Thread by @EdmondMKwan

On the eve of #ASCO25, I am delighted to share results from the correlative analyses of the @ANZUPtrials phase II TheraP study, now published in @NatureMedicine. Massive effort supported by dedicated co-investigators, coordinators, patients & families from 11 study sites across Australia 🙏🏼 🧵1/10

nature.com/articles/s4159…

Data from VISION and TheraP have firmly entrenched 177Lu-PSMA-617 as the standard-of-care in taxane- and ARPI-refractory PSMA-positive mCRPC. However, tools to prioritize which patients will benefit greatest from this treatment are lacking 🧵2/10

Clinicians currently use novel PET imaging to provide incredible spatial information and clinically-relevant insights: high PSMA predicts response (though it’s a spectrum) and PSMA-/FDG+ discordance enriches for aggressive disease 🧵3/10

We therefore set out to understand how ctDNA genomics could potentially complement PET imaging-based stratification. TheraP’s active and clinically-relevant cabazitaxel control arm provided the ideal platform to identify candidate prognostic and predictive biomarkers for 177Lu-PSMA-617 or cabazitaxel response, and characterize mechanisms of resistance. 🧵4/10

To our surprise, ctDNA% was a predictive biomarker for differential response to 177Lu-PSMA-617 and cabazitaxel. Low/undetected ctDNA% tumours responded better to LuPSMA, while high ctDNA% tumours rapidly progressed irrespective of treatment administered. This association holds even when accounting for baseline PSMA SUVmean. Link between disease burden and proliferation with treatment efficacy? Implications for 177Lu-PSMA-617 in earlier disease states? #PSMAfore #EnzaP #UpfrontPSMA 🧵5/10

TheraP had some of the highest ctDNA% samples we have ever encountered in a public cohort, enabling in deep dissection of the estimated number of functional alleles remaining for key PCa driver genes. We observed that PTEN-altered patients derived greater benefit (PFS and OS) from 177Lu-PSMA-617 (more apparent with PTEN-null) – but interestingly was driven by poor outcomes on cabazitaxel. A subset of patients with deleterious ATM mutations may also sensitize to 177Lu-PSMA-617🧵6/10

Despite an multi-pronged exhaustive search across serial samples, we found that acquired resistance to cabazitaxel or 177Lu-PSMA-617 was rarely genomically driven—findings that redirect future mechanistic studies towards non-genomic resistance pathways (epigenetic / phenotypic / TME?). 🧵7/10

So where to next? Can cfDNA epigenomic profiling and circulating lipids provide greater context - @mishabeltran, @sjostrom_martin, @David_A_Quigley, and Prof Lisa Horvath will lead the way. What about potential toxicity – check out Abs 5070 by talented PhD candidate Aslı Munzur in the ASCO Prostate Rapid Oral session. Many other datasets still to be explored!🧵8/10

We believe our results nominate candidate predictive biomarkers informing LuPSMA treatment timing in the post-docetaxel/ARPI setting and serve as framework for investigating ctDNA biomarkers for other emerging PSMA-targeting therapeutics, including combination therapies. 🧵9/10

So many to thank that played an outsized role in making this possible. Special mention to close friends in @ResearchWyatt lab for keeping me level-headed for last 2-3 years, @VanProstateCtr for providing a home away from home, @ANZUPtrials for bridging my return home through Synchrony Fellowship, and @PCF_Science for inspiring our team through a Challenge Award. Deeply thankful to the patients whose contributions continue to drive discoveries like this. Really the dream start as I build my team at @easternhealthau @Monash_FMNHS @MonashBDI @EHCSMonash🧵10/10 - end