Publications

Abstract Prostate cancer is a heterogeneous disease and genomic subtyping offers an opportunity to better understand underlying disease biology. Here, we performed transcriptional profiling by RNA-Seq (n=582) and targeted genomic sequencing by FoundationONE CDx (n=743) from prostate cancer tumor specimens in the phase III IPATential150 trial of first-line ipatasertib (Ipat) plus abiraterone (Abi) in metastatic castration-resistant prostate cancer (N=1101). Unsupervised transcriptomic analysis of the 582 samples with RNA-Seq with Nonnegative Matrix Factorization (NMF) reveals four consensus subtypes. This includes an immune/cell cycle-high, an AR signature/cell cycle-high, a stroma program-enriched, and an ERG fusion-enriched subtype. Subgroups of patients with immune/cell cycle-high and AR signature/cell cycle-high tumors had the shortest radiographic progression-free survival (rPFS) and were characterized by high MYC and cell cycle-related gene signatures. Patients with AR signature/cell cycle-high tumors showed the greatest increase in rPFS with Ipat + Abi vs. Placebo (Pbo) + Abi (HR = 0.58). Cluster n Enriched processes Median rPFS (Pbo + Abi) (months, 95% CI) Median rPFS (Ipat + Abi) (months, 95% CI) HR (95% CI) NMF1 84 Immune processes, metabolism, cell cycle 10.3 (8.3 - 12.7) 13.9 (10.9 - 16.4) 0.77 (0.47 - 1.28) NMF2 165 Androgen response signature, cell cycle, MYC signature 11.9 (8.8 - 16.5) 20.9 (16.4 - NA) 0.58 (0.38 - 0.90) NMF3 156 Fibroblast, Wnt, Notch, Hedgehog, TGFb 20.0 (16.4 - NA) 22.3 (15.6 - 24.9) 0.96 (0.59 - 1.56) NMF4 177 ERG fusion 18.4 (13.8 - 23.8) 24.7 (16.2 - NA) 0.78 (0.50 - 1.20) Citation Format: Zhen Shi, Malgorzata Nowicka, Johann de Bono, Kim N. Chi, Christopher Sweeney, Cora N. Sternberg, David Olmos, Sergio Bracarda, Christophe Massard, Nobuaki Matsubara, Josep Garcia, Geng Chen, Matthew Wongchenko, Shahneen K. Sandhu. Molecular subtyping in prostate cancer associate with outcomes to abiraterone and ipatasertib treatment from the phase III IPATential150 trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6317.

This paper will provide a summary of the new Australia-New Zealand Standard on the design of composite steel-concrete buildings ASNZS2327 which is due for release in 2017. This standard which has included over five years of development has harmonized design provisions across the Tasman Sea, in steel, concrete and composite structures. This project was carried out in parallel with the standard for bridge structures (ASNZS 5100.6) and thus there was significant commonality and cross-over. ASNZS2327 covers the design of structural elements such as slabs, beams, columns and joints, as well as addressing the system behaviour for serviceability and fire which are highly pertinent for the design of steel and composite structures. Methods for the design for earthquake have also been included. The standard allows for the increase in concrete compressive strength up to 100 MPa and steel strengths up to 690 MPa. In addition, the standard has involved significant amounts of structural reliability studies to be carried out. This paper will provide a summary of some of the salient issues as well as highlighting future areas of interest which may be considered for future revisions.

<p>Supplementary Figure 7. No cytokine storm was observed in WAP- and MMTV-Her2 mice post the ACTIV+Pano treatment.</p>

1703 Objectives: 177Lu-PSMA-617 is a radiolabelled small molecule that delivers β-radiation to cells expressing prostate specific membrane antigen (PSMA), with promising activity and safety in metastatic castration-resistant prostate cancer (mCRPC). We compared 177Lu-PSMA-617 and cabazitaxel in a randomised phase 2 trial. Methods: Men with mCRPC progressing after docetaxel with high PSMA tumour-expression were randomized to 177Lu-PSMA-617 (6-8.5 GBq intravenously 6 weekly up to 6 cycles) vs cabazitaxel (20 mg/m2 intravenously 3 weekly up to 10 cycles) at 11-sites in Australia. The primary endpoint was prostate specific antigen (PSA) response rate defined by ≥50% reduction (PSA50-RR). Secondary endpoints included progression-free survival (PFS) (PSA and radiographic PFS), objective response rate (ORR) (RECIST 1.1), adverse events (CTCAE v4.03), patient-reported outcomes (PROs) (EORTC QLQ-C30, PDF), and overall survival (OS). This trial is registered in ClinicalTrials.gov, NCT03392428. Results: 200 of 291 men identified as eligible on PET imaging were randomised to 177Lu-PSMA-617 (N=99) or cabazitaxel (N=101). 91% had received prior androgen receptor-directed therapy (ARDT). PSA50-RR was significantly higher in those assigned 177Lu-PSMA-617 versus cabazitaxel (66% [95%CI,56-75%] vs 37% [95%CI,27-46%]; P<0.001). PFS was significantly longer in those assigned 177Lu-PSMA-617 than cabazitaxel (rates at 1yr 19% [95%CI,12-27%] vs 3% [95%CI,1-9%], hazard ratio (HR) 0·63 [95%CI,0.46-0.86; P=0.003). ORR in 78 men with measurable disease was significantly higher with 177Lu-PSMA-617 than cabazitaxel (49% vs 24%, RR 2.12; P=0.026). Follow-up remains immature for OS. Grade 3-4 adverse events occurred in 32/98 (33%) with 177Lu-PSMA-617 vs 45/85 (55%) with cabazitaxel. Overall quality-of-life and health status were similar, with significantly better outcomes for multiple PRO domains including diarrhoea, fatigue, social functioning, insomnia, hair loss, skin rash and sore hands/feet with 177Lu-PSMA-617. Conclusions: 177Lu-PSMA-617 compared to cabazitaxel in men with mCRPC led to significantly higher PSA and ORR response rates, longer PFS, less grade 3 or 4 adverse events and significant improvements in several PRO domains. Acknowledgements: This investigator-initiated trial received support from the Prostate Cancer Foundation of Australia, Endocyte (a Novartis Company), Australian Nuclear Science and Technology Organization (ANSTO), Movember, It’s a Bloke Thing, CAN4CANCER. Results also presented at ASCO GU 2021.

&lt;div&gt;AbstractPurpose:&lt;p&gt;We evaluated the predictive value of pretreatment ctDNA to inform therapeutic outcomes in patients with metastatic melanoma relative to type and line of treatment.&lt;/p&gt;Experimental Design:&lt;p&gt;Plasma circulating tumor DNA (ctDNA) was quantified in 125 samples collected from 110 patients prior to commencing treatment with immune checkpoint inhibitors (ICIs), as first- (&lt;i&gt;n&lt;/i&gt; = 32) or second-line (&lt;i&gt;n&lt;/i&gt; = 27) regimens, or prior to commencing first-line BRAF/MEK inhibitor therapy (&lt;i&gt;n&lt;/i&gt; = 66). An external validation cohort included 128 patients commencing ICI therapies in the first- (&lt;i&gt;N&lt;/i&gt; = 77) or second-line (&lt;i&gt;N&lt;/i&gt; = 51) settings.&lt;/p&gt;Results:&lt;p&gt;In the discovery cohort, low ctDNA (≤20 copies/mL) prior to commencing therapy predicted longer progression-free survival (PFS) in patients treated with first-line ICIs [HR, 0.20; 95% confidence interval (CI) 0.07–0.53; &lt;i&gt;P&lt;/i&gt; &lt; 0.0001], but not in the second-line setting. An independent cohort validated that ctDNA is predictive of PFS in the first-line setting (HR, 0.42; 95% CI, 0.22–0.83; &lt;i&gt;P&lt;/i&gt; = 0.006), but not in the second-line ICI setting. Moreover, ctDNA prior to commencing ICI treatment was not predictive of PFS for patients pretreated with BRAF/MEK inhibitors in either the discovery or validation cohorts. Reduced PFS and overall survival were observed in patients with high ctDNA receiving anti–PD-1 monotherapy, relative to those treated with combination anti–CTLA-4/anti–PD-1 inhibitors.&lt;/p&gt;Conclusions:&lt;p&gt;Pretreatment ctDNA is a reliable indicator of patient outcome in the first-line ICI treatment setting, but not in the second-line ICI setting, especially in patients pretreated with BRAF/MEK inhibitors. Preliminary evidence indicated that treatment-naïve patients with high ctDNA may preferentially benefit from combined ICIs.&lt;/p&gt;&lt;/div&gt;