Background/Objectives: Early-phase clinical trials (EPCTs) focus on safety and preliminary efficacy, often assessed by RECIST (Response Evaluation Criteria in Solid Tumours) tumour response. Health-related quality of life (HRQoL) is rarely evaluated in EPCTs and may not align with radiological outcomes. Methods: The PEARLER (Patient Experience in Early-Phase Cancer Clinical Trials) study evaluated the demographics, tumour response, HRQoL, and therapy type in two early-phase trial units in Australia between August 2023 and 2024. Patients completed the EORTC QLQ-C30 at baseline and follow-ups. The Global Health Status (GHS) score was selected as the primary HRQoL measure. Tumour response was assessed using RECIST 1.1. Spearman correlation and Kruskal-Wallis testing assessed the associations between RECIST, cross-sectional GHS change (ΔGHS; follow-up minus baseline), and therapy types. Multilevel models were used to evaluate longitudinal GHS values per RECIST category. Results: Of 122 patients recruited to the PEARLER study, 74 patients had paired RECIST and HRQoL data (complete response (CR) n = 0; partial response (PR) n = 15; stable disease (SD) n = 39; progressive disease (PD) n = 20). The median change in GHS was zero across RECIST groups, with broad individual variability. Notably, 18 of 54 patients (33.3%) with stable or responding disease experienced HRQoL decline. Meanwhile, 10 of 20 (50%) patients with PD experienced stable or improving HRQoL. The best RECIST response and ΔGHS showed a weak but statistically significant negative relationship (Spearman ρ = -0.28, p = 0.017), with the Kruskal-Wallis test demonstrating χ2 = 6.20 (p = 0.045), indicating modest group differences driven by the deterioration in PD patients. The multilevel model demonstrated a lower GHS in patients with PD, with no statistically significant interaction of GHS change over time with the RECIST response (p = 0.226). Conclusions: HRQoL change is largely independent of radiologic tumour response and therapy type in EPCT participants. Patients experienced a HRQoL decline despite tumour response. Incorporating patient-reported outcomes alongside RECIST and safety outcomes is important to fully capture the impact of investigational therapies and guide patient-centred trial designs.

Background: Small cell breast carcinoma (SCBC) is a rare, aggressive neuroendocrine breast cancer subtype comprising less than 1% of all breast malignancies. With no standardized treatment guidelines, management is typically extrapolated from small cell lung cancer (SCLC) or triple-negative breast cancer (TNBC) protocols. Immune checkpoint inhibitors (ICIs) have shown promise in both TNBC and SCLC, but their role in SCBC remains undefined. Case Presentation: We report the case of a 65-year-old woman diagnosed with early-stage, triple-negative SCBC, exhibiting high-grade features and a Ki-67 index >90%. She received neoadjuvant cisplatin and etoposide with pembrolizumab, followed by breast-conserving surgery and adjuvant pembrolizumab. Histopathology demonstrated a complete pathological response. The patient tolerated treatment well and remains disease-free on follow-up. Conclusion: This is the first reported case of SCBC successfully treated with neoadjuvant chemoimmunotherapy, achieving complete pathological remission. It highlights the potential role of ICIs in SCBC and supports future research into biomarker-driven strategies for this rare and aggressive.

Abstract Background Culturally and ethnically diverse communities are underrepresented in cancer clinical trials, further contributing to existing health inequities. Research often overlooks how upstream social determinants of health (SDOH) might contribute to these inequities, instead focusing on individual-level barriers. Arabic is the third most spoken language in Australia and is the focus of this study. This study aims to explore how upstream SDOH influence clinical trial participation among Arabic-speaking cancer patients (ASCPs), as perceived by healthcare professionals (HCPs). Methods A qualitative study comprising virtual focus groups with HCPs with experience recruiting ASCPs into clinical trials. Participants were recruited via professional networks and social media using snowball sampling. The Sociocultural Framework for Health Service Disparities was used to identify perceived barriers and enablers to cancer clinical trial participation relating to structural, healthcare provider, and environmental factors. Focus groups were analysed using the Best Fit approach by two independent coders. Results Fourteen participants were recruited (ten medical specialists, two nurses, one clinical trial coordinator and one researcher). Structural and healthcare provider barriers centred on English-language proficiency. Structural barriers included limited consultation time, restrictive trial eligibility criteria, lack of translated study materials, and a lack of workforce diversity. Language discourse reduced HCPs’ confidence in patient understanding of trial information and consequently the informed consent procedure. By advocating for translated materials, booking longer consults, and engaging interpreters, HCPs became enablers to trial participation. Family support networks were identified as environmental enablers by facilitating trial-related conversations; however, they also acted as barriers by compromising patient autonomy in decision-making. Perceived scepticism and distress emerged as environmental barriers that shaped attitudes toward cancer diagnosis and trial participation. Conclusion Findings highlight how upstream SDOH can create barriers to cancer clinical trial access, thereby reducing opportunities for participation among ASCPs in Australia. Although the barriers were described in terms of language, they may reflect a broader lack of cultural competency. Further research into strategies integrating enablers such as time, workforce diversity, interpreter engagement and translated resources is essential to inform inclusive healthcare systems and research design, with potential implications beyond the Arabic-speaking community. Trial registration Ethical approval for this study was granted by the University of Technology Sydney Human Research Ethics Committee (ETH21-6506, 14/01/2022).

Patients with metastatic or unresectable gastro-oesophageal cancers (mGECs) have poor prognoses and often face high symptom burdens and rates of disease-related complications. Second-line treatments offer modest survival gains, which need to be balanced with treatment toxicities. Time toxicity (TT) is increasingly recognised as a hidden toxicity of cancer therapy, and thus, this study aimed to quantify TT to patients undergoing second-line treatment for mGECs. This was a retrospective cohort study across three major hospitals in Sydney, Australia. Records were reviewed for all patients who received second-line systemic therapy for mGECs over 10 years. TT was defined as the number of days patients spent physically interacting with the healthcare system. Eighty patients were identified, with the majority male (83

In recent years, there has been increasing interest in developing drugs that increase the precision targeting of molecular alterations in prostate cancer cells. Traditionally, tissue samples are used to screen for and study such alterations, but liquid biopsies emerge as very practical and potentially superior methodologies to longitudinally characterize cancer cell biology and evolution. The expression of androgen receptor variants correlates with the development of castrate resistance prostate cancer (CRPC), and the most studied variant 7 (AR-V7) is associated with CRPC, disease progression, and resistance to certain AR-pathway targeted treatments and is readily detectable in circulating tumor cells (CTCs). Here, we describe a method of AR-V7 detection in CTCs using highly sensitive droplet digital PCR (ddPCR).

Precision medicine prostate cancer drug development, which targets patient-specific molecular alterations in prostate cancer cells, is rapidly progressing. Traditionally, tissue samples are used to screen for and study molecular alterations, but liquid biopsies are emerging as practical and potentially superior methodologies to longitudinally characterize cancer cell biology and evolution. The expression of androgen receptor variants correlates with the development of castrate resistance prostate cancer (CRPC), and the most studied variant 7 (AR-V7) is associated with CRPC, disease progression, and resistance to certain AR-pathway targeted treatments and is readily detectable in circulating tumor cells (CTCs). While mainly detected at the transcript level, subcellular localization of the protein defines its activity as a transcription factor, and emerging evidence suggests that detection of nuclear AR-V7 in CTCs is central to its utility as a poor-prognosis biomarker. Thus, transcript and protein detection of the AR-V7 biomarker in CTCs may complement each other to achieve the highest sensitivity and specificity. Here, we describe a method of AR-V7 protein detection in CTCs using immunocytostaining.

Background Presence of RAS mutations in mCRC are negatively correlated with OS. NGS enables detailed information regarding the heterogeneity of RAS mutations including specific amino acid changes as well as variant allele frequency (VAF). Recently, VAF has been postulated to have a role in identifying resistance to treatments in multiple solid tumours but its role as a prognostic marker of OS in mCRC is not established. Methods This was a multicentre, retrospective cohort study investigating all patients with NGS confirmed RAS-mutated mCRC between 2021 and 2023. NGS results for VAF were collected and correlated with clinicopathological outcomes. A VAF of > 20% was considered “high” whilst ≤ 20% was considered “low.” Results 351 patients were screened for presence of NGS-confirmed RAS-mutated mCRC. 124 patents were identified with RAS-mutated mCRC of which 95 patients had reported VAF and thus were included in the final cohort. 62 (65%) had high VAF on NGS. The median age was 56 (36 – 89) with 61% (n=58) being male. All patients had histologically confirmed moderately or poorly differentiated adenocarcinoma and none had evidence of mismatch repair deficiency. The two most common RAS-mutation subtypes were G12D (n=29, 31%) and G13D (n=21, 22%). 29 patients also had concurrent TP53 mutations whilst another 19 had concurrent PIK3CA mutations. Median OS in the entire cohort was 20.8 months. High VAF was associated with poorer survival compared with low VAF (16.9 versus 23.0 months, HR 2.2 (95% CI 1.2 – 3.9), p < 0.01). Conclusion This is the first real world evidence of the potential prognostic significance of VAF in mCRC. Patients with low RAS VAF had better survival compared with high VAF counterparts. Presence of low RAS VAF in tumour samples may suggest that patients progress in a manner resembling RAS wild-type tumours.

150 Background: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha ( PIK3CA ) encodes the p110 catalytic subunit of PI3K. This is a crucial kinase in the PI3K/AKT/mTOR signaling pathway and oncogenic PIK3CA mutations promote colorectal cancer (CRC) cell growth and metastasis. We aimed to assess clinicopathological features and prevalence of PIK3CA alterations in metastatic colorectal cancer (mCRC). Methods: We analyzed clinicopathological data from 339 patients diagnosed with mCRC at Southwestern Sydney Local Health District from 2014-2021. We performed next-generation sequencing using the Qiagen 30-gene panel and recorded demographic characteristics, histological features and survival outcomes from electronic medical records. Results: Of the 339 mCRC cases, 84 (25%) had PIK3CA alterations of which 56% were men and 44% women, with median age of 72 years. 74% of patients with PIK3CA alterations were Caucasian, 13% Middle Eastern, 12% Asian and 1% South American. E542K and E545K (exon 9) and H1047R (exon 20) together made up over half of all PIK3CA mutations, and 15% of tumours had more than one PIK3CA alteration identified. 51% had concurrent KRAS mutations, 15% concurrent BRAF mutations and 17% were mismatch-repair deficient. Most tumours were adenocarcinoma (89%) and the remainder mucinous adenocarcinoma. 80% of tumours were moderately differentiated, 17% poorly differentiated and 3% well differentiated. 45% were stage IV at diagnosis with median survival of 22 months (vs 24 months for patients without PIK3CA alterations). Conclusions: A quarter of mCRC patients in our study had PIK3CA mutations. Defining these patients may have therapeutic implications, including the use of aspirin or PIK3CA inhibitors. Identifying PIK3CA exon 20 mutations is also of clinical importance as these have been associated with resistance to anti- EGFR therapy in some studies.

BACKGROUND:The inaugural Australian National Oncology Mentorship Programme 2023 (NOMP23) demonstrated that virtual matching of trainee oncologists (mentees) with senior clinicians (mentors) for a 1-year mentorship programme was associated with significant reductions in burnout and improved professional fulfilment. AIMS:This sub-study sought to determine the bidirectional benefits of the programme for both mentees and mentors and unpack themes discussed at mentorship meetings to provide an insight into the benefit of top-down-led mentorship programmes. METHODS:The NOMP23 programme methodology has been previously reported. Additionally, participants were invited to partake in semi-structured interviews that were transcribed and thematic analyses conducted to assess benefits, themes discussed and future directions to improve NOMP. RESULTS:Of 112 participants enrolled, 86% completed the baseline questionnaire, 62% completed the mid-programme questionnaire and 54% completed the end-of-programme questionnaire. Nine participants - four mentors and five mentees - were interviewed at NOMPs conclusion. A high level of connection between matched pairs with adequate ability for pairs to meet was identified. The most common topics discussed were career planning, professional fulfilment, research and time management. The benefits of the mentoring relationship fell into five themes: (i) professional guidance; (ii) personal connection; (iii) support and reassurance; (iv) external perspectives; and (v) future perspectives. Benefits of providing mentorship fell into two themes: (i) personal connection and (ii) future-proofing oncology as a profession. CONCLUSION:Qualitative analyses of the NOMP23 programme demonstrated a positive effect on trainee and mentor well-being with benefits including personal guidance for trainees, fulfilment for mentors and instilling hope for the future.

Early-phase clinical trials (EPCTs) are critical for evaluating the safety, tolerability, efficacy and pharmacokinetics of novel oncology therapies. However, older adults are underrepresented in all phases of oncology clinical trials, including early-phase trials, creating a significant gap in evidence-based cancer management in this population, which translates into clinical practice. This is despite cancer incidence increasing with age, and a substantial proportion of cancer diagnoses occurring in individuals aged ≥ 65 years. Ageing is associated with physiological, physical and psychosocial changes which could underlie the hesitancy to include older adults in early-phase clinical trials, due to concerns of excessively compromising their safety and quality of life. However, the landscape of EPCTs has changed with higher safety and efficacy data. This review explores the current landscape of older adults in early-phase clinical trials, including the participation rate, the outcomes, and the multifaceted challenges contributing to the underrepresentation of older adults, and examines the potential strategies to enhance the inclusivity of older adults for treating older adults with cancer.

BACKGROUND/OBJECTIVES:Patients with incurable cancers enrolled in early phase clinical trials often face uncertainty about prognosis, yet advance care planning (ACP) is frequently delayed. The objective of this study was to assess the documentation of ACP discussions among patients enrolled in early phase oncology trials. METHODS:We conducted a retrospective review of electronic medical records for all adults enrolled in early phase clinical trials at a single Australian institution (2012-2021). Data included time from metastatic diagnosis to first ACP discussion, clinical and sociodemographic factors, triggers for discussion, and clinician specialty. RESULTS:Among 170 patients (58% male; median age 65 years), ACP documentation was identified in 109 (64%). ACP was most often initiated within the final year of life (73.8%), with a median interval of 23.5 months from metastatic diagnosis to first documentation. Common triggers were disease progression (39.6%) and hospital admission (37.8%). Discussions were typically led by the treating oncologist or trials specialist (43%) and palliative care physician (37.8%). The most frequently documented topic was the limitations of invasive care such as intubation (60%). CONCLUSIONS:ACP documentation was present in two-thirds of patients enrolled in early phase clinical trials, typically late in the disease trajectory. Integrating structured, earlier ACP discussions into oncology pathways would improve alignment of care with patient goals and enhance end-of-life care.

INTRODUCTION:Health-related quality of life (HRQoL) is not routine in early phase clinical trials (EP-CTs), which focus on dose-limiting toxicities and safety. However, for clinicians, understanding the impact of such trials on HRQoL is fundamental to consent patients, especially when the benefits on tumor response may be unknown. AIMS AND METHODS:The PEARLER (Patient diversity And experience in eaRLy phase cancEr clinical tRials) study was conducted with a key aim of focusing on assessing HRQoL in participants undergoing EP-CTs using a multi-center prospective cohort setting. All participants completed a baseline demographic survey on Cycle 1 Day 1 with EORTC-QLQ-C30 on Day 1 of Cycles 1 through 6 or end of treatment (EoT). RESULTS:Overall, 122 participants were recruited with median age 62. Median baseline Global Health Status (GHS) was 67 and remained unchanged throughout EP-CT (P = .188). GHS deterioration occurred in 29/122 (24%) while improvement occurred in 16/122 (13%). Median baseline Physical Function Score (PFS) was 87. PFS deterioration occurred in 30/122 (25%) while improvement occurred in 6/122 (5%). Baseline median CFS was 84. Cognitive Function Score (CFS) deterioration occurred in 25/122 (20%) while improvement occurred in 20/122 (16%). Baseline median Emotional Function Score (EFS) was 77. EFS deterioration occurred in 14/122 (11%) while improvement occurred in 14/122 (11%). Presence of liver metastases was a negative predictive marker for GHS, CFS, and EFS over time (P = .01, P < .01, and P < .01). CONCLUSION:PEARLER is the first prospective cohort study investigating change in HRQoL over time in patients undergoing EP-CTs. Reassuringly, almost three-quarters of participants who undertake EP-CTs either sustain or improve their GHS or PFS. Presence of liver metastases appears to be a negative predictive marker of HRQoL.

PURPOSE:Early-phase clinical trials (EP-CTs) provide access to novel therapeutics for patients with limited standard treatment options. Beyond drug-related risks, participants may experience hidden toxicities, including time, financial, and social burdens that often go unmeasured. METHODS:The Patient Experience in Early-Phase Cancer Clinical Trials (PEARLER) study aimed to assess time, financial, and social toxicity (ST) in a prospective, multicenter cohort. Participants completed a time toxicity (TT) survey and the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire C30 on day 1 of cycles 1-6. Financial toxicity (FT) was assessed using the EORTC scoring manual; ST was evaluated using the social and role functioning domains. Multilevel models examined trends over time. RESULTS:A total of 122 participants (median age 62 years, range, 25-83) were enrolled. Median objective TT was 26%. Only 16% (20/122) reported subjective TT, most commonly during cycles 1-2 (85%). FT was reported by 44% (54/122), but did not significantly change over time (P = .136). Although 71% (87/122) reported some reduction in social function, social functioning scores remained stable throughout trial participation. Role functioning declined in participants age 60 years and younger but was maintained in those older than 60 years. CONCLUSION:To our knowledge, PEARLER is the first prospective study to assess TT, FT, and ST in Australian EP-CTs. Although objective time burden was measurable, few patients perceived it as problematic beyond early cycles. FT and ST were commonly reported but remained stable over time. These findings suggest that EP-CT participation may not negatively affect patient-reported quality-of-life domains and provide reassurance for both clinicians and patients considering enrollment.

Background/Objectives: Autophagy is a conserved self-degradation process by which cells break down and recycle their cellular constituents. This process is activated by various stressors, including nutrient deprivation and DNA damage, and has also been associated with tumor progression. In the present study, we aimed to determine the expression patterns, clinicopathological significance, and prognostic value of the autophagy marker microtubule-associated protein 1 light chain 3 alpha (LC3A)—an essential component of autophagic vacuoles—in rectal cancer. Methods: LC3A reactivity was measured by immunohistochemistry in tumor samples from 243 patients who underwent surgery for rectal cancer. Results: Three distinct patterns of LC3A expression were identified: diffuse cytoplasmic, perinuclear, and stone-like structures (SLS). In Kaplan–Meier survival analyses, patients positive for the SLS pattern of LC3A staining in the tumor periphery (TP) had worse overall survival (OS; p = 0.001) and disease-free survival (DFS; p = 0.030) than those without SLSs in this region, as determined by the log–rank test. When patients were stratified by tumor stage, this result was significant in those with stage T3–T4 (OS, p < 0.001; DFS, p = 0.001) but not T1–T2 disease. Multivariate Cox regression analysis further showed an association between TP-localized LC3A SLS positivity and reduced OS for the overall cohort (hazard ratio [HR] = 2.6313, 95% confidence interval [CI]: 1.090–6.349, p = 0.031) and specifically those in the T3–T4 subgroup (HR = 3.347, 95% CI: 1.657–6.760, p = 0.001). Conclusions: Our findings suggest that positivity for SLSs in the TP may hold clinical value as a biomarker for survival prognosis in rectal cancer patients.

Background: Melanoma patients with pre-existing autoimmune diseases (AIDs) have been excluded from clinical trials of immune checkpoint inhibitors (ICIs), due to a risk of flare and immune-related adverse effects (irAEs). Materials and methods: A comprehensive literature search of Medline, Embase, CINAHL and Scopus was carried out. Studies of melanoma patients with pre-existing AIDs were included. Two reviewers used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Outcomes assessed included all-grade and grade 3 or 4 de novo irAEs, AID flare, treatment discontinuation owing to adverse effect(s), treatment-related mortality and objective response rate (ORR). Results: Thirty-two percent of patients with AIDs developed a flare, with 80% requiring immunosuppression. In patients with AIDs, meta-analysis revealed a higher risk of all-grade irAEs [risk ratio (RR) 1.16, 95% confidence interval (CI) 1.01-1.33, P = 0.0106] but not grade 3 or 4 (RR 1.21, 95% CI 0.99-1.47, P = 0.0663). Treatment discontinuation, treatment-related mortality and ORR were not different among patients with AIDs. Conclusions: Melanoma patients with pre-existing AIDs are at significant risk of flare with ICI use. These patients had an increased risk of irAEs of any grade. Although there was a trend towards increased risk of severe irAEs, this was not statistically significant. irAEs did not result in treatment-related deaths, and there were no differences in treatment response. Risks should be discussed, coupled with close monitoring.

Liquid biopsy-derived circulating tumor cells (CTCs) offer a minimally invasive avenue for precision oncology by enabling longitudinal monitoring of actionable molecular and cell-phenotypic biomarkers. However, conventional immunofluorescence imaging-based CTC profiling captures just 4-5 markers per cell, restricting crucial insights into oncogenic and resistance drivers, as well as tumor cell heterogeneity. Here we present an integrated pipeline employing deep multiplexed imaging to profile up to 50 molecular markers per CTC, capturing expression, phosphorylation, and subcellular localization of diverse biomarkers. Validated in a multi-stage prostate cancer resistance model and applied to prostate cancer patient-derived CTCs, this approach enhances CTC classification and reveals inter– and intra-patient heterogeneity correlating with therapy response. Machine learning identified therapeutically actionable signatures, suggesting patient-specific treatment strategies. This deep multiplexed imaging pipeline advances the utility of CTCs in guiding personalized cancer therapy by providing comprehensive molecular and phenotypic insights through minimally invasive liquid biopsies. ![Figure][1] Graphical Abstract ### Competing Interest Statement The authors have declared no competing interest. National Health and Medical Research Council, GNT1184009, GNT2012848, GNT2028506 National Breast Cancer Foundation, 2024/CRA0020 [1]: pending:yes

Early Phase Clinical Trials (EP-CTs) continue to have significant difficulty with enrolling real-world populations with many minorities being underrepresented. Reasons for this include patient or clinician perception as well as cultural, linguistic or social barriers. In Australia, there is currently no prospective data in the EP-CT space regarding recruitment of priority populations. PEARLER (Patient divErsity in eARLy phasE clinical tRials) was a multi-centre, prospective, cohort study involving two major EP-CT centres in Sydney, Australia. All participants who were consented to an EP-CT between August 2023 and August 2024 were enrolled. Participants completed a baseline demographic survey which included cultural and linguistic status, sexual orientation, socioeconomic status and regional diversity. One-hundred and fourteen participants were recruited. Median age was 63 years (25-83 years) with predominance for female participants (52%). No participant reported a non-binary gender. All participants reported their sexuality as heterosexual with no LGBTQIA+ participants recruited. 34 participants (30%) were identified as culturally diverse whilst 28 (25%) were linguistically diverse. One patient identified as indigenous Australian. 26% of participants were born overseas with 44% having at least one parent born overseas. The majority were living in households with family members with 8% of participants living alone. PEARLER is the first prospective study that provides granular description of social, cultural, linguistic, economic and sexual diversity amongst EP-CT participants. Certain subgroups are under-represented including those with sexual diversity, gender diversity and indigenous backgrounds. Ongoing efforts to monitor and promote inclusion of diverse populations in clinical trials are vital.

BACKGROUND:Interim analysis of the ENZA-p trial showed improved prostate-specific antigen (PSA) progression-free survival with the addition of lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 to enzalutamide as first-line treatment of metastatic castration-resistant prostate cancer. Here, we report the secondary endpoints of overall survival and health-related quality of life (HRQOL) with longer follow-up. METHODS:ENZA-p was a multicentre, open-label, randomised, phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older who had not previously been treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga PSMA-PET-CT-positive disease, an Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, early docetaxel, and previous treatment with abiraterone. Treatment was oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks. The primary endpoint was prostate-specific antigen (PSA) progression-free survival, which has been previously reported. Overall survival, defined as the interval from the date of randomisation to date of death from any cause, or the date last known alive, and HRQOL were key secondary endpoints. HRQOL was assessed with the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and the Patient Disease and Treatment Assessment Form. For HRQOL analyses, deterioration-free survival was measured from randomisation until the earliest occurrence of death, clinical progression, discontinuation of study treatment; or a worsening of 10 points or more from baseline in physical function, or in overall health and QOL. Analyses of these secondary endpoints were prespecified and are by intention to treat. The trial is registered with ClinicalTrials.gov, NCT04419402, and follow-up is complete. FINDINGS:Between Aug 17, 2020, and July 26, 2022, 79 patients were randomly assigned to enzalutamide and 83 to enzalutamide plus [177Lu]Lu-PSMA-617. 96 deaths was reported after a median follow-up of 34 months (IQR 29-39): 53 (67%) in the enzalutamide group and 43 (52%) in the enzalutamide plus [177Lu]Lu-PSMA-617 group. Overall survival was longer in the enzalutamide plus [177Lu]Lu-PSMA-617 group than the enzalutamide group (median 34 months [95% CI 30-37] vs 26 months [23-31]; HR 0·55 [95% CI 0·36-0·84], log-rank p=0·0053). HRQOL was rated by 154 (95%) of 162 participants. Deterioration-free survival at 12 months and stratified log-rank p values favoured enzalutamide plus [177Lu]Lu-PSMA-617 for both physical function (median 10·64 months [95% CI 7·66-12·42] vs 3·42 months [3·19-7·89]; HR 0·51 [95% CI 0·36-0·72], log-rank p<0·0001) and overall health and QOL (8·71 months [6·41-11·56] vs 3·32 months [3·09-5·26]; HR 0·47 [95% CI 0·33-0·67], log-rank p=0·0001). Mean scores for pain until progression favoured enzalutamide plus [177Lu]Lu-PSMA-617 over enzalutamide (difference 7·3 [95% CI 1·6-12·9]; p=0·012). Mean scores for fatigue until progression favoured enzalutamide plus [177Lu]Lu-PSMA-617 over enzalutamide (difference 5·9 [95% CI 1·1-10·7]; p=0·016). The frequency of self-rated xerostomia was lower in the enzalutamide group than in the enzalutamide plus [177Lu]Lu-PSMA-617 group (43 [57%] of 75 vs 58 [74%] of 78; p=0·039), and scores were not significantly different between groups for all other domains. Grade 3-5 adverse events occurred in 35 (44%) of 79 patients in the enzalutamide group and 37 (46%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group. No deaths were attributed to study treatment in either group. INTERPRETATION:The addition of [177Lu] Lu-PSMA-617 to enzalutamide was associated with improved survival and some aspects of HRQOL in patients with high-risk metastatic castration-resistant prostate cancer. Our findings warrant phase 3 evaluation of adaptive-dosed [177Lu] Lu-PSMA-617 in combination with androgen receptor pathway inhibitors in people with metastatic prostate cancer. FUNDING:The Prostate Cancer Research Alliance initiative (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, RoyMorgan, AdAcAp (a Novartis company), and Astellas.

PURPOSE Although large language models (LLMs) are increasingly used in clinical practice, formal assessments of their quality, accuracy, and effectiveness in medical oncology remain limited. We aimed to evaluate the ability of ChatGPT, an LLM, to generate physician and patient letters from clinical case notes. METHODS Six oncologists created 29 (four training, 25 final) synthetic oncology case notes. Structured prompts for ChatGPT were iteratively developed using the four training cases; once finalized, 25 physician-directed and patient-directed letters were generated. These underwent evaluation by expert consumers and oncologists for accuracy, relevance, and readability using Likert scales. The patient letters were also assessed with the Patient Education Materials Assessment Tool for Print (PEMAT-P), Flesch Reading Ease, and Simple Measure of Gobbledygook index. RESULTS Among physician-to-physician letters, 95% (119/125) of oncologists agreed they were accurate, comprehensive, and relevant, with no safety concerns noted. These letters demonstrated precise documentation of history, investigations, and treatment plans and were logically and concisely structured. Patient-directed letters achieved a mean Flesch Reading Ease score of 73.3 (seventh-grade reading level) and a PEMAT-P score above 80%, indicating high understandability. Consumer reviewers found them clear and appropriate for patient communication. Some omissions of details (eg, side effects), stylistic inconsistencies, and repetitive phrasing were identified, although no clinical safety issues emerged. Seventy-two percent (90/125) of consumers expressed willingness to receive artificial intelligence (AI)-generated patient letters. CONCLUSION ChatGPT, when guided by structured prompts, can generate high-quality letters that align with clinical and patient communication standards. No clinical safety concerns were identified, although addressing occasional omissions and improving natural language flow could enhance their utility in practice. Further studies comparing AI-generated and human-written letters are recommended.

11118 Background: Early phase clinical trials (EP-CTs) provide patients with access to novel therapeutics once standard of care options are exhausted or not available. Health related quality of life (HRQoL) is not routine in all EP-CTs where key focus may lie on dose limited toxicities and safety analyses. However for clinicians, understanding the impact of such trials on HRQoL is fundamental to consent patients, especially when the benefits on tumour response may be unknown. Methods: The PEARLER (Patient Experience in eARLy phasE cancer clinical tRials) study was conducted with a key aim of focusing on assessing HRQoL in participants undergoing EP-CTs using a multi-centre prospective cohort setting. All participants completed a baseline demographic survey on cycle 1 day 1 with EORTC-QLQ-C30 on day 1 of cycles 1 through 6 or end of trial (EoT). Multilevel models were used to analyse trend over time for Global Health Status (GHS), and Physical Function Score (PFS). Results: A total of 122 participants were recruited. Median age was 62 years (25 – 83 years) with 63 (52%) participants identifying as female. Of the total participants, 47 (39%) were enrolled in immuno-oncology EP-CTs whilst the remainder participated in EP-CTs focused on targeted therapies. The median number of EP-CT cycles completed by participants was 3. Median GHS) Score was 67 at baseline and remained steady across all participants throughout their EP-CT (p=0.188). GHS deterioration, defined by a 10-point decrease from baseline to EoT, occurred in 29/122 (24%) whilst GHS improvement occurred in 16/122 (13%). Median Physical Function Score (PFS) was 87 at baseline and remained steady across all participants throughout their EP-CT (p=0.104). PFS deterioration, defined by a 10-point decrease from baseline to EoT, occurred in 30/122 (25%) whilst GHS improvement occurred in 6/122 (5%). There was no statistically difference in change in GHS or PFS in younger versus older patients (less than or equal to 60 years versus over 60 years), tumour type, EP-CT type, gender or those from lower versus higher socioeconomic backgrounds. Conclusions: PEARLER is the first prospective cohort study investigating change in GHS and PFS over time in patients undergoing EP-CTs. Although almost three-quarters of participants who undertake EP-CTs either sustain or improve their GHS or PFS, one quarter do not. Patients need to be educated not only on the potential response rate of the EP-CT they are enrolling into but also the possibility of reduced HRQoL whilst participating in studies. Further research is needed to identify predictive and protective factors of HRQoL in patients undergoing EP-CTs.