Abstract Background Antiretroviral therapy (ART) reduces cancer risk in people with HIV (PWH) but the long-term impact of immediate ART initiation on infection-related and infection-unrelated cancers remains unclear. Methods In the Strategic Timing of Antiretroviral Treatment (START) trial, 4684 ART-naïve adult PWH with CD4 + T-cell count above 500 cells/mm 3 were randomized to immediate or deferred ART initiation arms (i.e., until CD4 + T-cells below 350 cells/mm 3 ). In May 2015, unblinding revealed a 74% reduction in infection-related cancer risk in the immediate arm. Post-2016, participants in the deferred arm were recommended to start ART, and follow-up continued through 2021. This analysis evaluates cancer incidence (by infection-related and infection-unrelated diagnoses) between the treatment arms by time-period (overall, pre-2016 and post-2016). Results Over a median follow-up of 9 years, 120 participants were diagnosed with cancer. The overall hazard ratio (HR) for cancer risk in the immediate versus deferred arms was 0.50 (95% CI: 0.34 to 0.73; p < 0.001). Pre-2016, the HR (immediate vs. deferred) was 0.33 (95% CI: 0.19 to 0.60; P < 0.001), while post-2016, it was 0.69 (95% CI: 0.42 to 1.13; P = 0.14), and P = 0.062 for the difference. For infection-related cancers in pre-2016 the HR was 0.24 (95% CI: 0.11 to 0.55; P < 0.001) and post-2016, HR was 0.53 (95% CI: 0.23 to 1.18; P = 0.12) and P = 0.18 for the difference. For infection-unrelated cancers, there was no significant difference in HR between immediate and deferred arms in either time period. Conclusion Immediate ART initiation significantly reduces infection-related cancer risk in PWH that persists long-term. Clinical trial registration NCT00867048.

PURPOSE:The Personalising Radiotherapy Dose in Anal Cancer (PLATO) platform was designed to evaluate risk‑adapted dose optimisation for anal squamous cell carcinoma (ASCC). A key secondary objective was to assess the impact of tailored treatment on patient‑reported outcomes (PROs), using the EORTC QLQ‑ANL27, the first anal cancer-specific validated PRO. METHODS:PLATO comprises three integrated trials: ACT3 (adjuvant chemoradiotherapy vs observation following local excision of T1N0/x anal margin tumours), ACT4 (reduced‑ vs standard‑dose chemoradiotherapy for T1/2 ≤ 4 cmN0/x ASCC), and ACT5 (three dose‑escalated chemoradiotherapy regimens for T3/4 or TanyN + disease). PROs (EORTC QLQ‑C30, QLQ-ANL27) were collected at baseline, end of treatment, 6-weeks, 6, 12, 24 and 36-months. Descriptive analyses to 6-months defined clinically relevant change as > 10‑point differences in mean scores. RESULTS:Between 1/2/2017-31/8/2023, 709 patients were recruited across 36 UK sites; 706 formed the mITT population (PRO consent 98.9 %; 86.0 % completion at 6-months). ACT5 patients reported markedly worse function and symptom scores at baseline than ACT3 and ACT4. All treated groups showed large declines at end of treatment, with improvement to baseline by 6-months for most issues; however, ACT5 participants continued to report residual deficits for bowel function compared with ACT3/4 cohorts. Poorer sexual function was reported in the ACT4 standard‑dose and ACT5 arms at 6-months, with interpretation of ACT3 sexual function limited by small numbers. CONCLUSION:PLATO demonstrates the feasibility of risk‑adapted radiotherapy dosing, with excellent PRO compliance. Most quality-of-life deficits improved by 6-months, although persistent impairments remained in ACT5 patients. Follow‑up to 36-months will further define late effects.

Background:The rising cancer burden in low- and middle-income countries (LMICs) has been accompanied by an increase in clinical trials. However, there is a paucity of research from LMICs on patient preferences for trial participation. Methods:We undertook a cross-sectional qualitative study using in-depth interviewing to explore the views of Indian cancer patients (n = 11), caregivers(n = 10) and public (n = 10), regarding clinical trials. Clinical researchers (n = 10) were also interviewed. Data were analysed using the framework of qualitative content analysis. Results:Five themes were identified regarding clinical trials: a) Perception: Only a minority had a prior understanding; when explained, most were willing to be randomised and attend additional monitoring visits. b) Recruitment: Consensus that trial discussions should be with the patient, with caregivers and family included where appropriate, variability in when a patient should be first approached. c) Patient information: Need for both written and audio-visual information material using simple local language. d) Benefits/adverse effects : Discussion of all pros and cons, including the possibility of dying was preferred. There were divided views regarding disclosure of all versus common risks. Challenges in understanding quantitative risks/benefits were voiced. e) Consent: Honesty and transparency, imbalance of power/trust between trialists and participants and financial vulnerability of patients were voiced by participants. Conclusion:Cancer clinical trials in LMICs can be enriched by patient and public involvement during planning research and conduct of the clinical trial. The financial vulnerability of patients and the power imbalance between them and researchers need to be addressed, especially in international multiregional clinical trials.

3525 Background: SCAC is a rare cancer with high unmet medical need and no FDA-approved treatment options. POD1UM-303 is the only phase 3 study of systemic therapy completed to date in advanced SCAC. The study met its primary endpoint of progression-free survival (PFS; 9.3 mo in the retifanlimab group vs 7.4 mo in the placebo group [HR, 0.63; 95% CI, 0.47, 0.84; P = 0.0006]) (Rao S, et al. Ann Oncol . 2024;35:S1217). Based on these results, retifanlimab combined with carboplatin-paclitaxel represents a new standard of care (SOC) for inoperable locally recurrent/metastatic SCAC. Here, we present outcomes for predefined subgroups of interest in POD1UM-303 and exploratory analyses in patients who received open-label retifanlimab in the crossover phase of the study. Methods: The POD1UM-303 study design and methods were previously presented at ESMO 2024. PFS comparisons for predefined subgroups, including PD-L1 expression, region of enrollment, presence of liver metastases, extent of disease, as well as HPV and HIV status, were performed. Exploratory analyses of investigator-assessed response to retifanlimab, overall survival (OS), and safety during crossover treatment were also performed. Results: A total of 308 patients were enrolled (1:1) to receive retifanlimab or placebo with chemotherapy; 69 (45%) from the placebo + chemotherapy group received crossover treatment with retifanlimab monotherapy upon confirmed progression. A consistent PFS benefit in favor of retifanlimab + chemotherapy was observed for all predefined subgroups, including tumors with PD-L1 expression < 1%, patients with liver metastases, and regardless of HPV or HIV status. Median PFS in the retifanlimab + chemotherapy group was higher in the PD-L1 ≥1% vs PD-L1 < 1% groups (9.3 mo; HR, 0.64 vs 7.5 mo; HR, 0.53) but was not impacted by presence of liver metastases. During crossover, investigator-assessed overall response rate was qualitatively similar to that seen in the POD1UM-202 study, which enrolled a similar platinum-refractory population. Median OS for patients receiving crossover treatment with retifanlimab was 24.3 mo, compared with 29.2 mo for patients who were assigned to retifanlimab + chemotherapy at randomization. Safety during crossover was consistent with earlier observations and comparable with experience in POD1UM-202. Conclusions: The benefits of retifanlimab combined with carboplatin-paclitaxel extend to the broad population of SCAC, including those with tumors not expressing PD-L1 and liver metastases. Response rate and safety profile of retifanlimab monotherapy in the crossover period were consistent with the previous POD1UM-202 experience; however, exploratory analysis of survival in crossover patients suggests first-line retifanlimab with SOC chemotherapy is preferable to sequential treatment after progression on chemotherapy. Clinical trial information: NCT04472429 .

3521 Background: People living with HIV (PLHIV) usually have more advanced cancer at diagnosis and a higher cancer-related mortality, posing a significant burden on health care. However, clinical studies often exclude cancer patients with HIV, thereby limiting access to therapies for this patient population. PLHIV have a 25- to 35-fold higher chance of being diagnosed with SCAC than individuals who are HIV negative. We therefore evaluated safety and efficacy of retifanlimab in PLHIV with SCAC. Methods: The study designs for POD1UM-202 (NCT03597295) and POD1UM-303/InterAACT-2 (NCT04472429) have previously been described. Both trials permitted PLHIV to enroll if CD4+ count was ≥200/μL with an undetectable viral load per standard of care assay, and who did not experience any HIV-related opportunistic infection for ≥4 weeks prior to study enrollment. Patients continued to receive antiretroviral therapy (ART/HAART) without interruption or dose reduction. HIV viral load and CD4+ cell count was assessed every 8 weeks during the studies and could be reduced to every 6 months during safety and disease follow-up. Results: Patient and disease characteristics were similar among PLHIV and the overall study populations. Among the 20 patients with HIV enrolled in these SCAC trials, median age was 58 years, 70% (n = 14) were male, and 80% (n = 16) were White. Forty-five percent (n = 9) of patients received retifanlimab and 30% (n = 6) received retifanlimab with platinum-based chemotherapy, whereas the remaining 5 patients were assigned to placebo plus chemotherapy. During these studies, no patient experienced a sustained drop in CD4+ T-cell counts or increase in HIV viral load of clinical significance. No treatment-emergent opportunistic infections were recorded. Immune-related adverse events (irAEs) and grade ≥3 irAEs were consistent with the non-HIV population. Objective response rates were 22% (2/9) with retifanlimab in second-line and 67% (4/6) with retifanlimab and chemotherapy in first-line (previously untreated). Patient-reported outcomes showed no negative impact and based on Quality-of-Life Questionnaire for Anal Cancer, good scores for bowel function, sexual, and symptom domains were maintained. Retifanlimab pharmacokinetics was independent of HIV status and not impacted by the HAART required for ongoing HIV management. Conclusions: Among PLHIV and advanced SCAC who received treatment, retifanlimab showed significant clinical activity with efficacy qualitatively similar to patients without HIV and no excess toxicity or reduced HIV control. The analysis indicates that retifanlimab is generally safe for PLHIV and SCAC and also supports inclusion of HIV-positive patients in other immunotherapy trials. The favorable outcomes in PLHIV are encouraging because infection with HIV is among the most important risk factors for SCAC. Clinical trial information: NCT03597295 and NCT04472429 .

OBJECTIVES:Androgen deprivation therapy (ADT) forms the mainstay of treatment for advanced prostate cancer. Traditionally administered as a luteinising hormone-releasing hormone (LHRH) agonist depot injection, newer options for ADT include transdermal oestradiol patches (tE2) or oral LHRH antagonists. This study aimed to identify whether this is an important choice for men, which treatment men would choose if offered either LHRH agonist injections, tE2 patches or oral LHRH antagonists as ADT, and to explore the factors influencing this decision. SUBJECTS, PATIENTS, AND METHODS:Five focus groups were conducted. A total of 24 men from around the UK participated in discussions, of whom 10 had never had prostate cancer and 14 had early prostate cancer but had not received ADT. Focus groups were co-facilitated with patient and public involvement representatives. Transcripts were analysed using a critical realist thematic analysis approach. RESULTS:Participants reported that having a choice of ADT is important and being involved in making treatment decisions can help men maintain an element of control. Most men expressed a preference to avoid ADT with LHRH agonist injections; 14 of the 24 men reported they would choose an oral LHRH antagonist, eight reported they would choose tE2 patches, and two that they would choose LHRH agonist injections. Participants reported a large number of factors that influenced their treatment choice that were grouped into: (i) side-effects of treatment, (ii) logistical aspects, and (iii) advice from trusted others. Personal preferences between different types of ADT were based on factors that participants identified as important to them, this prioritisation of factors was influenced by participants' past experiences, current health beliefs, and future expectations. CONCLUSIONS:Men wish to have choice of ADT, and many would not choose LHRH agonists injections if there were other ADT options available. This should be considered, as reimbursement committees and guideline-makers consider the role of alternative ADT strategies.

INTRODUCTION:The incidence of anal carcinoma is increasing, with the current gold standard treatment being chemoradiotherapy. There is currently a wide range in the radiotherapy dose used internationally which may lead to overtreatment of early-stage disease and potential undertreatment of locally advanced disease.PLATO is an integrated umbrella trial protocol which consists of three trials focused on assessing risk-adapted use of adjuvant low-dose chemoradiotherapy in anal margin tumours (ACT3), reduced-dose chemoradiotherapy in early anal carcinoma (ACT4) and dose-escalated chemoradiotherapy in locally advanced anal carcinoma (ACT5), given with standard concurrent chemotherapy. METHODS AND ANALYSIS:The primary endpoints of PLATO are locoregional failure (LRF)-free rate for ACT3 and ACT4 and LRF-free survival for ACT5. Secondary objectives include acute and late toxicities, colostomy-free survival and patient-reported outcome measures. ACT3 will recruit 90 participants: participants with removed anal tumours with margins ≤1 mm will receive lower dose chemoradiotherapy, while participants with anal tumours with margins >1 mm will be observed. ACT4 will recruit 162 participants, randomised on a 1:2 basis to receive either standard-dose intensity modulated radiotherapy (IMRT) in combination with chemotherapy or reduced-dose IMRT in combination with chemotherapy. ACT5 will recruit 459 participants, randomised on a 1:1:1 basis to receive either standard-dose IMRT in combination with chemotherapy, or one of two increased-dose experimental arms of IMRT with synchronous integrated boost in combination with chemotherapy. ETHICS AND DISSEMINATION:This study has been approved by Yorkshire & The Humber - Bradford Leeds Research Ethics Committee (ref: 16/YH/0157, IRAS: 204585), July 2016. Results will be disseminated via national and international conferences, peer-reviewed journal articles and social media. A plain English report will be shared with the study participants, patients' organisations and media. TRIAL REGISTRATION NUMBER:ISRCTN88455282.

BACKGROUND:Metformin is a widely used anti-diabetic drug. Several studies have suggested that metformin has anticancer activity in some malignancies, including prostate cancer. Metformin might also mitigate the adverse metabolic effects of androgen-deprivation therapy (ADT). We hypothesised that metformin might improve survival in patients with metastatic hormone-sensitive prostate cancer and reduce metabolic complications associated with ADT. METHODS:The STAMPEDE multi-arm, multi-stage, randomised phase 3 trial recruited patients with high-risk locally advanced or metastatic adenocarcinoma of the prostate staged by conventional imaging with isotope bone and CT scanning. This publication reports findings for the most recent STAMPEDE research question, testing the addition of metformin to standard of care for non-diabetic (glycated haemoglobin [HbA1c] <48 mmol/mol [equivalent to <6·5%]) patients with metastatic disease with adequate renal function (glomerular filtration rate ≥45 ml/min/1·73 m2) and WHO performance status 0-2. This trial recruited from 112 hospitals in the UK and Switzerland to the STAMPEDE protocol. Patients were randomly allocated (1:1) to standard of care or standard of care plus metformin 850 mg twice daily. Random assignment was by telephone using minimisation with a random element of 20% (developed and maintained by the MRC Clinical Trials Unit at UCL), stratified for randomising hospital, age (<70 years vs ≥70 years), WHO performance status (0 vs 1 or 2), type of ADT, regular long-term use of aspirin or non-steroidal anti-inflammatory drugs (NSAIDs; yes vs no), pelvic nodal status (positive vs negative), planned radiotherapy (yes vs no), and planned docetaxel or androgen receptor pathway inhibitor (ARPI) use (docetaxel vs abiraterone, enzalutamide, or apalutamide vs none). Standard of care comprised ADT with or without radiotherapy and with or without docetaxel or ARPI. The primary outcome measure was overall survival, defined as the time to death from any cause, assessed in the intention-to-treat population. Safety was assessed in patients who started treatment. The trial is registered with ClinicalTrials.gov, NCT00268476 and ISRCTN, ISRCTN78818544. FINDINGS:Between Sep 5, 2016, and Mar 31, 2023, 1874 patients with metastatic disease were randomly allocated to standard of care (n=938) or standard of care plus metformin (n=936). The median patient age was 69 years (IQR 63-73) and the median PSA was 84 ng/mL (24-352). 1758 (94%) of 1874 patients were newly diagnosed with metastatic disease and 116 (6%) were diagnosed with metachronous relapsing disease. 1543 (82%) of 1874 patients received ADT plus docetaxel and 52 (3%) received abiraterone, enzalutamide, or apalutamide. The median time to most recent case report form follow-up was 60 months (IQR 49-72). 473 deaths were reported in the standard of care group; median survival was 61·8 months (IQR 29·7 to not reached). There were 453 deaths in the metformin group; median survival was 67·4 months (32·5 to not reached; HR 0·91, 95% CI 0·80-1·03; p=0·15). Grade 3 or worse adverse events were reported in 487 (52%) of 938 patients in the standard of care group and 523 (57%) of 921 patients in the standard of care plus metformin group. 61 (7%) patients in the standard of care group and 84 (9%) patients in the standard of care plus metformin group reported at least one grade 3 or worse gastrointestinal adverse event; all other body systems showed no difference in grade 3 adverse events. There were six drug-related deaths in the standard of care group and one in the standard of care plus metformin group. INTERPRETATION:We did not find significant evidence of an overall survival benefit of adding metformin to standard of care in the overall population of patients with metastatic hormone-sensitive prostate cancer. The side-effect profile of metformin was as expected and consisted mainly of diarrhoea. Adverse metabolic side-effects of ADT were significantly reduced in the metformin group compared with the standard of care group. FUNDING:Cancer Research UK, Prostate Cancer UK, and UK Research and Innovation Medical Research Council.

A dose optimization trial in oncology may be performed to compare an approved dose level of a given drug with a reduced dose level, testing the hypothesis that efficacy is maintained whilst reducing side effects and consequently improving adherence and quality-of-life. This is particularly relevant with modern therapeutic agents whose mechanisms of action imply that efficacy may not necessarily be linearly related to the dose. Using a conventional non-inferiority framework leads to large sample sizes that are often unfeasible in the phase IV setting. An alternative is to use a margin of practical non-inferiority, which we define in this paper and show how it can be exploited to justify a sample size. Whilst defining the extent of the margin, researchers also pre-specify the other dimensions of interest, such as receptor occupancy and/or side effects and quality-of-life, that will be used to establish practical non-inferiority if the observed efficacy of the reduced dose level lies within the margin. The comparison of efficacy is based on the observed difference between the reduced and the approved levels, instead of the confidence interval of this difference, leading to a reduction in sample size. The reduction in precision due to the smaller sample size is compensated by formally pre-specifying the additional dimensions to the decision process, allowing a more thorough assessment of the opportunity to reduce a dose in practice, with the many advantages that this may involve.

Optimising the use of approved drugs requires evidence from post-approval trials that investigate variations of their use. Determining optimal drug use goes beyond the dominant, academic effort to conduct trials to identify effective lower doses of new drugs. Other important therapeutic approaches that use either less, similar, or more drug than the standard dose need testing in clinical trials, to get the most out of these drugs. Trial objectives on survival outcomes vary greatly; some aim for superiority, others for equivalent exposure or non-inferiority. This Personal View aims to inform academic trialists in how to conceive and prioritise questions aimed at determining the optimal use of drugs, taking into account the perspectives of patients, clinicians, and trial funders, to maximise the chances of successful delivery and impact for patients globally.

Background and objective:Outcomes after nephrectomy for intermediate- and high-risk renal cell carcinoma (RCC) according to histological subtype are poorly characterised. This study aims to determine the value of RCC histology in predicting survival and to inform on surveillance strategies in relation to patterns of first recurrence. Methods:We pooled data from phase 3 trials: SORCE (n = 1689) and ASSURE (n = 1853). Of 3542 patients, 2881 had clear-cell RCC (ccRCC), 269 had papillary RCC (pRCC), 201 had chromophobe RCC (chRCC), and 191 had sarcomatoid RCC (sRCC). Relapse rates, median time to relapse (TTR), and first relapse sites were reported. Multivariable Cox regression models evaluated overall survival by histology, adjusting for initial relapse location and other important clinical factors. Key findings and limitations:Patients with pRCC and ccRCC had similar overall survival (log-rank p = 0.1). The median TTR for those with pRCC was 1.34 yr (interquartile range [IQR] 0.76, 2.59) compared with 1.78 yr (IQR 0.96, 3.38) for ccRCC patients (p = 0.012). Patients with chRCC had a median TTR of 2.72 yr (IQR 0.91, 4.11), and those with sRCC had a median TTR of 0.74 yr (IQR 0.50, 1.55). For sRCC patients, relapsing in the chest was associated with a lower risk of death than those relapsing in the abdomen (hazard ratio [HR] 0.5, confidence interval [CI]: 0.3, 0.88; p = 0.06). A similar trend was shown for pRCC (HR 0.5, CI: 0.2, 1.3; p = 0.1). Recurrence patterns for World Health Organization 2020 molecularly classified RCCs were not included. Despite pooling phase three datasets, small event numbers led to imprecise estimates, particularly for chRCC. Conclusions and clinical implications:Patients with intermediate and high-risk pRCC relapse earlier than those with ccRCC. Papillary RCC and sRCC first recurring in the abdomen exhibit poor prognosis, warranting consideration of additional abdominal imaging to enhance early relapse detection. ChRCC exhibits favourable prognosis and could avoid image-based surveillance until year 2. Patient summary:This study evaluates pooled data from large phase 3 trials to precisely delineate relapse patterns for patients with intermediate- and high-risk cell renal cell carcinoma (RCC) according to their histology. The site and timing of first relapse provide useful information to support histology-specific RCC surveillance after nephrectomy. Development of genetic and molecular signatures corresponding to relapses at poor prognosis sites for each histology will individualise follow-up and is the next step.

BACKGROUND:Localised squamous cell carcinoma of the anus is treated with radical chemoradiotherapy. Cure rates are high, but treatment can result in substantial acute and long-term morbidity. We aimed to assess whether lower dose chemoradiotherapy maintains high local control rates in patients with early-stage disease, with the secondary aim of reducing toxicity. METHODS:ACT4 is a phase 2, prospective, multicentre, open-label, two-arm non-comparative, randomised, controlled trial, investigating reduced-dose intensity-modulated radiotherapy (rd-IMRT: 41·4 Gy in 23 fractions) in patients with early-stage anal cancer; T1-2 (≤4 cm) N0-NxM0. Eligible patients were at least 16 years of age, with an Eastern Cooperative Oncology Group performance status of 0-1. The primary outcome is 3-year loco-regional failure rates. Patients were randomly assigned 1:2 (with stratification by T stage, N stage, gender, HIV status, and randomising site) to standard-dose IMRT (sd-IMRT: 50·4 Gy in 28 fractions) or rd-IMRT with concurrent mitomycin and capecitabine chemotherapy. Here, we report the pre-planned, modified intention-to-treat analysis of secondary endpoints 6 months after treatment end-complete clinical response, compliance, patient-reported outcomes (EORTC QLQ-C30 and ANL27), and safety data. The trial is registered at the ISRCTN registry (ISRCTN88455282) and is ongoing but no longer recruiting. FINDINGS:163 patients were recruited from 28 UK tertiary centres between April 24, 2017, and Dec 1, 2020. 160 patients were included in the primary analysis (sd-IMRT n=55; dr-IMRT n=105). Data on ethnicity were not collected. The median patient age was 66 years (IQR 58-72 years); 117 (73%) were female and 43 (27%) male; and 129 (94%) of 138 evaluable samples were p16 positive. Complete clinical responses at 6 months were 87% (46 of 53) for sd-IMRT and 92% (89 of 97) for rd-IMRT. Radiotherapy interruptions of 3 days or more occurred in 14 (26%) of 55 patients in sd-IMRT and 16 (15%) of 105 patients in rd-IMRT. Chemotherapy modifications occurred in 27 (49%) of 55 patients in sd-IMRT and 39 (37%) of 105 patients in rd-IMRT. Grade 3 or worse acute toxicity was reported in 25 (46%) of 55 patients in sd-IMRT and 37 (35%) of 105 patients in rd-IMRT. The most common grade 3 or worse adverse events were radiation dermatitis (seven [13%] of 55 in sd-IMRT and ten [10%] of 105 in rd-IMRT), and diarrhoea (four [7%] of 55 in sd-IMRT and nine [9%] of 105 in rd-IMRT). Serious adverse events occurred in eight (15%) of 55 patients in sd-IMRT and ten (10%) of 105 patients in rd-IMRT. Patient-reported outcomes for most issues deteriorated at the end of treatment and resolved to baseline by 6 weeks in both groups. Poorer sexual function for men and women was observed at 6 months following sd-IMRT. INTERPRETATION:Good 6-month complete clinical responses rates were seen in both groups. Early results suggest rd-IMRT is well tolerated with oncological outcomes maintained. 3-year locoregional failure rates are awaited. FUNDING:Cancer Research UK and Stand Up to Cancer.

21 Background: Recent phase III data (n=1360) has shown that starting ADT with tE2 patches is non-inferior in terms of metastasis-free survival (with similar overall survival) to luteinising hormone releasing hormone analogues (LHRHa) for locally advanced (M0) prostate cancer. For both M0 and M1 patients, tE2 has advantages in terms of reported quality of life, bone mineral density, hot flushes and metabolic outcomes compared to LHRHa, with no excess of thromboembolic events. However, there is currently no data on the use of androgen receptor pathway inhibitors (ARPIs) (abiraterone, enzalutamide or apalutamide) with tE2. Methods: STAMPEDE [NCT00268476] is a multi-arm, multi-stage platform trial. This embedded phase 2 randomised study assessed efficacy and toxicity in participants (pts) randomly allocated (1:1) to tE2 patches (releasing 100mcg/24hrs, 3 patches changed twice weekly once testosterone ≤1.7ng/ml) or LHRHa (standard doses) and scheduled to receive ARPIs. Primary outcome measure was the proportion of pts reaching a PSA nadir of ≤0.2ng/ml during the first 6 months. Other PSA parameters, testosterone ≤1.7ng/ml at 12 weeks with tE2, and adverse events within the first 12 months (including hypertension, hot flushes and gynaecomastia) were assessed. Results: Between Oct-2020 and Mar-2023, 79 pts with histologically confirmed M1 prostate cancer (median (IQR) age 69 (65-75), median (IQR) baseline PSA 43.3 (11.5-296.2)) received either LHRHa+ARPI (n=41) or tE2+ARPI (n=38). Baseline characteristics were similar between the 2 groups. The proportion of pts achieving PSA ≤0.2ng/ml was LHRHa+ARPI 25/41 (61%) and tE2+ARPI 23/38 (61%). LHRHa v tE2: PSA90 (93% v 95%) and PSA50 (100% v 100%). 31/34 (91%) men treated with tE2 had testosterone ≤1.7ng/ml at 12 weeks. Hot flushes: LHRHa (grade 1: 32%, grade 2: 20%) v tE2 (grade 1: 24%, grade 2: 5%). Gynaecomastia: LHRHa (grade 1: 10%, grade 2: 0%) v tE2 (grade 1: 35%, grade 2: 8%) and any grade hypertension LHRHa v tE2 17% versus 5%. Conclusions: PSA responses were similar in pts treated with tE2+ARPI or LHRHa+ARPI further supporting the use of tE2 patches for ADT in prostate cancer management. tE2 patches provide patients with ADT choices about expected toxicity profiles, including reduced hot flushes (and subsequent impact on quality of life), and mode of administration. Clinical trial information: NCT00268476 .

Abstract IntroductionAnal cancer is rare, but its incidence is increasing. Chemoradiotherapy is the primary treatment modality. Outcomes used in anal cancer trials vary which hinders evidence synthesis. Using a systematic review, patient interviews and a 2-stage Delphi consensus survey, the first CORMAC project brought together patients and healthcare professionals from across the world to agree shared priorities and make sure that studies of chemoradiotherapy treatments for anal cancer report outcomes that are meaningful to patients and health care professionals. CORMAC-1 established an internationally ratified core outcome set (COS) of 19 outcomes across 4 domains. These 19 outcomes are an agreed minimum that all clinical trials in chemoradiotherapy anal cancer trials should report. CORMAC-2 is the next phase which seeks to reach international agreement on the definitions for the 11 core outcomes in the domains of disease activity and survival. Agreeing definitions for these core outcomes will facilitate utilisation of the core outcome set, increasing outcome standardisation across trials thereby increasing the quality of data available for clinical decision-making and ultimately enhancing patient care.MethodsThe original CORMAC systematic review will be updated, focusing on 2 of the 4 COS domains, disease activity and survival domains. An international steering committee composed of international anal cancer trial experts will be formed. The committee will review the updated search results to develop a 2-stage Delphi consensus survey. The survey will be publicised through conferences, email lists, domestic and international bodies and will target healthcare and allied healthcare professional involved in the design, running, recruitment and publication of anal cancer trials. Following the 2-stage survey, a stakeholder meeting composed of the steering committee and selection of survey participants will ratify the results and agree a final set of core outcome definitions.Ethics and disseminationCORMAC-2 results will be disseminated through journal and conference publications to inform clinical teams and patient support groups to raise awareness and implementation of the core outcome set. Results will feed into the DECREASE study and it is registered with the Core Outcome Measures in Effectiveness Trials (COMET) initiative (1,2). As per the University of Manchester ethic decision tool, no ethical approval is required. Further information is available at https://cormacstudy.wordpress.com.