the extremes, one patient had an extensive tumor-infiltrating lymphocyte (TIL) response post-HDRBT, comprising T cells (CD4 + > CD8 + > Treg), B cells, and PDL1 + antigen presenting cells (macrophages and CD11c+ dendritic cells); another had a substantial baseline immune infiltrate eliminated by HDRBT. TIL-hi cases (either before or after HDRBT) had a conserved signature of T cell activation, differentiation, and trafficking, with upregulation of checkpoint molecules PD1, IDO1, BTLA, CTLA4, ICOS, B7-H3 and FoxP3. Those TIL-hi specifically in response to HDRBT also had down-regulation of genes regulating myeloid differentiation and granulocyte chemotaxis pre-HDBRT. Conversely, a monocyte-like myeloid-derived suppressor cell signature was seen in the TIL-lo responders. The median number of dominant clones ( > 1% prevalence) determined by TCR sequencing was 24.5 and 26.5 pre- and post-HDRBT respectively. Only 2 clones (in 1 patient) were present at both time points with the T cell repertoire otherwise being completely new following HDRBT. A subset of PC-associated T cell dominant clones was also present in the PB in all patients, suggesting HDRBT can induce systemic immunity. Conclusions: We have shown that treatment of localized prostate cancer with HDRBT induces a marked clonal TIL infiltrate dominated by T cells likely to be operating under the control of multiple checkpoints. These first-in-human data may be able to inform the rational selection of immunotherapy to combine with HDRBT.

<p>Supplementary Figure 1. Flow chart of patient selection. Supplementary Figure 2. Flowchart of patients with disease response assessment available (n = 57).</p>

Enzalutamide, an androgen-receptor inhibitor, has been associated with improved overall survival in men with castration-resistant prostate cancer. It is not known whether adding enzalutamide to testosterone suppression, with or without early docetaxel, will improve survival in men with metastatic, hormone-sensitive prostate cancer.In this open-label, randomized, phase 3 trial, we assigned patients to receive testosterone suppression plus either open-label enzalutamide or a standard nonsteroidal antiandrogen therapy (standard-care group). The primary end point was overall survival. Secondary end points included progression-free survival as determined by the prostate-specific antigen (PSA) level, clinical progression-free survival, and adverse events.A total of 1125 men underwent randomization; the median follow-up was 34 months. There were 102 deaths in the enzalutamide group and 143 deaths in the standard-care group (hazard ratio, 0.67; 95% confidence interval [CI], 0.52 to 0.86; P = 0.002). Kaplan-Meier estimates of overall survival at 3 years were 80% (based on 94 events) in the enzalutamide group and 72% (based on 130 events) in the standard-care group. Better results with enzalutamide were also seen in PSA progression-free survival (174 and 333 events, respectively; hazard ratio, 0.39; P<0.001) and in clinical progression-free survival (167 and 320 events, respectively; hazard ratio, 0.40; P<0.001). Treatment discontinuation due to adverse events was more frequent in the enzalutamide group than in the standard-care group (33 events and 14 events, respectively). Fatigue was more common in the enzalutamide group; seizures occurred in 7 patients in the enzalutamide group (1%) and in no patients in the standard-care group.Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. The enzalutamide group had a higher incidence of seizures and other toxic effects, especially among those treated with early docetaxel. (Funded by Astellas Scientific and Medical Affairs and others; ENZAMET (ANZUP 1304) ANZCTR number, ACTRN12614000110684; ClinicalTrials.gov number, NCT02446405; and EU Clinical Trials Register number, 2014-003190-42.).

&lt;p&gt;CD3+ (Combined TIL grade) between MCV negative (V-MGG) versus MCV-positive (V+MGG) MCCs. n.s., not significant.&lt;/p&gt;

Introduction: Excessive daytime sleepiness (EDS) is one of the common and burdensome non-motor symptoms of Parkinson's disease (PD). However, the underlying neuropathology mechanism in PD patients with EDS remains unclear. The present study aims to delineate potential locations of structural alteration of subcortical regions in early-stage and drug naïve PD patients with EDS. Methods: The study had 252 patients with PD and 92 matched healthy controls (HC). EDS was estimated with the Epworth sleepiness scale, with a cutoff of 10. Ultimately, 59 patients were considered as PD patients with EDS (PD-EDS). The remaining 193 were PD patients without EDS (PD-nEDS). FMRIB's Integrated Registration and Segmentation Tool (FIRST) was employed to assess the volumetric and surface alterations of subcortical nuclei in PD and PD-EDS. Results: Volumetric analyses found no difference in the subcortical nucleus volume between PD and HC, or PD-EDS and PD-nEDS groups. The shape analyses revealed that the local atrophic changes in bilateral caudate and right putamen in patients with PD. In addition, the hypertrophic changes were located in the right putamen and left pallidum in PD-EDS than in PD-nEDS. Conclusion Our findings revealed the regional hypertrophy of the striatum in PD patients with EDS. Our results indicate that local hypertrophic striatum would be a valuable early biomarker for detecting the alteration in PD patients with EDS. The shape analysis contributes valuable information when investigating PD patients with EDS.