RESUMEN
BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, 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, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given 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 dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Dipéptidos , Compuestos Heterocíclicos con 1 Anillo , Lutecio , Nitrilos , Feniltiohidantoína , Neoplasias de la Próstata Resistentes a la Castración , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/mortalidad , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/uso terapéutico , Feniltiohidantoína/análogos & derivados , Anciano , Dipéptidos/uso terapéutico , Dipéptidos/administración & dosificación , Dipéptidos/efectos adversos , Compuestos Heterocíclicos con 1 Anillo/uso terapéutico , Compuestos Heterocíclicos con 1 Anillo/administración & dosificación , Compuestos Heterocíclicos con 1 Anillo/efectos adversos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno Prostático Específico/sangre , Supervivencia sin Progresión , Radioisótopos/uso terapéutico , Anciano de 80 o más Años , RadiofármacosRESUMEN
INTRODUCTION: Local Australian guidelines for the optimal management of stage III unresectable non-small cell lung cancer (NSCLC) are lacking. The American Society of Clinical Oncology (ASCO) guidelines recommend consolidation durvalumab for all patients with unresectable stage III NSCLC, irrespective of their PD-L1 expression or driver mutation status. The European Society of Medical Oncology (ESMO) differs, with consolidation durvalumab only recommended in those patients whose tumours express PD-L1. METHODS: Due to differing global guidelines, we conducted an Australia and New Zealand wide survey of medical oncologists specialising in thoracic cancer to determine the variations in patterns of prescribing durvalumab in stage III unresectable NSCLC. This survey was done electronically and sponsored by the Thoracic Oncology Group of Australia (TOGA). RESULTS: Thirty-two medical oncologists completed the survey. In patients with EGFR-mutated stage III unresectable NSCLC, 6% of respondents stated that they prescribed durvalumab for all patients, while an additional 6% strongly recommended treatment. Forty-four percent suggested little benefit of consolidation durvalumab in this cohort, with an additional 19% advocating for observation only. In patients with PD-L1 negative (0%) stage III unresectable NSCLC, 13% of respondents prescribed durvalumab for all patients, while an additional 56% strongly recommended treatment. Interestingly, 18%, 10%, and 10% of prescribers discussed self-funded oral tyrosine kinase inhibitor therapy in patients with EGFR, ALK, or ROS-1-mutated NSCLC respectively as a substitute for consolidation durvalumab. CONCLUSION: Overall, the clinical practice of Australian and New Zealand Medical Oncologists is variable, but remains consistent with either the ASCO or ESMO guidelines. Local practice guidelines are required to ensure consistency in prescribing patterns across Australia, as well as providing evidence for self-funded treatments outside standard of care.
Asunto(s)
Anticuerpos Monoclonales , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Estadificación de Neoplasias , Oncólogos , Pautas de la Práctica en Medicina , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/genética , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/genética , Australia , Anticuerpos Monoclonales/uso terapéutico , Pautas de la Práctica en Medicina/estadística & datos numéricos , Oncólogos/estadística & datos numéricos , Encuestas y Cuestionarios , Antineoplásicos Inmunológicos/uso terapéutico , Nueva ZelandaRESUMEN
PURPOSE: Many people with cancer (patients) want to know their prognosis (a quantitative estimate of their life expectancy) but this is often not discussed or poorly communicated. The optimal timing of prognostic discussions with people with advanced cancer is highly personalised and complex. We aimed to find, organise, and summarise research regarding the timing of discussions of prognosis with people with advanced cancer. METHODS: We conducted a systematic review of publications from databases, clinical practice guidelines, and grey literature from inception to 2023. We also searched the reference lists of systematic reviews, editorials, and clinical trial registries. Eligibility criteria included publications regarding adults with advanced cancer that reported a timepoint when a discussion of prognosis occurred or should occur. RESULTS: We included 63 of 798 identified references; most of which were cross-sectional cohort studies with a range of 4-9105 participants. Doctors and patients agreed on several timepoints including at diagnosis of advanced cancer, when the patient asked, upon disease progression, when there were no further anti-cancer treatments, and when recommending palliative care. Most of these timepoints aligned with published guidelines and expert recommendations. Other recommended timepoints depended on the doctor's clinical judgement, such as when the patient 'needed to know' or when the patient 'seemed ready'. CONCLUSIONS: Prognostic discussions with people with advanced cancer need to be individualised, and there are several key timepoints when doctors should attempt to initiate these conversations. These recommended timepoints can inform clinical trial design and communication training for doctors to help improve prognostic understanding.
Asunto(s)
Neoplasias , Adulto , Humanos , Estudios Transversales , Progresión de la Enfermedad , Neoplasias/terapia , PronósticoRESUMEN
BACKGROUND: Patients with advanced cancer who misunderstand their prognosis and chance of cure tend to overestimate the likely benefits of palliative systemic therapy. AIM: To determine patient perceptions of palliative systemic therapy benefits in advanced cancer. METHODS: We surveyed 104 outpatients with advanced cancer receiving systemic anticancer therapy and their treating oncologists. Patients recorded their understanding of treatment impact on chance of cure and symptoms. Life expectancy was estimated by patients and oncologists. A visual analogue scale (0-10) was used to record how patients and oncologists valued quality of life (QOL) and length of life (LOL) (<4 QOL most important; 4-7 QOL and LOL equal; >7 LOL most important). Patient-oncologist discordance was defined as a ≥4-point difference. RESULTS: The main reasons patients selected for receiving treatment were to live longer (54%) and cure their cancer (36%). Most patients reported treatment was very/somewhat likely to prolong life (84%) and improve symptoms (76%), whereas 20% reported treatment was very/somewhat likely to cure their cancer. 42% of patients selected a timeframe for life expectancy (choice of four timeframes between <1 year and ≥5 years); of these, 62% selected a longer timeframe than their oncologist. When making treatment decisions, 71% of patients (52% of oncologists) valued QOL and LOL equally. Patient-oncologist discordance was 21%, mostly because of oncologists valuing QOL more than their patients (70%). CONCLUSION: At least 20% of patients receiving systemic therapy for advanced cancer reported an expectation of cure. Most patients and oncologists value QOL and LOL equally when making treatment decisions.
Asunto(s)
Esperanza de Vida , Neoplasias , Cuidados Paliativos , Calidad de Vida , Humanos , Masculino , Neoplasias/psicología , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Femenino , Persona de Mediana Edad , Anciano , Adulto , Anciano de 80 o más Años , Encuestas y Cuestionarios , Percepción , Oncólogos/psicología , Antineoplásicos/uso terapéuticoRESUMEN
OBJECTIVE: To determine whether the addition of inhaled methoxyflurane to periprostatic infiltration of local anaesthetic (PILA) during transrectal ultrasonography-guided prostate biopsies (TRUSBs) improved pain and other aspects of the experience. PATIENTS AND METHODS: We conducted a multicentre, placebo-controlled, double-blind, randomized phase 3 trial, involving 420 men undergoing their first TRUSB. The intervention was PILA plus a patient-controlled device containing either 3 mL methoxyflurane, or 3 mL 0.9% saline plus one drop of methoxyflurane to preserve blinding. The primary outcome was the pain score (0-10) reported by the participant after 15 min. Secondary outcomes included ratings of other aspects of the biopsy experience, willingness to undergo future biopsies, urologists' ratings, biopsy completion, and adverse events. RESULTS: The mean (SE) pain scores 15 min after TRUSB were 2.51 (0.22) in those assigned methoxyflurane vs 2.82 (0.22) for placebo (difference 0.31, 95% confidence interval [CI] -0.75 to 0.14; P = 0.18). Methoxyflurane was associated with better scores for discomfort (difference -0.48, 95% CI -0.92 to -0.03; P = 0.035, adjusted [adj.] P = 0.076), whole experience (difference -0.50, 95% CI -0.92 to -0.08; P = 0.021, adj. P = 0.053), and willingness to undergo repeat biopsies (odds ratio 1.67, 95% CI 1.12-2.49; P = 0.01) than placebo. Methoxyflurane resulted in higher scores for drowsiness (difference +1.64, 95% CI 1.21-2.07; P < 0.001, adj. P < 0.001) and dizziness (difference +1.78, 95% CI 1.31-2.24; P < 0.001, adj. P < 0.001) than placebo. There was no significant difference in the number of ≥ grade 3 adverse events. CONCLUSIONS: We found no evidence that methoxyflurane improved pain scores at 15 min, however, improvements were seen in patient-reported discomfort, overall experience, and willingness to undergo repeat biopsies.
Asunto(s)
Próstata , Neoplasias de la Próstata , Anestesia Local , Anestésicos Locales/uso terapéutico , Biopsia/efectos adversos , Biopsia/métodos , Humanos , Lidocaína/uso terapéutico , Masculino , Metoxiflurano , Dolor/tratamiento farmacológico , Dolor/etiología , Dolor/prevención & control , Dimensión del Dolor , Próstata/diagnóstico por imagen , Próstata/patología , Neoplasias de la Próstata/patología , UltrasonografíaRESUMEN
OBJECTIVES: To determine the activity and safety of lutetium-177 (177 Lu)-prostate-specific membrane antigen (PSMA)-617 in men with metastatic castration-resistant prostate cancer (mCRPC) commencing enzalutamide, who are at high risk of early progression, and to identify potential prognostic and predictive biomarkers from imaging, blood and tissue. PARTICIPANTS AND METHODS: ENZA-p (ANZUP 1901) is an open-label, randomized, two-arm, multicentre, phase 2 trial. Participants are randomly assigned (1:1) to treatment with enzalutamide 160 mg daily alone or enzalutamide plus 177 Lu-PSMA-617 7.5 GBq on Days 15 and 57. Two additional 177 Lu-PSMA-617 doses are allowed, informed by Day-92 Gallium-68 (68 Ga)-PSMA positron emission tomography (PET; up to four doses in total). The primary endpoint is prostate-specific antigen (PSA) progression-free survival (PFS). Other major endpoints include radiological PFS, PSA response rate, overall survival, health-related quality of life, adverse events and cost-effectiveness. Key eligibility criteria include: biochemical and/or clinical progression; 68 Ga-PSMA PET-avid disease; no prior androgen signalling inhibitor, excepting abiraterone; no prior chemotherapy for mCRPC; and ≥2 high-risk features for early enzalutamide failure. Assessments are 4 weekly during study treatment, then 6 weekly until radiographic progression. Response Evaluation Criteria in Solid Tumours (RECIST) are used to assess imaging conducted every 12 weeks, 68 Ga-PSMA PET at baseline, Days 15 and 92, and at progression, and 18 F-fluorine deoxyglucose (18 F-FDG) PET at baseline and progression. Translational samples include blood (and optional biopsies) at baseline, Day 92, and first progression. Correlative studies include identification of prognostic and predictive biomarkers from 68 Ga-PSMA and 18 F-FDG PET/CT, circulating tumour cells and circulating tumour DNA. The trial will enrol 160 participants, providing 80% power with a two-sided type-1 error rate of 5% to detect a hazard ratio of 0.625 assuming a median PSA-PFS of 5 months with enzalutamide alone. RESULTS AND CONCLUSION: The combination of 177 Lu-PSMA-617 and enzalutamide may be synergistic. ENZA-p will determine the safety and efficacy of the combination in addition to developing predictive and prognostic biomarkers to better guide treatment decisions.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Glutamato Carboxipeptidasa II/antagonistas & inhibidores , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Antígenos de Superficie , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas/administración & dosificación , Ensayos Clínicos Fase II como Asunto , Análisis Costo-Beneficio , Dipéptidos/administración & dosificación , Dipéptidos/efectos adversos , Dipéptidos/economía , Fluorodesoxiglucosa F18 , Isótopos de Galio , Radioisótopos de Galio , Compuestos Heterocíclicos con 1 Anillo/administración & dosificación , Compuestos Heterocíclicos con 1 Anillo/efectos adversos , Compuestos Heterocíclicos con 1 Anillo/economía , Humanos , Lutecio/administración & dosificación , Masculino , Terapia Molecular Dirigida , Estudios Multicéntricos como Asunto , Nitrilos/administración & dosificación , Feniltiohidantoína/administración & dosificación , Tomografía Computarizada por Tomografía de Emisión de Positrones , Pronóstico , Supervivencia sin Progresión , Antígeno Prostático Específico/administración & dosificación , Antígeno Prostático Específico/efectos adversos , Antígeno Prostático Específico/sangre , Antígeno Prostático Específico/economía , Neoplasias de la Próstata Resistentes a la Castración/sangre , Calidad de Vida , Radioisótopos/administración & dosificación , Radiofármacos , Ensayos Clínicos Controlados Aleatorios como Asunto , Criterios de Evaluación de Respuesta en Tumores Sólidos , Tasa de SupervivenciaRESUMEN
Prostate cancer remains the commonest cancer diagnosed in males and a leading cause of cancer-related death. Men with metastatic castration-resistant prostate cancer (mCRPC) who have progressed on chemotherapy and androgen receptor pathway inhibitors (ARPI) have limited treatment options, significant morbidity, and poor outcomes. Prostate-specific membrane antigen (PSMA)-directed radionuclide therapy (RNT) is emerging as an efficacious and well-tolerated therapy; however, disease progression is universal. Several ongoing RNT trials focus on combination strategies to improve efficacy and durability of treatment response, including combinations with ARPIs, chemotherapy, immunotherapy, and targeted therapies. Further, efforts are underway to expand the role of PSMA-directed RNT to earlier stages of disease including hormone-sensitive and localized prostate cancer. In this review, we discuss the rationale and ongoing RNT combination therapeutic trials in prostate cancer and summarize the efficacy and toxicity associated with RNT.