RESUMEN
BACKGROUND: Metastatic prostate cancer (PCa) is associated with considerable diminished overall survival (OS). Standard treatment for metastatic PCa has long been androgen deprivation therapy alone, with patients initially responding to this treatment and then progressing to a castration-resistant phase. SUMMARY: The advent of novel therapeutic agents has changed this paradigm, with high-level evidence that upfront combination therapy with either docetaxel or new hormonal agents results in improved OS for patients with metastatic hormone-sensitive PCa. In the absence of a comprehensive clinical trial investigating the comparative efficacy and safety of all agents, clinicians are responsible for choosing the most appropriate therapy in close coordination with patients. Furthermore, the same therapeutic agents are also efficient in the castration-resistant phase, leading to the issue of the best therapeutic sequence. Finally, along with systemic therapy and molecular imaging advancements, radiotherapy was investigated in the oligometastatic setting, whether it is to treat the primary tumour or metastases. Key Messages: In this complex landscape, where providers have multiple effective therapeutic options to treat metastatic PCa patients, priority must be given to determine which treatment combination and sequence is best suited to a particular patient, given his comorbidities and preferences.
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Antineoplásicos/uso terapéutico , Inmunoterapia/métodos , Neoplasias de la Próstata/terapia , Radioterapia/métodos , Ensayos Clínicos como Asunto , Terapia Combinada , Humanos , Masculino , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Radiofármacos/uso terapéuticoRESUMEN
BACKGROUND: Accurate staging is of major importance to determine the optimal treatment modality for patients with prostate cancer. Positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) is a promising technique that outperformed conventional imaging in the detection of nodal and distant metastases in previous studies. However, it is still unclear whether the superior sensitivity and specificity also translate into improved patient management. The aim of this study was to assess the performance of 68Ga-PSMA-11 PET for staging of intermediate and high-risk prostate cancer and its potential impact on disease management. METHODS: In this retrospective analysis, 116 patients who underwent 68Ga-PSMA-11 PET/CT or MRI scans for staging of their intermediate or high-risk prostate cancer between April 2016 and May 2018 were included. The potential impact of 68Ga-PSMA-11 PET staging on patient management was assessed within a simulated multidisciplinary tumour board where hypothetical treatment decisions based on clinical information and conventional imaging alone was determined. This treatment decision was compared with the treatment recommendation based on clinical information and 68Ga-PSMA-11 PET imaging. RESULTS: The primary tumour was positive on 68Ga-PSMA-11 PET in 113 patients (97%). Nodal metastases were detected in 28 patients (24%) and bone metastases in 14 patients (12%). Compared with clinical staging and conventional imaging, 68Ga-PSMA-11 PET resulted in new information in 42 of 116 patients (36%). In 32 of 116 patients (27%), this information would most likely have changed the management into a different therapy modality (15 patients, 13%) or adjusted treatment details (e.g. modification of radiotherapy field or lymph node dissection template; 17 patients, 14%). CONCLUSION: Information from 68Ga-PSMA-11 PET staging has the potential to change the management in more than a fourth of the patients who underwent PET staging for their intermediate to high-risk prostate cancer. Whether these more personalized 68Ga-PSMA-11 PET-based treatment decisions will improve patient outcome needs further investigation.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Toma de Decisiones Clínicas , Ácido Edético/análogos & derivados , Isótopos de Galio , Radioisótopos de Galio , Humanos , Masculino , Estadificación de Neoplasias , Oligopéptidos , Tomografía de Emisión de Positrones , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Estudios RetrospectivosRESUMEN
PURPOSE: Prostate cancer care in the Middle East is highly variable and access to specialist multidisciplinary management is limited. Academic tertiary referral centers offer cutting-edge diagnosis and treatment; however, in many parts of the region, patients are managed by non-specialists with limited resources. Due to many factors including lack of awareness and lack of prostate-specific antigen (PSA) screening, a high percentage of men present with locally advanced and metastatic prostate cancer at diagnosis. The aim of these recommendations is to assist clinicians in managing patients with different levels of access to diagnostic and treatment modalities. METHODS: The first Advanced Prostate Cancer Consensus Conference (APCCC) satellite meeting for the Middle East was held in Beirut, Lebanon, November 2017. During this meeting a consortium of urologists, medical oncologists, radiation oncologist and imaging specialists practicing in Lebanon, Syria, Iraq, Kuwait and Saudi Arabia voted on a selection of consensus questions. An additional workshop to formulate resource-stratified consensus recommendations was held in March 2019. RESULTS: Variations in practice based on available resources have been proposed to form resource-stratified recommendations for imaging at diagnosis, initial management of localized prostate cancer requiring therapy, treatment of castration-sensitive/naïve advanced prostate cancer and treatment of castration-resistant prostate cancer. CONCLUSION: This is the first regional consensus on prostate cancer management from the Middle East. The following recommendations will be useful to urologists and oncologists practicing in all areas with limited access to specialist multi-disciplinary teams, diagnostic modalities and treatment resources.
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Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Recursos en Salud , Accesibilidad a los Servicios de Salud , Prostatectomía , Neoplasias de la Próstata/terapia , Radioterapia Adyuvante , Acetato de Abiraterona/uso terapéutico , Antineoplásicos/uso terapéutico , Benzamidas , Biopsia con Aguja Gruesa , Neoplasias Óseas/secundario , Neoplasias Óseas/terapia , Docetaxel/uso terapéutico , Endosonografía , Humanos , Irak , Calicreínas/metabolismo , Kuwait , Líbano , Escisión del Ganglio Linfático , Imagen por Resonancia Magnética , Masculino , Márgenes de Escisión , Medio Oriente , Metástasis de la Neoplasia , Nitrilos , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/uso terapéutico , Tomografía de Emisión de Positrones , Antígeno Prostático Específico/metabolismo , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/patología , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico , Neoplasias de la Próstata Resistentes a la Castración/epidemiología , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/terapia , Riesgo , Terapia Recuperativa , Arabia Saudita , SiriaRESUMEN
The management of advanced prostate cancer has changed substantially with the availability of multiple effective novel treatments, which has led to improved disease survival. In the era of personalized cancer treatments, more precise imaging may help physicians deliver better care. More accurate local staging and earlier detection of metastatic disease, accurate identification of oligometastatic disease, and optimal assessment of treatment response are areas where modern imaging is rapidly evolving and expanding. Next-generation imaging modalities, including whole-body MRI and molecular imaging with combined PET and CT and combined PET and MRI using novel radiopharmaceuticals, create new opportunities for imaging to support and refine management pathways in patients with advanced prostate cancer. This article demonstrates the potential and challenges of applying next-generation imaging to deliver the clinical promise of treatment breakthroughs.
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Imagen por Resonancia Magnética/métodos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias de la Próstata/diagnóstico por imagen , Neoplasias de la Próstata/patología , Estudios de Seguimiento , Humanos , Masculino , Imagen Multimodal/métodos , Estadificación de Neoplasias , Tomografía de Emisión de Positrones , Próstata/diagnóstico por imagen , Próstata/patologíaRESUMEN
PURPOSE: The fast-increasing use of positron emission tomography (PET) with prostate-specific membrane antigen (PSMA) ligand for the imaging of prostate cancer (PCA) biochemical recurrence has led to a rapid change in treatment concepts. Since the superiority of 68Ga-PSMA-11 PET in detecting recurrent PCA is well established, the aim of our study was to assess its effect on management and outcome in all patients imaged during the first year after its introduction into clinical routine. METHODS: Of 327 patients imaged, 223 were referred for recurrent PCA and gave written informed consent for further analysis of their data for this retrospective consecutive cohort analysis. Twenty patients were lost to further follow-up. The rate of detection of recurrence by 68Ga-PSMA-11 PET was based on the clinical reports. Management before the availability of PET diagnostic information was assessed according to guidelines (therapy option without 68Ga-PSMA-11 PET). In the 203 patients with follow-up 6 months after 68Ga-PSMA-11 PET, the therapies effectively implemented as well as follow-up PSA levels were evaluated, with a PSA value of <0.2 ng/ml representing a complete response and a decrease in PSA value of at least 50% from baseline representing a partial response. RESULTS: 68Ga-PSMA-11 PET was positive and identified recurrence in 166 of the 223 patients (74%), with a detection rate of 50% for recurrent disease at low PSA values of <0.5 ng/ml. 68Ga-PSMA-11 PET led to a change in management in 122 of the 203 patients (60%). A substantial increase in the use of metastasis-targeted treatment and a reduction in the use of systemic treatment were observed, with 59 of the 203 patients (29%) undergoing targeted radiotherapy (RTXa) only, and 20 patients (10%) undergoing RTXa with hormonal therapy as the two most frequently selected therapy options. The proportion of patients in whom systemic therapy was selected decreased from 60% (133 of 223 patients) to 34% (70 of 203 patients) on the basis of the information provided by the 68Ga-PSMA-11 PET scan. PSMA PET-directed metastasis-targeted treatment led to a complete response after 6 months in 45% of patients. CONCLUSION: The high rate of recurrence detection by PSMA PET was confirmed and PSMA PET led to a change in management in 60% of patients. Focal therapy for PSMA-positive lesions is a promising approach with complete responses in 45% of patients.
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Ácido Edético/análogos & derivados , Oligopéptidos , Tomografía de Emisión de Positrones , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/diagnóstico por imagen , Anciano , Anciano de 80 o más Años , Isótopos de Galio , Radioisótopos de Galio , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/terapia , Recurrencia , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Prostate cancer is a heterogeneous disease, but current treatments are not based on molecular stratification. We hypothesized that metastatic, castration-resistant prostate cancers with DNA-repair defects would respond to poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibition with olaparib. METHODS: We conducted a phase 2 trial in which patients with metastatic, castration-resistant prostate cancer were treated with olaparib tablets at a dose of 400 mg twice a day. The primary end point was the response rate, defined either as an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1, or as a reduction of at least 50% in the prostate-specific antigen level or a confirmed reduction in the circulating tumor-cell count from 5 or more cells per 7.5 ml of blood to less than 5 cells per 7.5 ml. Targeted next-generation sequencing, exome and transcriptome analysis, and digital polymerase-chain-reaction testing were performed on samples from mandated tumor biopsies. RESULTS: Overall, 50 patients were enrolled; all had received prior treatment with docetaxel, 49 (98%) had received abiraterone or enzalutamide, and 29 (58%) had received cabazitaxel. Sixteen of 49 patients who could be evaluated had a response (33%; 95% confidence interval, 20 to 48), with 12 patients receiving the study treatment for more than 6 months. Next-generation sequencing identified homozygous deletions, deleterious mutations, or both in DNA-repair genes--including BRCA1/2, ATM, Fanconi's anemia genes, and CHEK2--in 16 of 49 patients who could be evaluated (33%). Of these 16 patients, 14 (88%) had a response to olaparib, including all 7 patients with BRCA2 loss (4 with biallelic somatic loss, and 3 with germline mutations) and 4 of 5 with ATM aberrations. The specificity of the biomarker suite was 94%. Anemia (in 10 of the 50 patients [20%]) and fatigue (in 6 [12%]) were the most common grade 3 or 4 adverse events, findings that are consistent with previous studies of olaparib. CONCLUSIONS: Treatment with the PARP inhibitor olaparib in patients whose prostate cancers were no longer responding to standard treatments and who had defects in DNA-repair genes led to a high response rate. (Funded by Cancer Research UK and others; ClinicalTrials.gov number, NCT01682772; Cancer Research UK number, CRUK/11/029.).
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Antineoplásicos/uso terapéutico , Reparación del ADN , Inhibidores Enzimáticos/uso terapéutico , Ftalazinas/uso terapéutico , Piperazinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Neoplasias de la Próstata/tratamiento farmacológico , Adulto , Anciano , Anemia/inducido químicamente , Proteínas de la Ataxia Telangiectasia Mutada/genética , Reparación del ADN/genética , Resistencia a Antineoplásicos , Inhibidores Enzimáticos/efectos adversos , Fatiga/inducido químicamente , Genes BRCA2 , Genes Supresores de Tumor , Humanos , Masculino , Persona de Mediana Edad , Mutación , Metástasis de la Neoplasia/tratamiento farmacológico , Ftalazinas/efectos adversos , Piperazinas/efectos adversos , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patologíaRESUMEN
Purpose To determine the correlation between the volume of bone metastasis as assessed with diffusion-weighted (DW) imaging and established prognostic factors in metastatic castration-resistant prostate cancer (mCRPC) and the association with overall survival (OS). Materials and Methods This retrospective study was approved by the institutional review board; informed consent was obtained from all patients. The authors analyzed whole-body DW images obtained between June 2010 and February 2013 in 53 patients with mCRPC at the time of starting a new line of anticancer therapy. Bone metastases were identified and delineated on whole-body DW images in 43 eligible patients. Total tumor diffusion volume (tDV) was correlated with the bone scan index (BSI) and other prognostic factors by using the Pearson correlation coefficient (r). Survival analysis was performed with Kaplan-Meier analysis and Cox regression. Results The median tDV was 503.1 mL (range, 5.6-2242 mL), and the median OS was 12.9 months (95% confidence interval [CI]: 8.7, 16.1 months). There was a significant correlation between tDV and established prognostic factors, including hemoglobin level (r = -0.521, P < .001), prostate-specific antigen level (r = 0.556, P < .001), lactate dehydrogenase level (r = 0.534, P < .001), alkaline phosphatase level (r = 0.572, P < .001), circulating tumor cell count (r = 0.613, P = .004), and BSI (r = 0.565, P = .001). A higher tDV also showed a significant association with poorer OS (hazard ratio, 1.74; 95% CI: 1.02, 2.96; P = .035). Conclusion Metastatic bone disease from mCRPC can be evaluated and quantified with whole-body DW imaging. Whole-body DW imaging-generated tDV showed correlation with established prognostic biomarkers and is associated with OS in mCRPC. (©) RSNA, 2016 Online supplemental material is available for this article.
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Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/secundario , Imagen de Difusión por Resonancia Magnética/métodos , Neoplasias de la Próstata Resistentes a la Castración/patología , Imagen de Cuerpo Entero/métodos , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias Óseas/patología , Huesos/diagnóstico por imagen , Huesos/patología , Supervivencia sin Enfermedad , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Reproducibilidad de los Resultados , Estudios Retrospectivos , Carga TumoralRESUMEN
With five novel therapies shown to improve survival in metastatic castration-resistant prostate cancer (CRPC) in the last 3 years, patients are now living longer and experiencing better quality of life. Since docetaxel became standard of care for men with symptomatic metastatic CRPC, three artificial treatment "spaces" have emerged for prostate cancer drug development: pre-docetaxel, docetaxel combinations, and following docetaxel. Multiple therapies are currently under development in both early and late stage CRPC. Additionally, the novel agents abiraterone, radium-223, cabazitaxel, and enzalutamide have all been approved in the post-docetaxel setting. Strategies for patient selection and treatment sequencing are therefore urgently required. In this comprehensive review, we will summarize the preclinical and clinical data available with regards to sequencing of the novel treatments for CRPC.
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Neoplasias de la Próstata Resistentes a la Castración/patología , Animales , Ensayos Clínicos Fase III como Asunto , Terapia Combinada , Descubrimiento de Drogas , Humanos , Masculino , Metástasis de la Neoplasia , Neoplasias de la Próstata Resistentes a la Castración/terapia , Resultado del TratamientoRESUMEN
BACKGROUND: PTEN gene loss occurs frequently in castration-resistant prostate cancer (CRPC) and may drive progression through activation of the PI3K/AKT pathway. Here, we developed a novel CTC-based assay to determine PTEN status and examined the correlation between PTEN status in CTCs and matched tumour tissue samples. METHODS: PTEN gene status in CTCs was evaluated on an enrichment-free platform (Epic Sciences) by fluorescence in situ hybridisation (FISH). PTEN status in archival and fresh tumour tissue was evaluated by FISH and immunohistochemistry. RESULTS: Peripheral blood was collected from 76 patients. Matched archival and fresh cancer tissue was available for 48 patients. PTEN gene status detected in CTCs was concordant with PTEN status in matched fresh tissues and archival tissue in 32 of 38 patients (84%) and 24 of 39 patients (62%), respectively. CTC counts were prognostic (continuous, P=0.001). PTEN loss in CTCs associated with worse survival in univariate analysis (HR 2.05; 95% CI 1.17-3.62; P=0.01) and with high lactate dehydrogenase (LDH) in metastatic CRPC patients. CONCLUSIONS: Our results illustrate the potential use of CTCs as a non-invasive, real-time liquid biopsy to determine PTEN gene status. The prognostic and predictive value of PTEN in CTCs warrants investigation in CRPC clinical trials of PI3K/AKT-targeted therapies.
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Células Neoplásicas Circulantes/patología , Fosfohidrolasa PTEN/genética , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Anciano , Progresión de la Enfermedad , Humanos , Inmunohistoquímica/métodos , Hibridación Fluorescente in Situ/métodos , L-Lactato Deshidrogenasa/genética , Masculino , Fosfatidilinositol 3-Quinasas/genética , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/metabolismoRESUMEN
BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR), a marker of inflammation, has been reported to be a poor prognostic indicator in prostate cancer. Here we explore the use of the NLR to establish a simple prognostic score for men with metastatic castration-resistant prostate cancer (mCRPC) treated with docetaxel. METHODS: In the training cohort, the NLR and other known prognostic variables were evaluated among a cohort of chemotherapy-naïve patients treated with thrice-weekly docetaxel at the Princess Margaret Cancer Centre. Significant prognostic variables identified by univariable Cox regression were evaluated by the area under the receiver operating characteristic curves. Multivariable Cox regression was then used to derive a prognostic score where 1 risk point was assigned for each significant variable. The model was externally validated in a cohort of patients treated at the Royal Marsden. RESULTS: Three hundred fifty-seven patients were analyzed in the training cohort. Median age was 71 years, 12% had liver metastasis, and median overall survival (OS) was 14.7 months. Liver metastases, hemoglobin <12 g/dL, alkaline phosphatase >2.0× upper limit of normal (ULN), lactate dehydrogenase >1.2× ULN, and NLR >3 were associated with significantly worse OS in multivariable analysis. Four risk categories were subsequently established with 0, 1, 2, and 3-5 points. Two-year OS rates for these categories were 43%, 37%, 12%, and 3%, respectively. Area under the curve for the training cohort was 0.78 (95% CI, 0.72-0.84) compared with 0.66 (95% CI, 0.58-0.74) for the 215 patients in the validation cohort. CONCLUSIONS: This simple risk score provides good prognostic and discriminatory accuracy for men with mCRPC.
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Linfocitos/patología , Neutrófilos/patología , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Adulto , Anciano , Anciano de 80 o más Años , Docetaxel , Humanos , Masculino , Persona de Mediana Edad , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Taxoides/administración & dosificaciónRESUMEN
BACKGROUND: ASP9521 is a first-in-class orally available inhibitor of the enzyme 17 ß-hydroxysteroid dehydrogenase type 5 (17 ßHSD5; AKR1C3), catalysing the conversion of dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. It has demonstrated anti-tumour activity in in vitro and in vivo preclinical models. MATERIAL AND METHODS: This first-in-man phase I/II study utilised a 3 + 3 dose escalation design starting at 30 mg ASP9521/day, with the aim of defining a maximum tolerated dose, as defined by the incidence of dose-limiting toxicities. Eligible patients received ASP9521 orally for 12 weeks. Safety, tolerability, pharmacokinetics (PK), pharmacodynamics and anti-tumour activity were assessed. RESULTS: Thirteen patients (median age: 68 years; range 52-76) with metastatic castration-resistant prostate cancer (mCRPC) progressing after chemotherapy were included; 12 patients discontinued treatment at or before week 13, mainly due to disease progression. The most common adverse events were grade 1/2 and included asthenia (N = 5), constipation (N = 4), diarrhoea (N = 3), back pain (N = 3) and cancer pain (N = 3). PK demonstrated a half-life (t1/2) ranging from 16 to 35 h, rapid absorption and dose proportionality. No biochemical or radiological responses were identified; neither endocrine biomarker levels nor circulating tumour cell counts were altered by ASP9521. Given the lack of observable clinical activity, the study was terminated without implementing a planned 12-week dose expansion part at selected doses or a planned food-effect study part. CONCLUSIONS: In patients with mCRPC, ASP9521 demonstrated dose-proportional increase in exposure over the doses evaluated, with an acceptable safety and tolerability profile. However, the novel androgen biosynthesis inhibitor showed no relevant evidence of clinical activity.
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3-Hidroxiesteroide Deshidrogenasas/antagonistas & inhibidores , Antagonistas de Andrógenos/uso terapéutico , Antineoplásicos/uso terapéutico , Hidroxiprostaglandina Deshidrogenasas/antagonistas & inhibidores , Indoles/uso terapéutico , Piperidinas/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Miembro C3 de la Familia 1 de las Aldo-Ceto Reductasas , Antagonistas de Andrógenos/efectos adversos , Antagonistas de Andrógenos/farmacocinética , Antagonistas de Andrógenos/farmacología , Antineoplásicos/efectos adversos , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Recuento de Células , Dihidrotestosterona/sangre , Humanos , Indoles/efectos adversos , Indoles/farmacocinética , Indoles/farmacología , Calicreínas/sangre , Masculino , Persona de Mediana Edad , Piperidinas/efectos adversos , Piperidinas/farmacocinética , Piperidinas/farmacología , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/patología , Testosterona/sangre , Resultado del TratamientoRESUMEN
AIMS: The aim of this article was to evaluate afatinib (BIBW 2992), an ErbB family blocker, and nintedanib (BIBF 1120), a triple angiokinase inhibitor, in castration-resistant prostate cancer patients. PATIENTS & METHODS: Patients were randomized to receive nintedanib (250 mg twice daily), afatinib (40 mg once daily [q.d.]), or alternating sequential 7-day nintedanib (250 mg twice daily) and afatinib (70 mg q.d. [Combi70]), which was reduced to 40 mg q.d. (Combi40) due to adverse events. The primary end point was progression-free rate at 12 weeks. RESULTS: Of the 85 patients treated 46, 20, 16 and three received nintedanib, afatinib, Combi40 and Combi70, respectively. At 12 weeks, the progression-free rate was 26% (seven out of 27 patients) for nintedanib, and 0% for afatinib and Combi40 groups. Two patients had a ≥50% decline in PSA (nintedanib and the Combi40 groups). The most common drug-related adverse events were diarrhea, nausea, vomiting and lethargy. CONCLUSION: Nintedanib and/or afatinib demonstrated limited anti-tumor activity in unselected advanced castration-resistant prostate cancer patients.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Afatinib , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Indoles/administración & dosificación , Masculino , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neoplasias de la Próstata Resistentes a la Castración/patología , Quinazolinas/administración & dosificación , Resultado del TratamientoRESUMEN
BACKGROUND: Poly(ADP-ribose) polymerase (PARP) is implicated in DNA repair and transcription regulation. Niraparib (MK4827) is an oral potent, selective PARP-1 and PARP-2 inhibitor that induces synthetic lethality in preclinical tumour models with loss of BRCA and PTEN function. We investigated the safety, tolerability, maximum tolerated dose, pharmacokinetic and pharmacodynamic profiles, and preliminary antitumour activity of niraparib. METHODS: In a phase 1 dose-escalation study, we enrolled patients with advanced solid tumours at one site in the UK and two sites in the USA. Eligible patients were aged at least 18 years; had a life expectancy of at least 12 weeks; had an Eastern Cooperative Oncology Group performance status of 2 or less; had assessable disease; were not suitable to receive any established treatments; had adequate organ function; and had discontinued any previous anticancer treatments at least 4 weeks previously. In part A, cohorts of three to six patients, enriched for BRCA1 and BRCA2 mutation carriers, received niraparib daily at ten escalating doses from 30 mg to 400 mg in a 21-day cycle to establish the maximum tolerated dose. Dose expansion at the maximum tolerated dose was pursued in 15 patients to confirm tolerability. In part B, we further investigated the maximum tolerated dose in patients with sporadic platinum-resistant high-grade serous ovarian cancer and sporadic prostate cancer. We obtained blood, circulating tumour cells, and optional paired tumour biopsies for pharmacokinetic and pharmacodynamic assessments. Toxic effects were assessed by common toxicity criteria and tumour responses ascribed by Response Evaluation Criteria in Solid Tumors (RECIST). Circulating tumour cells and archival tumour tissue in prostate patients were analysed for exploratory putative predictive biomarkers, such as loss of PTEN expression and ETS rearrangements. This trial is registered with ClinicalTrials.gov, NCT00749502. FINDINGS: Between Sept 15, 2008, and Jan 14, 2011, we enrolled 100 patients: 60 in part A and 40 in part B. 300 mg/day was established as the maximum tolerated dose. Dose-limiting toxic effects reported in the first cycle were grade 3 fatigue (one patient given 30 mg/day), grade 3 pneumonitis (one given 60 mg/day), and grade 4 thrombocytopenia (two given 400 mg/day). Common treatment-related toxic effects were anaemia (48 patients [48%]), nausea (42 [42%]), fatigue (42 [42%]), thrombocytopenia (35 [35%]), anorexia (26 [26%]), neutropenia (24 [24%]), constipation (23 [23%]), and vomiting (20 [20%]), and were predominantly grade 1 or 2. Pharmacokinetics were dose proportional and the mean terminal elimination half-life was 36·4 h (range 32·8-46·0). Pharmacodynamic analyses confirmed PARP inhibition exceeded 50% at doses greater than 80 mg/day and antitumour activity was documented beyond doses of 60 mg/day. Eight (40% [95% CI 19-64]) of 20 BRCA1 or BRCA2 mutation carriers with ovarian cancer had RECIST partial responses, as did two (50% [7-93]) of four mutation carriers with breast cancer. Antitumour activity was also reported in sporadic high-grade serous ovarian cancer, non-small-cell lung cancer, and prostate cancer. We recorded no correlation between loss of PTEN expression or ETS rearrangements and measures of antitumour activity in patients with prostate cancer. INTERPRETATION: A recommended phase 2 dose of 300 mg/day niraparib is well tolerated. Niraparib should be further assessed in inherited and sporadic cancers with homologous recombination DNA repair defects and to target PARP-mediated transcription in cancer. FUNDING: Merck Sharp and Dohme.
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Proteína BRCA1/genética , Proteína BRCA2/genética , Indazoles/uso terapéutico , Mutación/genética , Recurrencia Local de Neoplasia/diagnóstico , Neoplasias/tratamiento farmacológico , Piperidinas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Adulto , Anciano , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Heterocigoto , Humanos , Indazoles/farmacocinética , Masculino , Dosis Máxima Tolerada , Persona de Mediana Edad , Recurrencia Local de Neoplasia/genética , Neoplasias/genética , Neoplasias/patología , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/patología , Piperidinas/farmacocinética , Pronóstico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Distribución TisularRESUMEN
Although intermittent androgen deprivation therapy was often recommended for metastatic hormone-sensitive cancer therapy in the past, we do not know whether its use can be extrapolated to combination therapy. Trials evaluating intermittent therapy are necessary as this strategy could improve patient quality of life and reduce adverse events and costs.
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BACKGROUND: Prostate cancer (PC) is the most prevalent cancer in men in Switzerland. However, evidence on the real-world health care use of PC patients is scarce. The aim of this study is to describe health care utilization, treatment patterns, and medical costs in PC patients over a period of five years (2014-2018). METHOD: We used routinely collected longitudinal individual-level claims data from a major provider of mandatory health insurance in Switzerland. Due to the lack of diagnostic coding in the claims data, we identified treated PC patients based on the treatments received. We described health care utilization and treatment pathways for patients with localized and metastatic PC. Costs were calculated from a health care system perspective. RESULTS: A total of 5591 PC patients met the inclusion criteria. Between 2014 and 2018, 1741 patients had outpatient radiotherapy for localized or metastatic PC and 1579 patients underwent radical prostatectomy. 3502 patients had an androgen deprivation therapy (ADT). 9.5% of these patients had a combination therapy with docetaxel, and 11.0% had a combination with abiraterone acetate. Docetaxel was the most commonly used chemotherapy (first-line; n = 413, 78.4% of all patients in chemotherapy). Total medical costs of PC in Switzerland were estimated at CHF 347 m (95% CI 323-372) in 2018. CONCLUSION: Most PC patients in this study were identified based on the use of ADT. Medical costs of PC in Switzerland amounted to 0.45% of total health care spending in 2018. Treatment of metastatic PC accounted for about two thirds of spending.
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Costos de la Atención en Salud , Neoplasias de la Próstata , Humanos , Masculino , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/economía , Suiza , Anciano , Costos de la Atención en Salud/estadística & datos numéricos , Persona de Mediana Edad , Prostatectomía/economía , Anciano de 80 o más Años , Aceptación de la Atención de Salud/estadística & datos numéricos , Revisión de Utilización de Seguros , Antagonistas de Andrógenos/uso terapéutico , Antagonistas de Andrógenos/economíaRESUMEN
PURPOSE: To assess efficacy and safety of prostatic artery embolization (PAE) in patients with advanced prostate cancer (PCa). MATERIALS AND METHODS: In this prospective single-center, single-arm, pilot study, 9 men with advanced PCa underwent PAE. PAE was performed with the use of 250-400 µm Embozene microspheres (Boston Scientific, Natick, Massachusetts, USA). International Prostate Symptoms Score (IPSS), urinary peak flow (Qmax) and post-void residual urine volume (PVR) was assessed at 12 weeks and up to 12 months. Changes in total prostate volume (TPV) and tumor responses by PSA, changes in tumor volume and evaluation of tumor regression by multiparametric magnetic resonance imaging were assessed at 12 weeks after PAE. RESULTS: IPSS reduction in median 6 points (0-19) and a significant decrease in PVR from median 70 (20-600) mL to 10 (0-280) mL could be achieved within 12 weeks after PAE. Median TPV and tumor volumes (TV) increased slightly from 19.7 (6.4-110.8) mL to 23.4 (2.4-66.3) mL and 6.4 (4.6-18.3) mL to 8.1 (2.4-25.6) mL at a median of 12 weeks after the procedure. Significant tumor necrosis (≥ 50%) was found in one patient. Eight patients showed > 50% of viable tumor on post-PAE MRI according to MRI. Only one Clavien-Dindo Grade 1 adverse event related to PAE occurred. CONCLUSIONS: PAE with the use of 250-400 µm microspheres is feasible, safe and effective in some patients with advanced PCa regarding functional outcomes. A cytoreductive effect might be achieved in individual patients but must be further assessed. TRIALS REGISTRATION: NCT03457805.
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Embolización Terapéutica , Próstata , Neoplasias de la Próstata , Humanos , Masculino , Proyectos Piloto , Embolización Terapéutica/métodos , Estudios Prospectivos , Anciano , Neoplasias de la Próstata/terapia , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/diagnóstico por imagen , Próstata/irrigación sanguínea , Próstata/diagnóstico por imagen , Próstata/patología , Resultado del Tratamiento , Persona de Mediana Edad , Microesferas , Imagen por Resonancia Magnética/métodos , Anciano de 80 o más Años , Resinas Acrílicas , GelatinaRESUMEN
BACKGROUND: Immune checkpoint inhibitors (ICIs) improve overall survival (OS) in advanced/metastatic urothelial cancer (a/mUC) patients. Preliminary evidence suggests a prognostic role of inflammatory biomarkers in this setting. We aimed to develop a disease-specific prognostic inflammatory index for a/mUC patients on ICIs. METHODS: Fifteen variables were retrospectively correlated with OS and progression-free survival (PFS) in a development (D, n = 264) and a validation (V, n = 132) cohort of platinum-pretreated a/mUC pts receiving ICIs at L2 or further line. A nomogram and inflammatory prognostic index (U-IPI) were developed. The index was also tested in a control cohort of patients treated with chemotherapy only (C, n = 114). RESULTS: The strongest predictors of OS were baseline platelet/lymphocyte (PLR) and neutrophil/lymphocyte (NLR) ratios, and lactate dehydrogenase (LDH), NLR, and albumin changes at 4 weeks. These were used to build the U-IPI, which can distinctly classify patients into good or poor response groups. The nomogram scoring is significant for PFS and OS (p < 0.001 in the D, V, and combined cohorts) for the immunotherapy (IO) cohort, but not for the control cohort. CONCLUSIONS: The lack of a baseline systemic inflammatory profile and the absence of early serum inflammatory biomarker changes are associated with significantly better outcomes on ICIs in a/mUC pts. The U-IPI is an easily applicable dynamic prognostic tool for PFS and OS, allowing for the early identification of a sub-group with dismal outcomes that would not benefit from ICIs, while distinguishing another that draws an important benefit.
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BACKGROUND: KEYNOTE-199 (NCT02787005) is a multicohort phase 2 study evaluating pembrolizumab in patients with metastatic castration-resistant prostate cancer (mCRPC). Results from cohorts 4 (C4) and 5 (C5) are presented. METHODS: Eligible patients had not received chemotherapy for mCRPC and had responded to enzalutamide prior to developing resistance as defined by Prostate Cancer Clinical Trials Working Group 3 guidelines. Patients with RECIST-measurable disease were enrolled in C4, and patients with bone-only or bone-predominant disease were enrolled in C5. All patients received pembrolizumab 200 mg every 3 weeks for ≤35 cycles with ongoing enzalutamide until progression, unacceptable toxicity, or withdrawal. The primary end point was objective response rate (ORR) per RECIST v1.1 by blinded independent central review in C4. Secondary end points included disease control rate (DCR), overall survival, and safety in each cohort and both cohorts combined. RESULTS: A total of 126 patients were treated (C4, n = 81; C5, n = 45). Median age was 72 years (range 43-92), and 87.3% had received ≥6 months of enzalutamide prior to study entry. Confirmed ORR was 12.3% (95% CI 6.1-21.5%) for C4. Median duration of response in C4 was 8.1 months (range, 2.5+ to 15.2), and 5 of these patients experienced an objective response lasting ≥6 months. DCR was 53.1% (95% CI 41.7-64.3%) in C4 and 51.1% (95% CI 35.8-66.3%) in C5. Median overall survival was 17.6 months (95% CI 14.0-22.6) in C4 and 20.8 months (95% CI 14.1-28.9) in C5. Grade ≥3 treatment-related adverse events occurred in 35 patients (27.8%); 2 patients in C4 died from immune-related adverse events (myasthenic syndrome and Guillain-Barré syndrome). CONCLUSIONS: The addition of pembrolizumab to ongoing enzalutamide treatment in patients with mCRPC that progressed on enzalutamide after initial response demonstrated modest antitumor activity with a manageable safety profile. CLINICAL TRIAL REGISTRY AND ID: ClinicalTrials.gov, NCT02787005.