RESUMO
BACKGROUND: MAGNITUDE (NCT03748641) demonstrated favourable outcomes with niraparib plus abiraterone acetate plus prednisone (+AAP) versus placebo+AAP in patients with BRCA1/2-altered metastatic castration-resistant prostate cancer (mCRPC). Imbalances in prognostic variables were reported between arms, which impacts estimation of both the clinical benefit and costeffectiveness of niraparib+AAP for healthcare systems. A pre-specified multivariable analysis (MVA) demonstrated improved overall survival (OS) with niraparib+AAP. Here, we used an inverse probability of treatment weighting (IPTW) model to adjust for covariate imbalances and assess time-to-event outcomes. METHODS: IPTW analysis of time-to-event outcomes was conducted using data from patients with BRCA1/2-altered mCRPC (N = 225) in MAGNITUDE. Patients received niraparib+AAP or placebo+AAP. OS, radiographic progression-free survival, time to symptomatic progression, time to initiation of cytotoxic chemotherapy and time to prostate-specific antigen progression were assessed. Weighted Kaplan-Meier curves were generated for each endpoint, and adjusted hazard ratios (HR) were obtained from a weighted Cox model. RESULTS: Improvements in survival outcomes were estimated for niraparib+AAP versus placebo+AAP: unadjusted median OS was 30.4 months versus 28.6 months, respectively (HR: 0.79; 95 % confidence interval [CI]: 0.55, 1.12; p = 0.183). Following IPTW, median OS increased to 34.1 months with niraparib+AAP versus a decrease to 27.4 with placebo (HR: 0.65; 95 % CI: 0.46, 0.93; p = 0.017). Similar improvements were observed for other time-to-event endpoints. CONCLUSIONS: IPTW adjustment provided a more precise estimate of the clinical benefit of niraparib+AAP versus placebo+AAP in patients with BRCA1/2-altered mCRPC. Results were consistent with the pre-specified MVA, and further demonstrated the value of adjusting for baseline imbalances, particularly in smaller studies. TRIAL REGISTRATION: NCT03748641 (MAGNITUDE).
RESUMO
Despite several improvements in outcomes, metastatic prostate cancer remains deadly. Alterations in the homologous recombination repair (HRR) pathway are associated with more aggressive disease. Olaparib and rucaparib, two poly-ADP-ribose polymerase (PARP) inhibitors, have received approval from the authorities of several countries for their anti-tumoral effects in patients with metastatic castration-resistant prostate cancers harboring HRR gene alterations, in particular BRCA2. More recently, it has been hypothesized that new hormonal therapies (NHTs) and PARP inhibitors (PARPi) could have synergistic actions and act independently of HRR deficiency. This review proposes to discuss the advantages and disadvantages of PARPi used as monotherapy or in combination with NHTs and whether there is a need for molecular selection.
RESUMO
While androgen deprivation therapy (ADT) has been the standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC), recent strategies like intensification of systemic treatment (Rozet et al., 2020) (i.e. adding another treatment to ADT) and radiotherapy have improved overall survival. PROFILE, a national retrospective multicentric real-world study, involved patients with mCSPC recruited by medical oncologists, urologists, and radiation oncologists, and who started treatment between November 2020 and May 2021. Patients by sites were included consecutively. Data were collected from medical records. Primary objectives were to: (1) describe retrospectively the characteristics of whole population of patients with mCSPC as well as subgroups defined by prognostic factors in France at diagnosis; (2) identify current practices for managing mCSPC in a real-life clinical setting. Among the 416 patients with mCSPC included in the PROFILE study, 315 (76%) were synchronous (metastasis at the initial diagnosis) and 101 (24%) were metachronous patients (metastasis diagnosed post-progression). A majority (83% of synchronous and 73% of metachronous patients) received an intensified systemic treatment (ADT plus ARSI [androgen-receptor signaling inhibitors]±chemotherapy±primary tumour radiotherapy±metastasis-directed therapy [MDT]), while only 40% of low-volume patients received prostate radiotherapy. This study depicts the standardization of new therapeutic strategies for patients with mCSPC in France with most of them receiving an intensified treatment, mainly with ADT+ARSI (64% of synchronous intensified patients and 76% of metachronous intensified patients). Most of patients were assessed using conventional imaging (CT scan and/or bone scan). Overall, PROFILE results are in line with French and European guidelines for diagnosis, management, and follow-up of such patients (Rozet et al., 2020; Cornford et al., 2021).
Assuntos
Metástase Neoplásica , Humanos , Masculino , França/epidemiologia , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Antagonistas de Androgênios/uso terapêutico , Idoso de 80 Anos ou mais , Neoplasias de Próstata Resistentes à Castração/patologia , Neoplasias de Próstata Resistentes à Castração/terapia , Neoplasias de Próstata Resistentes à Castração/radioterapia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológicoRESUMO
BACKGROUND AND OBJECTIVE: Metastatic prostate cancer (mPCa) harbors genomic alterations that may predict targeted therapy efficacy. These alterations can be identified not only in tissue but also directly in biologic fluids (ie, liquid biopsies), mainly blood. Liquid biopsies may represent a safer and less invasive alternative for monitoring patients treated for mPCa. Current research focuses on the description and validation of novel predictive biomarkers to improve precision medicine in mPCa. Our aim was to systematically review the current evidence on liquid biopsy biomarkers for predicting treatment response in mPCa. METHODS: We systematically searched Medline, Web of Science, and evidence-based websites for publications on circulating biomarkers in mPCa between March 2013 and February 2024 for review. Endpoints were: prediction of overall survival, biochemical or radiographic progression-free survival after treatment (chemotherapy, androgen deprivation therapy, androgen receptor pathway inhibitors [ARPIs], immunotherapy, or PARP inhibitors [PARPIs]). For each biomarker, the level of evidence (LOE) for clinical validity was attributed: LOE IA and IB, high level of evidence; LOE IIB and IIC, intermediate level; and LOE IIIC and LOE IV-VD, weak level. KEY FINDINGS AND LIMITATIONS: The predictive value of each biomarker for the response to several therapies was evaluated in both metastatic hormone-sensitive (mHSPC) and castration-resistant prostate cancer (mCRPC). In patients with mCRPC, BRCA1/2 or ATM mutations predicted response to ARPIs (LOE IB) and PARPIs (LOE IIB), while AR-V7 transcripts or AR-V7 protein levels in circulating tumor cells (CTCs) predicted response to ARPIs and taxanes (LOE IB). CTC quantification predicted response to cabazitaxel, abiraterone, and radium-223 (LOE IIB), while TP53 alterations predicted response to 177Lu prostate-specific membrane antigen radioligand treatment (LOE IIB). AR copy number in circulating tumor DNA before the first treatment line and before subsequent lines predicted response to docetaxel, cabazitaxel, and ARPIs (LOE IIB). In mHSPC, DNA damage in lymphocytes was predictive of the response to radium-223 (LOE IIB). CONCLUSIONS AND CLINICAL IMPLICATIONS: BRCA1/2, ATM, and AR alterations detected in liquid biopsies may help clinicians in management of patients with mPCa. The other circulating biomarkers did not reach the LOE required for routine clinical use and should be validated in prospective independent studies. PATIENT SUMMARY: We reviewed studies assessing the value of biomarkers in blood or urine for management of metastatic prostate cancer. The evidence indicates that some biomarkers could help in selecting patients eligible for specific treatments.
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This ABIGENE pharmacokinetic (PK) study sought mainly to characterize the unchanged drug PK during long-term abiraterone acetate (AA) administration in advanced prostate cancer patients (81 patients). It was observed that individual AA concentrations remained constant over treatment time, with no noticeable changes during repeated long-term drug administration for up to 120 days. There was no correlation between AA concentrations and survival outcomes. However, a significant association between higher AA concentrations and better clinical benefit was observed (p = 0.041). The safety data did not correlate with the AA PK data. A significant positive correlation (r = 0.40, p < 0.001) was observed between mean AA concentration and patient age: the older the patient, the higher the AA concentration. Patient age was found to impact steady-state AA concentration: the older the patient, the higher the mean AA concentration. Altogether, these data may help to guide future research and clinical trials in order to maximize the benefits of AA metastatic castration-resistant prostate cancer patients.
Assuntos
Acetato de Abiraterona , Neoplasias de Próstata Resistentes à Castração , Humanos , Masculino , Acetato de Abiraterona/farmacocinética , Acetato de Abiraterona/uso terapêutico , Acetato de Abiraterona/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Idoso , Pessoa de Meia-Idade , Idoso de 80 Anos ou mais , Seguimentos , Metástase Neoplásica , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/administração & dosagemRESUMO
The advent of new systemic therapies resulted in a significant decrease in prostate cancer (PCa) death in the past decades. It comes at the cost of an increase in the proportion of men living with long-term treatment-induced hypogonadism. In a population of men with no history of PCa, the testosterone replacement therapy (TRT) proved its ability to both improve erectile function and reduce cardiovascular morbidity, translating into an improved overall survival. Whether TRT is safe and efficient in PCa patients remains an open question. Here, we present an overview on the safety of TRT for PCa patients and discuss the optimal population eligible for TRT after the PCa treatment.
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BACKGROUND: Combination of androgen deprivation therapy (ADT) with external beam radiation therapy (EBRT) is a standard of care for patients with intermediate-risk prostate cancer (PCa). However, 6 months of ADT generates multiple side effects impacting quality of life (QoL). Darolutamide (an androgen receptor targeting agent [ARTA]) is associated with low blood-brain barrier penetrance and less drug-drug interaction. OBJECTIVE: To assess the efficacy of a combination of 6 months of darolutamide with EBRT to treat patients with unfavorable intermediate-risk PCa. DESIGN, SETTING, AND PARTICIPANTS: The DARIUS trial is a multicenter randomized non comparative phase 2 trial, randomizing the 6-months darolutamide + EBRT arm versus 6-months ADT + EBRT in patients with unfavorable intermediate-risk PCa. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint is a biological response defined as prostate-specific antigen ≤0.1 ng/ml at month six of darolutamide or ADT. The key secondary endpoints are biochemical recurrence-free survival, disease-free survival, safety, and QoL. Ancillary studies using radiomics and genomic classifier are planned. Sixty-two patients will be included. RESULTS AND LIMITATIONS: In this population of patients requiring ADT combined with EBRT, the use of an ARTA alone, such as darolutamide, may demonstrate antitumoral efficacy while minimizing toxicity and maintaining QoL. Limitations are mainly inherent to the open-label design of this study. CONCLUSIONS: Six months of darolutamide + EBRT compared with 6 months of ADT + EBRT may be efficient in terms of a biological response, avoiding toxicity and altered QoL attributable to ADT in patients with unfavorable intermediate-risk PCa. PATIENT SUMMARY: The ongoing DARIUS clinical trial assesses short-term (6 months) darolutamide treatment in association with external beam radiation therapy in men with localized prostate cancer. The trial investigates whether single-agent darolutamide can improve the biological response while maintaining a favorable tolerability profile.
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BACKGROUND: Prostate cancer is regulated by steroid hormones, even in castration-resistant disease. ODM-208, a novel inhibitor of cytochrome P450 11A1 (which catalyzes the first step of steroid-hormone biosynthesis), was investigated in patients with heavily pretreated metastatic castration-resistant prostate cancer (mCRPC). METHODS: CYPIDES is a first-in-human phase 1 (3 + 3 design) and phase 2 study. We administered ODM-208 twice daily with glucocorticoid/mineralocorticoid replacement and ongoing androgen deprivation therapy to adults with previously treated mCRPC, regardless of androgen receptor gene (AR) ligand-binding domain mutations (phase 1) and with activating AR ligand-binding domain mutations (ARmut; phase 2). Safety, pharmacokinetics, steroid-hormone pharmacodynamics, and preliminary efficacy were the key outcomes. RESULTS: Ninety-two patients received one or more doses of ODM-208: 47 in phase 1 (20 [42.6%] with ARmut) and 45 in phase 2 (all ARmut). A dose of ODM-208 of 5 mg twice a day with dexamethasone 1 mg/fludrocortisone 0.1 mg provided a balance between decreased steroidogenesis and toxicity. Treatment-related adrenal insufficiency was the most common toxicity in phase 1 (n=17, 36.2%; necessitating ODM-208 discontinuation in one patient); this toxicity occurred in six patients (13.3%) at 5 mg twice a day in phase 2. Median circulating testosterone levels declined from 3.0 ng/dl (interquartile range, 1.3 to 6.2 ng/dl) at baseline to undetectable levels within the first week of ODM-208 5 mg twice a day treatment in 46 of 53 (87%) patients. A decrease in prostate-specific antigen levels of 50% or more occurred in 14 of 19 (73.7%) patients with ARmut and 2 of 23 (8.7%) patients with AR wild type in phase 1 and in 24 of 45 (53.3%) patients with ARmut in phase 2. CONCLUSIONS: ODM-208 potently inhibited steroid-hormone biosynthesis with the expected toxicity of adrenal insufficiency. Evidence of antitumor activity was observed in this heavily pretreated mCRPC population, especially in those with ARmut. (Funded by Orion Pharma; ClinicalTrials.gov number, NCT03436485.)