RESUMO
AIM: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). MATERIALS AND METHODS: This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. RESULTS: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT. CONCLUSIONS: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.
Assuntos
Adamantano , Compostos Benzidrílicos , Diabetes Mellitus Tipo 2 , Dipeptídeos , Quimioterapia Combinada , Glucosídeos , Hemoglobinas Glicadas , Hipoglicemiantes , Metformina , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/sangue , Metformina/uso terapêutico , Metformina/administração & dosagem , Metformina/efeitos adversos , Glucosídeos/administração & dosagem , Glucosídeos/efeitos adversos , Glucosídeos/uso terapêutico , Masculino , Feminino , Compostos Benzidrílicos/uso terapêutico , Compostos Benzidrílicos/administração & dosagem , Compostos Benzidrílicos/efeitos adversos , Pessoa de Meia-Idade , Dipeptídeos/efeitos adversos , Dipeptídeos/administração & dosagem , Dipeptídeos/uso terapêutico , Adamantano/análogos & derivados , Adamantano/administração & dosagem , Adamantano/efeitos adversos , Adamantano/uso terapêutico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/uso terapêutico , Hipoglicemiantes/efeitos adversos , Hemoglobinas Glicadas/análise , Hemoglobinas Glicadas/metabolismo , Idoso , Resultado do Tratamento , Hipoglicemia/induzido quimicamente , Compostos de Sulfonilureia/uso terapêutico , Compostos de Sulfonilureia/administração & dosagem , Compostos de Sulfonilureia/efeitos adversos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Adulto , Aumento de Peso/efeitos dos fármacos , Fosfato de Sitagliptina/uso terapêutico , Fosfato de Sitagliptina/administração & dosagem , Fosfato de Sitagliptina/efeitos adversosRESUMO
PURPOSE: This pilot study investigates the efficacy and safety profile as well as predictive biomarkers of 225 Ac-PSMA-617-augmented 177 Lu-PSMA-617 radioligand therapy (RLT) in a cohort of high-risk patients with metastatic castration-resistant prostate cancer (mCRPC), enrolled in a prospective registry (NCT04833517). PATIENTS AND METHODS: A group of n = 33 high-risk mCRPC patients received 177 Lu-PSMA-617 RLT, augmented by 1 or more cycles of 225 Ac-PSMA-617. Response was assessed by prostate-specific antigen (PSA) serum value after 2 cycles of treatment. Overall survival (OS) and PSA-based progression-free survival were evaluated using Kaplan-Meier analysis. To assess the side effect profile, Common Terminology Criteria for Adverse Events were applied. In total, 12 potential pretherapeutic biomarkers were tested for association with OS. RESULTS: The median decrease in serum PSA value was -49.1%, and 16/33 (48.5%) patients experienced a partial response after 2 cycles RLT. The median PSA-based progression-free survival and median OS was 7.2 and 14.8 months, respectively. Alkaline phosphatase ( P < 0.001), lactate dehydrogenase ( P = 0.035), Eastern European Oncology Group Performance Score ( P = 0.037), and the presence of visceral metastases ( P = 0.029) revealed significant association with OS in Kaplan-Meier analysis (log-rank test). Most of the recorded adverse events were rated as mild or moderate. Higher-grade adverse events were very limited with only 1 case (3.0%) of grade 3 anemia. Treatment-related mild xerostomia was recorded in 6/33 (18.2%) patients. CONCLUSIONS: 225 Ac-PSMA-617 augmentation in high-risk mCRPC undergoing 177 Lu-PSMA-617 RLT appears to be an effective treatment option with a favorable safety profile. The pretherapeutic values of alkaline phosphatase, lactate dehydrogenase, the Eastern European Oncology Group Performance Score, and the presence of visceral metastases may be appropriate biomarkers predicting survival outcome of this treatment regimen.
Assuntos
Compostos Heterocíclicos com 1 Anel , Lutécio , Neoplasias de Próstata Resistentes à Castração , Sistema de Registros , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Idoso , Projetos Piloto , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Pessoa de Meia-Idade , Estudos Prospectivos , Antígeno Prostático Específico/sangue , Dipeptídeos/uso terapêutico , Dipeptídeos/efeitos adversos , Idoso de 80 Anos ou mais , Ligantes , Resultado do Tratamento , Risco , Actínio , RadioisótoposRESUMO
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).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica , Benzamidas , Dipeptídeos , Compostos Heterocíclicos com 1 Anel , Lutécio , Nitrilas , Feniltioidantoína , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/mortalidade , Feniltioidantoína/administração & dosagem , Feniltioidantoína/uso terapêutico , Feniltioidantoína/análogos & derivados , Idoso , Dipeptídeos/uso terapêutico , Dipeptídeos/administração & dosagem , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno Prostático Específico/sangue , Intervalo Livre de Progressão , Radioisótopos/uso terapêutico , Idoso de 80 Anos ou mais , Compostos RadiofarmacêuticosRESUMO
Treatment options for patients with metastatic castration-resistant prostate cancer include use of radioligand therapy with 177Lu-PSMA-617. 177Lu-PSMA-617 is used to target prostate cancer cells selectively by targeting prostate specific membrane antigen (PSMA); however, PSMA is also expressed on lacrimal glands among other tissues. Herein, we report on a case of a Common Terminology Criteria for Adverse Events version 5 grade 3 dry eye event with concomitant blepharitis after administration of 177Lu-PSMA-617. The patient was managed with neomycin-polymyxin-dexamethasone 3.5-10000-0.1 ophthalmic suspension, artificial tears, lubricating ointments, lid scrubs, and oral antihistamines.
Assuntos
Dipeptídeos , Síndromes do Olho Seco , Compostos Heterocíclicos com 1 Anel , Lutécio , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Síndromes do Olho Seco/etiologia , Lutécio/uso terapêutico , Lutécio/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Dipeptídeos/uso terapêutico , Dipeptídeos/efeitos adversos , Idoso , Compostos Radiofarmacêuticos/uso terapêutico , Compostos Radiofarmacêuticos/efeitos adversos , Antígeno Prostático EspecíficoRESUMO
In metastatic castration-resistant prostate cancer (mCRPC) patients treated with prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (RLT), the recently proposed criteria for evaluating response to PSMA PET (RECIP 1.0) based on 68Ga- and 18F-labeled PET agents provided prognostic information in addition to changes in prostate-specific antigen (PSA) levels. Our aim was to evaluate the prognostic performance of this framework for overall survival (OS) in patients undergoing RLT and imaged with [18F]PSMA-1007 PET/CT and compare the prognostic performance with the PSA-based response assessment. Methods: In total, 73 patients with mCRPC who were scanned with [18F]PSMA-1007 PET/CT before and after 2 cycles of RLT were retrospectively analyzed. We calculated the changes in serum PSA levels (ΔPSA) and quantitative PET parameters for the whole-body tumor burden (SUVmean, SUVmax, PSMA tumor volume, and total lesion PSMA). Men were also classified following the Prostate Cancer Working Group 3 (PCWG3) criteria for ΔPSA and RECIP 1.0 for PET imaging response. We performed univariable Cox regression analysis, followed by multivariable and Kaplan-Meier analyses. Results: Median OS was 15 mo with a median follow-up time of 14 mo. Univariable Cox regression analysis provided significant associations with OS for ΔPSA (per percentage, hazard ratio [HR], 1.004; 95% CI, 1.002-1.007; P < 0.001) and PSMA tumor volume (per unit, HR, 1.003; 95% CI, 1.000-1.005; P = 0.03). Multivariable Cox regression analysis confirmed ΔPSA (per percentage, HR, 1.004; 95% CI, 1.001-1.006; P = 0.006) as an independent prognosticator for OS. Kaplan-Meier analyses provided significant segregation between individuals with versus those without any PSA response (19 mo vs. 14 mo; HR, 2.00; 95% CI, 0.95-4.18; P = 0.04). Differentiation between patients with or without progressive disease (PD) was also feasible when applying PSA-based PCWG3 (19 mo vs. 9 mo for non-PD and PD, respectively; HR, 2.29; 95% CI, 1.03-5.09; P = 0.01) but slightly failed when applying RECIP 1.0 (P = 0.08). A combination of both response systems (PCWG3 and RECIP 1.0), however, yielded the best discrimination between individuals without versus those with PD (19 mo vs. 8 mo; HR, 2.78; 95% CI, 1.32-5.86; P = 0.002). Conclusion: In patients with mCRPC treated with RLT and imaged with [18F]PSMA-1007, frameworks integrating both the biochemical (PCWG3) and PET-based response (RECIP 1.0) may best assist in identifying subjects prone to disease progression.
Assuntos
Niacinamida , Oligopeptídeos , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Ureia , Humanos , Masculino , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Lutécio , Niacinamida/análogos & derivados , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Prognóstico , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Estudos Retrospectivos , Resultado do Tratamento , Ureia/análogos & derivadosAssuntos
Adamantano , Adamantano/análogos & derivados , Dermatite Alérgica de Contato , Dermatite Ocupacional , Dipeptídeos , Olanzapina , Humanos , Adamantano/efeitos adversos , Dermatite Alérgica de Contato/etiologia , Dermatite Alérgica de Contato/diagnóstico , Olanzapina/efeitos adversos , Dermatite Ocupacional/etiologia , Dipeptídeos/efeitos adversos , Testes do Emplastro , Masculino , Antipsicóticos/efeitos adversos , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Pessoa de Meia-Idade , Adulto , FemininoRESUMO
BACKGROUND: Despite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer. METHODS: This is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS). DISCUSSION: Our prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT06059014.
Assuntos
Antígenos de Superfície , Carcinoma de Células Renais , Glutamato Carboxipeptidase II , Neoplasias Renais , Lutécio , Radioisótopos , Compostos Radiofarmacêuticos , Humanos , Masculino , Carcinoma de Células Renais/radioterapia , Carcinoma de Células Renais/tratamento farmacológico , Dipeptídeos/efeitos adversos , Dipeptídeos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Lutécio/efeitos adversos , Lutécio/uso terapêutico , Estudos Prospectivos , Qualidade de Vida , Radioisótopos/efeitos adversos , Radioisótopos/uso terapêutico , Resultado do Tratamento , Microambiente Tumoral , Feminino , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/radioterapia , Ensaios Clínicos Fase I como Assunto , Ensaios Clínicos Fase II como Assunto , Estudos Multicêntricos como Assunto , Antígenos de Superfície/metabolismo , Glutamato Carboxipeptidase II/antagonistas & inibidores , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Radiofarmacêuticos/uso terapêuticoRESUMO
BACKGROUND: Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world. METHODS: This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival. FINDINGS: Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded. INTERPRETATION: 225Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events. FUNDING: None.
Assuntos
Actínio , Neoplasias de Próstata Resistentes à Castração , Rádio (Elemento) , Xerostomia , Idoso , Humanos , Masculino , Dipeptídeos/efeitos adversos , Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/radioterapia , Radioisótopos , Compostos Radiofarmacêuticos , Estudos Retrospectivos , Resultado do Tratamento , Xerostomia/induzido quimicamente , Xerostomia/tratamento farmacológico , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Life expectancy of patients with metastatic castration-resistant prostate cancer (mCRPC) is still limited despite several systemic treatments. Within five years after diagnosis of primary prostate cancer, 10-20% of the patients have mCRPC and curation is not an option. Radionuclide therapy (RNT) targeted against prostate-specific membrane antigen (PSMA) emerged as a new treatment option and showed effective results in patients with mCRPC. Survival benefit after [177Lu]Lu-PSMA RNT has already been demonstrated in several clinical trials. However, [225Ac]Ac-PSMA (225Ac-PSMA) appears to be an even more promising radiopharmaceutical for the treatment of mCRPC. The use of alpha emitting radionuclides offers advantages over beta emitting radionuclides due to the high linear energy transfer effective for killing tumor cells and the limited range to reduce the radiation effects on the healthy tissue. However, these results are based on retrospective data and safety data of 225Ac-PSMA are still limited. Therefore, a prospective trial is needed to determine the optimal amount of activity that can be administered. METHODS: The 225Ac-PSMA-Imaging & Therapy (I&T) trial is an investigator-initiated phase I, single-center, open label, repeated dose-escalation and expansion trial. Patient with PSMA-positive mCRPC after at least one line of chemotherapy and/or one line of nonsteroidal antiandrogen will be treated with 225Ac-PSMA-I&T in increasing amount of activity per cycle. Dose-escalation following an accelerated 3 + 3 design which allows to open the next dose-level cohort in the absence of dose limiting toxicity while the previous one is still ongoing. Up to 4 treatment cohorts will be explored including up to 3 dose-escalation cohorts and one expansion cohort where patients will be administered with the recommended dose. A total of up to 30 patients will be enrolled in this trial. All patients will be evaluated for safety. Additionally, dosimetry was performed for the patients in the dose-escalation cohorts after the first 225Ac-PSMA-I&T administration. DISCUSSION: This trial will assess the safety and tolerability of 225Ac-PSMA-I&T in patients with mCRPC to recommend the optimal dose for the phase II trial. TRIAL REGISTRATION: ClinicalTrials.gov, (NCT05902247). Retrospectively registered 13 June 2023.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Antígeno Prostático Específico , Estudos Prospectivos , Estudos Retrospectivos , Dipeptídeos/efeitos adversos , Radioisótopos/uso terapêutico , Compostos Radiofarmacêuticos/efeitos adversos , Compostos Heterocíclicos com 1 Anel , Resultado do TratamentoRESUMO
ß-emitting 177Lu targeting prostate-specific membrane antigen (PSMA) is an approved treatment option for metastatic castration-resistant prostate cancer. Data on its long-term nephrotoxicity are sparse. This study aimed to retrospectively evaluate post-177Lu-PSMA estimated glomerular filtration rate (eGFR) dynamics for at least 12 mo in a cohort of metastatic castration-resistant prostate cancer patients. Methods: The institutional databases of 3 German tertiary referral centers identified 106 patients who underwent at least 4 cycles of 177Lu-PSMA and had at least 12 mo of eGFR follow-up data. eGFR (by the Chronic Kidney Disease Epidemiology Collaboration formula) at 3, 6, and 12 mo after 177Lu-PSMA radioligand therapy was estimated using monoexponentially fitted curves through available eGFR data. eGFR changes were grouped (≥15%-<30%, moderate; ≥30%-<40%, severe; and ≥40%, very severe). Associations between eGFR changes (%) and nephrotoxic risk factors, prior treatment lines, and number of 177Lu-PSMA cycles were analyzed using multivariable linear regression. Results: At least moderate eGFR decreases were present in 45% (48/106) of patients; of those, nearly half (23/48) had a severe or very severe eGFR decrease. A higher number of risk factors at baseline (-4.51, P = 0.03) was associated with a greater eGFR decrease. Limitations of the study were the retrospective design, lack of a control group, and limited number of patients with a follow-up longer than 1 y. Conclusion: A considerable proportion of patients may experience moderate or severe decreases in eGFR 1 y from initiation of 177Lu-PSMA. A higher number of risk factors at baseline seems to aggravate loss of renal function. Further prospective trials are warranted to estimate the nephrotoxic potential of 177Lu-PSMA.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Estudos Retrospectivos , Resultado do Tratamento , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Antígeno Prostático Específico , Dipeptídeos/efeitos adversos , Lutécio/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversosRESUMO
OBJECTIVE: 177 Lu-PSMA-617-radioligand therapy (RLT) has shown promising therapeutic role in patients with metastatic castration-resistant prostate cancer. However, off-target action in salivary glands often presents with xerostomia. Personalized dosimetry can help in optimizing the treatment, however, has so far been tedious due to multiple time-point imaging. In this prospective study, we intended to estimate the absorbed dose delivered to the salivary glands in patients undergoing 177 Lu-PSMA-617-RLT using quantitative SPECT/CT at a single time point. METHODS: Patients undergoing 177 Lu-PSMA-617 RLT were included in this prospective study. Post-therapy whole-body images and regional quantitative single time-point SPECT/CT were acquired at 24â h with high-energy collimator. The data was processed and analyzed using Q.Metrix software. A scaling factor, that is, the time-integrated activity conversion factor was applied for the image acquired at 24â h. Absorbed doses were computed using MIRD scheme and OLINDA software. RESULTS: A total of 21 patients (mean age: 66â ±â 9 years) were included. The value of mean absorbed dose for the parotid glands was 1.90â ±â 1.31Gy (range: 0.26-6.23) and that for the submandibular glands was 1.37â ±â 0.94Gy (range: 0.16-3.65). The mean absorbed doses per administered activity for the parotid and submandibular glands were 0.26â ±â 0.18 Gy/GBq and 0.19â ±â 0.12 Gy/GBq, respectively. The absorbed doses were estimated for one cycle of therapy and were well within acceptable limits. None of the patients experienced dryness of mouth. CONCLUSION: Single time-point dosimetry with quantitative SPECT/CT is feasible and can be standardized to estimate the absorbed dose to salivary glands instead of multiple time-point acquisitions.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Estudos Prospectivos , Estudos de Viabilidade , Compostos Radiofarmacêuticos/uso terapêutico , Dipeptídeos/uso terapêutico , Dipeptídeos/efeitos adversos , Antígeno Prostático Específico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Glândula Parótida , Lutécio/uso terapêuticoRESUMO
PURPOSE: 177 Lu-PSMA-617 has been shown to improve survival outcomes in patients with end-stage metastatic castration-resistant prostate cancer. However, data in earlier lines remain limited. In this study, we intended to evaluate the efficacy and safety of 177 Lu-PSMA-617 in patients with synchronous high-volume metastatic hormone-sensitive prostate cancer (mHSPC). PATIENTS AND METHODS: Hormone-sensitive prostate cancer patients with synchronous high-volume metastases (defined as ≥4 skeletal metastases with ≥1 extra-axial site or any visceral metastasis) showing high PSMA expression on 68 Ga-PSMA-11 PET/CT and ineligible/unwilling for conventional chemohormonal treatment options were selected. Approximately, ~5.55-7.4 GBq of 177 Lu-PSMA-617 was administered intravenously at 8-12 weeks intervals, up to 6 cycles. All patients underwent concomitant androgen deprivation therapy/orchiectomy. The outcome measures included the proportion of patients achieving an undetectable serum prostate-specific antigen (PSA) (ie, ≤0.2 ng/mL) at any time point after therapy, best PSA response rate, objective radiographic response rate, radiographic progression-free survival, overall survival, and adverse events. RESULTS: Ten patients with high-volume mHSPC received a median cumulative activity of 32.4 GBq (range, 7.4-44.4) of 177 Lu-PSMA-617 over 1-6 cycles. Five patients (50%) achieved an undetectable PSA with 9 patients (90%) showing a ≥50% decline in PSA from baseline. Nine patients underwent radiological follow-up, of which 7 (77.8%) had an objective response. The median radiographic progression-free survival was 24 months (95% confidence interval, 18-30), whereas the median overall survival was not reached. None of the patients had any grade 3/4 adverse event. CONCLUSIONS: 177 Lu-PSMA-617 seems to be a promising efficacious and safe treatment option for patients with synchronous high-volume mHSPC.
Assuntos
Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Resultado do Tratamento , Antagonistas de Androgênios/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Lutécio/uso terapêutico , Hormônios , Estudos RetrospectivosRESUMO
In the VISION trial, [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) plus protocol-permitted standard of care significantly improved overall survival and radiographic progression-free survival compared with standard of care alone in patients with prostate-specific membrane antigen-positive metastatic castration-resistant prostate cancer. This VISION dosimetry substudy quantified absorbed doses of 177Lu-PSMA-617 in the kidneys and other organs. Methods: Participants were a separate cohort of 30 nonrandomized patients receiving standard of care plus 177Lu-PSMA-617 at 7.4 GBq per cycle for up to 6 cycles. Blood samples, whole-body conjugate planar image scintigraphy, and abdominal SPECT/CT images were collected. SPECT/CT images were collected at 2, 24, 48, and 168 h after administration in cycle 1 and at a single time point 48 h after administration in cycles 2-6. Outcomes were absorbed dose per unit activity per cycle and cumulative absorbed dose over all cycles. Cumulative absorbed doses were predicted by extrapolation from cycle 1, and calculation of observed values was based on measurements of cycle 1 and cycles 2-6. Safety was also assessed. Results: Mean (±SD) absorbed doses per cycle in the kidneys were 0.43 ± 0.16 Gy/GBq in cycle 1 and 0.44 ± 0.21 Gy/GBq in cycles 2-6. The observed and predicted 6-cycle cumulative absorbed doses in the kidneys were 15 ± 6 and 19 ± 7 Gy, respectively. Observed and predicted cumulative absorbed doses were similar in other at-risk organs. Safety findings were consistent with those in the VISION study; no patients experienced renal treatment-emergent adverse events of a grade higher than 3. Conclusion: The renal cumulative absorbed 177Lu-PSMA-617 dose was below the established limit. 177Lu-PSMA-617 had a good overall safety profile, and low renal radiotoxicity was not a safety concern. Cumulative absorbed doses in at-risk organs over multiple cycles can be predicted by extrapolation from cycle 1 data in patients with metastatic castration-resistant prostate cancer receiving 177Lu-PSMA-617.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/patologia , Compostos Radiofarmacêuticos/efeitos adversos , Dipeptídeos/efeitos adversos , Antígeno Prostático Específico , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Rim , Lutécio/efeitos adversosRESUMO
OBJECTIVE: High rectal sensory thresholds (RSTs) are associated with chronic constipation (CC), especially in older patients. Bile acids (BAs) affect the RSTs of healthy individuals. Here, we aimed to investigate the effects of the BA transporter inhibitor elobixibat in patients with CC aged ≥60 years. DESIGN: We prospectively compared the RSTs of 17 patients with CC aged ≥60 years with those of 9 healthy individuals of the same age range. We next performed a prospective, randomised, parallel-group, double-blind, placebo-controlled clinical trial of 17 patients with CC who administered elobixibat or placebo daily for 1 week. Using barostat methodology, their first constant sensation volume (FCSV), defaecatory desire volume (DDV), and maximum tolerable volume (MTV) thresholds; their rectal compliance; and their faecal BA concentrations were measured before and after treatment. RESULTS: There were no significant differences in the RSTs of healthy individuals and patients with CC, but all of these tended to be higher in the latter group. Elobixibat increased the desire to defaecate, significantly reduced the threshold for FCSV (p=0.0018), and tended to reduce the threshold for DDV (p=0.0899) versus placebo. However, there were no differences in the MTV or rectal compliance of the two groups. The total faecal BA concentration increased, and particularly that of secondary BAs in the elobixibat group. Elobixibat was most efficacious in participants with a longer duration of CC and a history of treatment for CC. CONCLUSION: Elobixibat reduces the RSTs of patients with CC aged ≥60 years, which may be important for its therapeutic effects. TRIAL REGISTRATION NUMBER: jRCTs061200030.
Assuntos
Constipação Intestinal , Tiazepinas , Humanos , Idoso , Estudos Prospectivos , Constipação Intestinal/tratamento farmacológico , Constipação Intestinal/induzido quimicamente , Dipeptídeos/efeitos adversos , Tiazepinas/efeitos adversos , Ácidos e Sais Biliares/uso terapêuticoRESUMO
223Ra-dichloride (223Ra) and 177Lu-prostate-specific membrane antigen (PSMA) are approved treatments for metastatic castration-resistant prostate cancer (mCRPC). The safety and effectiveness of sequential use of 223Ra and 177Lu-PSMA in patients with mCRPC are not well described. This study aimed to evaluate 177Lu-PSMA safety and efficacy in patients with mCRPC previously treated with 223Ra. Methods: The radiumâlutetium (RALU) study was a multicenter, retrospective, medical chart review. Participants had received at least 1 223Ra dose and, in any subsequent therapy line, at least 1 177Lu-PSMA dose. Primary endpoints included the incidence of adverse events (AEs), serious AEs, grade 3-4 hematologic AEs, and abnormal laboratory values. Secondary endpoints included overall survival, time to next treatment/death, and change from baseline in serum prostate-specific antigen and alkaline phosphatase levels. Results: Data were from 133 patients. Before 177Lu-PSMA therapy, 56% (75/133) of patients received at least 4 life-prolonging therapies; all patients received 223Ra (73% received 5-6 injections). Overall, 27% (36/133) of patients received at least 5 177Lu-PSMA infusions. Any-grade treatment-emergent AEs were reported in 79% (105/133) of patients and serious AEs in 30% (40/133). The most frequent grade 3-4 laboratory abnormalities were anemia (30%, 40/133) and thrombocytopenia (13%, 17/133). Median overall survival was 13.2 mo (95% CI, 10.5-15.6 mo) from the start of 177Lu-PSMA. Conclusion: In this real-world setting, 223Ra followed by 177Lu-PSMA therapy in heavily pretreated patients with mCRPC was clinically feasible, with no indication of impairment of 177Lu-PSMA safety or effectiveness.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Rádio (Elemento) , Masculino , Humanos , Lutécio/uso terapêutico , Rádio (Elemento)/efeitos adversos , Resultado do Tratamento , Estudos Retrospectivos , Próstata/patologia , Compostos Radiofarmacêuticos/uso terapêutico , Antígeno Prostático Específico , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversosRESUMO
We aimed to evaluate the role of prostate-specific membrane antigen (PSMA) PET/CT for response assessment and outcome prediction in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with androgen receptor pathway inhibitors (ARPIs), including abiraterone acetate or enzalutamide. Methods: We retrospectively analyzed 30 ARPI-treated mCRPC patients who underwent 68Ga-PSMA-11 PET/CT within 8 wk before (baseline) and 12 ± 4 wk after treatment initiation. Total PSMA tumor volume was calculated using the fixed threshold method (SUV ≥ 3). Patients were categorized as PSMA responders (PSMA-Rs) or PSMA nonresponders (PSMA-NRs) on the basis of both European Association of Urology/European Association of Nuclear Medicine (EAU/EANM) criteria and Response Evaluation Criteria in PSMA PET/CT (RECIP) 1.0. PSMA-R included patients with a complete response, a partial response, or stable disease, and PSMA-NR included those with progressive disease. On the basis of prostate-specific antigen (PSA), patients were classified as biochemical responders if PSA decreased by at least 50% and as nonresponders if it did not. The Φ-coefficient was used to evaluate the correlation of PSMA- and PSA-based responses. Survival analysis was performed using the Cox regression hazard model and the Kaplan-Meier method. Predictive accuracy was tested for both response criteria. Results: On the basis of PSMA PET/CT, 13 (43%) patients were PSMA-NR according to the EAU/EANM criteria and 11 (37%) patients were PSMA-NR according to RECIP 1.0. Significant correlations were observed between PSMA- and PSA-based responses for both criteria (Φ = 0.79 and 0.66, respectively). After a median follow-up of 25 mo (interquartile range, 21-43 mo), the median overall survival was significantly longer for PSMA-R than PSMA-NR (54 vs. 22 mo) for both the EAU/EANM criteria and RECIP 1.0, with hazard ratios of 6.9 (95% CI, 1.9-26; P = 0.004) and 5.6 (95% CI, 1.69-18.26, P = 0.005), respectively. No significant difference in predictive accuracy was found between the 2 criteria (C-index, 0.79 vs. 0.76, respectively, P = 0.54). Flare phenomena at the second PSMA PET study were not observed in our cohort. Conclusion: Our results demonstrate that PSMA PET/CT is a valuable imaging biomarker for response assessment and overall survival prediction when performed at 3 mo after ARPI treatment initiation in mCRPC patients. Both proposed PSMA response criteria (EAU/EANM and RECIP 1.0) seem to perform equally well. No PSMA flare was observed. Prospective validation of these findings is strongly needed.
Assuntos
Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Neoplasias de Próstata Resistentes à Castração/diagnóstico por imagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Receptores Androgênicos , Antígeno Prostático Específico , Estudos Retrospectivos , Resultado do Tratamento , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Lutécio , Dipeptídeos/efeitos adversosRESUMO
177Lu-PSMA-617 and 177Lu-PSMA I&T (collectively termed 177Lu-PSMA) are currently being used for the treatment of selected metastatic castration-resistant prostate cancer (mCRPC) patients with PSMA PET-positive disease, but biomarkers for these agents remain incompletely understood. Methods: Pretreatment circulating tumor DNA (ctDNA) samples were collected from 44 mCRPC patients receiving 177Lu-PSMA treatment. Prostate-specific antigen responders and nonresponders were assessed relative to the ctDNA findings at baseline. Results: The ctDNA findings indicated that nonresponders were more likely to have gene amplifications than were responders (75% vs. 39.2%, P = 0.03). In particular, amplifications in FGFR1 (25% vs. 0%, P = 0.01) and CCNE1 (31.2% vs. 0%, P = 0.001) were more likely to be present in nonresponders. CDK12 mutations were more likely to be present in nonresponders (25% vs. 3.6%, P = 0.05). Conclusion: Our analyses indicate that ctDNA assays may contain specific biomarkers predictive of response or resistance for 177Lu-PSMA-treated mCRPC patients. Additional confirmatory studies are required before clinicians can use these findings to make personalized treatment decisions.
Assuntos
DNA Tumoral Circulante , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , DNA Tumoral Circulante/genética , Compostos Radiofarmacêuticos/efeitos adversos , Neoplasias de Próstata Resistentes à Castração/genética , Neoplasias de Próstata Resistentes à Castração/radioterapia , Antígeno Prostático Específico , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Lutécio/uso terapêutico , Resultado do Tratamento , Estudos RetrospectivosRESUMO
PURPOSE: Despite the existence of various treatment options, the prognosis for patients with metastatic castration-resistant prostate cancer (mCRPC) remains unfavorable. One potential therapeutic approach is the use of [225Ac]Ac-PSMA-617, a targeted alpha therapy (TAT) that administers alpha-particle radiation specifically to prostate cancer cells expressing PSMA. In this study, we report the long-term survival outcomes of this novel therapy in a series of patients with mCRPC who have exhausted all standard treatment options. METHODS: The study enrolled patients with mCRPC who had shown resistance to standard lines of therapies, including next-generation anti-androgen therapies and taxane-based chemotherapies. These eligible patients received treatment with [225Ac]Ac-PSMA-617 at 100-150 kBq/kg doses administered every 8 weeks. The primary objective of the study was to assess overall survival (OS), while secondary objectives included evaluating radiological progression-free survival (rPFS), monitoring serum prostate-specific antigen (PSA) levels as a measure of biochemical response, and assessing adverse events using the CTCAE v5.0 grading system. RESULTS: Among the 63 initially enrolled patients, a total of 56 patients who had completed at least two cycles of [225Ac]Ac-PSMA-617 were included in this study. The mean age was 67 years (range, 39-87) and patients received a total of 204 cycles of [225Ac]Ac-PSMA-617 TAT. 91% of patients exhibited any PSA decline, with 67.8% experiencing a decline of 50% or more. The median follow-up was of 22 months (range: 6-59 months). Imaging-based disease progression was observed in 68% of patients, and 66% of patients succumbed to the disease. The median OS was 15 months (95% CI: 10-19). In univariate analysis, factors such as lack of >50% PSA decline (P=0.031), Eastern Cooperative Oncology Group (ECOG) performance status of 2 or higher (P=0.048), and radiological progression (rPD) (P<0.001) were found to be predictors of poor OS. However, in multivariate analysis, only rPD emerged as an independent prognostic factor with a hazard ratio (HR) of 8.264 (95% CI: 1.429-16.497, P=0.004). The estimated median rPFS was 9 months (95% CI: 7-15). Moreover, patients who demonstrated any PSA decline had a median rPFS of 10 months compared to only 3 months in patients without any PSA decline (multivariate HR: 6.749; 95% CI: 1.949-23.370; P=0.002). Fatigue was one of the most common treatment-emergent adverse events, with grades 1/2 occurring in 70% of patients and grades 3 or higher in 3.5% of patients. This fatigue was transient and resolved before the next treatment cycle. Additionally, approximately one-third of patients experienced xerostomia (grades 1/2: 32.1%). CONCLUSION: [225Ac]Ac-PSMA-617 targeted alpha therapy, was found to be well-tolerated with acceptable adverse events and effective in the treatment of patients with end-stage mCRPC.
Assuntos
Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Idoso , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Resultado do Tratamento , Dipeptídeos/efeitos adversos , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Lutécio/uso terapêuticoRESUMO
Patients with metastatic prostate cancer are more likely than other groups to present for radiopharmaceutical therapy with urinary incontinence due to complications from prior local prostate cancer treatment. A consequence of urinary incontinence in patients receiving radiopharmaceutical therapy is the potential production of contaminated solid waste, which must be managed by the licensee and, at home, managed by and disposed of by the patient. Prolonging the patient stay in the treating facility after radiopharmaceutical therapy administration, until the first urinary void or potentially overnight, may moderately reduce the quantity of contaminated waste being managed by the patient at home. However, this approach does not fully mitigate the need for a patient waste-management strategy. In this brief communication, the relative radiation safety merits of contaminated waste disposal in the normal household waste stream in comparison to other waste management strategies are evaluated.