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1.
Cancer Immunol Res ; 12(6): 704-718, 2024 Jun 04.
Artículo en Inglés | MEDLINE | ID: mdl-38552171

RESUMEN

The checkpoint immunotherapeutic pembrolizumab induces responses in a small minority of patients with metastatic castration-resistant prostate cancer (mCRPC). Radium-223 (R223) may increase immunogenicity of bone metastases and increase pembrolizumab (P) activity. In a randomized phase II study, we assessed the effect of R223+P compared with R223 on tumor immune infiltration, safety, and clinical outcomes in patients with mCRPC. The primary endpoint was differences in CD4+ and CD8+ T-cell infiltrate in 8-week versus baseline bone metastasis biopsies; secondary endpoints were safety, radiographic progression-free survival (rPFS), and overall survival (OS). Of the 42 treated patients (29 R223+P, 13 R223), 18 R223+P and 8 R223 patients had evaluable paired tumor biopsies. Median fold-change of CD4+ T cells was -0.7 (range: -9.3 to 4.7) with R223+P and 0.1 (-11.1 to 3.7) with R223 (P = 0.66); for CD8+ T cells, median fold-change was -0.6 (-7.4 to 5.3) with R223+P and -1.3 (-3.1 to 4.8) with R223 (P = 0.66). Median rPFS and OS was 6.1 (95% confidence interval: 2.7-11.0) and 16.9 months [12.7-not reached (NR)], respectively, with R223+P and 5.7 (2.6-NR) and 16.0 (9.0-NR), respectively, with R223. Although R223+P was well tolerated with no unexpected toxicity, the combination did not improve efficacy. High-dimensional flow cytometry demonstrated minimal immune modulation with R223, whereas R223+P induced CTLA-4 expression on circulating CD4+ T cells. Clinical responders possessed lower circulating frequencies of Ki67+ T and myeloid cells at baseline and higher circulating frequencies of TIM-3+ T and myeloid cells by week 9. Although R223+P did not induce T-cell infiltration into the tumor microenvironment, exhaustion of induced peripheral T-cell immune responses may dampen the combination's clinical activity.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Neoplasias de la Próstata Resistentes a la Castración , Radio (Elemento) , Humanos , Masculino , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/patología , Neoplasias de la Próstata Resistentes a la Castración/radioterapia , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anciano , Radio (Elemento)/uso terapéutico , Persona de Mediana Edad , Anciano de 80 o más Años , Neoplasias Óseas/secundario , Neoplasias Óseas/tratamiento farmacológico , Linfocitos T CD8-positivos/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos
2.
Cancer ; 130(9): 1629-1641, 2024 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-38161319

RESUMEN

BACKGROUND: Patients with localized, unfavorable intermediate-risk and high-risk prostate cancer have an increased risk of relapse after radical prostatectomy (RP). The authors previously reported on part 1 of this phase 2 trial testing neoadjuvant apalutamide, abiraterone, prednisone, plus leuprolide (AAPL) or abiraterone, prednisone, and leuprolide (APL) for 6 months followed by RP. The results demonstrated favorable pathologic responses (tumor <5 mm) in 20.3% of patients (n = 24 of 118). Herein, the authors report the results of part 2. METHODS: For part 2, patients were randomized 1:1 to receive either AAPL for 12 months (arm 2A) or observation (arm 2B), stratified by neoadjuvant therapy and pathologic tumor classification. The primary end point was 3-year biochemical progression-free survival. Secondary end points included safety and testosterone recovery (>200 ng/dL). RESULTS: Overall, 82 of 118 patients (69%) enrolled in part 1 were randomized to part 2. A higher proportion of patients who were not randomized to adjuvant therapy had a favorable prostatectomy pathologic response (32.3% in nonrandomized patients compared with 17.1% in randomized patients). In the intent-to-treat analysis, the 3-year biochemical progression-free survival rate was 81% for arm 2A and 72% for arm 2B (hazard ratio, 0.81; 90% confidence interval, 0.43-1.49). Of the randomized patients, 81% had testosterone recovery in the AAPL group compared with 95% in the observation group, with a median time to recovery of <12 months in both arms. CONCLUSIONS: In this study, because 30% of patients declined adjuvant treatment, part B was underpowered to detect differences between arms. Future perioperative studies should be biomarker-directed and include strategies for investigator and patient engagement to ensure compliance with protocol procedures.


Asunto(s)
Antígeno Prostático Específico , Neoplasias de la Próstata , Masculino , Humanos , Leuprolida/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía , Neoplasias de la Próstata/diagnóstico , Antagonistas de Andrógenos/efectos adversos , Andrógenos , Prednisona , Resultado del Tratamiento , Recurrencia Local de Neoplasia/cirugía , Prostatectomía/métodos , Testosterona
3.
Clin Cancer Res ; 27(13): 3610-3619, 2021 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-33849963

RESUMEN

PURPOSE: Enzalutamide is a second-generation androgen receptor (AR) inhibitor that has improved overall survival (OS) in metastatic castration-resistant prostate cancer (CRPC). However, nearly all patients develop resistance. We designed a phase II multicenter study of enzalutamide in metastatic CRPC incorporating tissue and blood biomarkers to dissect mechanisms driving resistance. PATIENTS AND METHODS: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy and then initiated enzalutamide 160 mg daily. A repeat metastasis biopsy was obtained at radiographic progression from the same site when possible. Blood for circulating tumor cell (CTC) analysis was collected at baseline and progression. The primary objective was to analyze mechanisms of resistance in serial biopsies. Whole-exome sequencing was performed on tissue biopsies. CTC samples underwent RNA sequencing. RESULTS: A total of 65 patients initiated treatment, of whom 22 (33.8%) had received prior abiraterone. Baseline biopsies were enriched for alterations in AR (mutations, amplifications) and tumor suppression genes (PTEN, RB1, and TP53), which were observed in 73.1% and 92.3% of baseline biopsies, respectively. Progression biopsies revealed increased AR amplifications (64.7% at progression vs. 53.9% at baseline) and BRCA2 alterations (64.7% at progression vs. 38.5% at baseline). Genomic analysis of baseline and progression CTC samples demonstrated increased AR splice variants, AR-regulated genes, and neuroendocrine markers at progression. CONCLUSIONS: Our results demonstrate that a large proportion of enzalutamide-treated patients have baseline and progression alterations in the AR pathway and tumor suppressor genes. We demonstrate an increased number of BRCA2 alterations post-enzalutamide, highlighting the importance of serial tumor sampling in CRPC.


Asunto(s)
Benzamidas/uso terapéutico , Resistencia a Antineoplásicos/fisiología , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Humanos , Masculino , Metástasis de la Neoplasia , Estudios Prospectivos , Neoplasias de la Próstata Resistentes a la Castración/patología
4.
J Urol ; 206(1): 80-87, 2021 07.
Artículo en Inglés | MEDLINE | ID: mdl-33683939

RESUMEN

PURPOSE: This multicenter randomized phase 2 trial investigates the impact of intense androgen deprivation on radical prostatectomy pathologic response and radiographic and tissue biomarkers in localized prostate cancer (NCT02903368). MATERIALS AND METHODS: Eligible patients had a Gleason score ≥4+3=7, prostate specific antigen >20 ng/mL or T3 disease and lymph nodes <20 mm. In Part 1, patients were randomized 1:1 to apalutamide, abiraterone acetate, prednisone and leuprolide (AAPL) or abiraterone, prednisone, leuprolide (APL) for 6 cycles (1 cycle=28 days) followed by radical prostatectomy. Surgical specimens underwent central review. The primary end point was the rate of pathologic complete response or minimum residual disease (minimum residual disease, tumor ≤5 mm). Secondary end points included prostate specific antigen response, positive margin rate and safety. Magnetic resonance imaging and tissue biomarkers of pathologic outcomes were explored. RESULTS: The study enrolled 118 patients at 4 sites. Median age was 61 years and 94% of patients had high-risk disease. The combined pathologic complete response or minimum residual disease rate was 22% in the AAPL arm and 20% in the APL arm (difference: 1.5%; 1-sided 95% CI -11%, 14%; 1-sided p=0.4). No new safety signals were observed. There was low concordance and correlation between posttherapy magnetic resonance imaging assessed and pathologically assessed tumor volume. PTEN-loss, ERG positivity and presence of intraductal carcinoma were associated with extensive residual tumor. CONCLUSIONS: Intense neoadjuvant hormone therapy in high-risk prostate cancer resulted in favorable pathologic responses (tumor <5 mm) in 21% of patients. Pathologic responses were similar between treatment arms. Part 2 of this study will investigate the impact of adjuvant hormone therapy on biochemical recurrence.


Asunto(s)
Acetato de Abiraterona/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Antineoplásicos/uso terapéutico , Leuprolida/uso terapéutico , Prednisona/uso terapéutico , Prostatectomía , Neoplasias de la Próstata/cirugía , Tiohidantoínas/uso terapéutico , Anciano , Terapia Combinada , Quimioterapia Combinada , Humanos , Masculino , Persona de Mediana Edad , Periodo Preoperatorio , Neoplasias de la Próstata/patología , Medición de Riesgo , Resultado del Tratamiento
5.
Int J Radiat Oncol Biol Phys ; 110(5): 1416-1422, 2021 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-33636278

RESUMEN

PURPOSE: Androgen deprivation therapy (ADT) is often used as adjuvant treatment with radiation therapy (RT) for intermediate-risk prostate cancer. ADT is associated with multiple side effects, including weight gain, loss of libido, and hot flashes. In contrast, antiandrogen monotherapy has been generally better tolerated. This study aimed to assess the effectiveness of enzalutamide (an antiandrogen) monotherapy with RT for the treatment of intermediate-risk prostate cancer. METHODS AND MATERIALS: This trial was an open-label, phase 2 study of 6 months of enzalutamide monotherapy with external beam RT for intermediate-risk prostate cancer. Enzalutamide was initiated 2 months before external beam RT. The primary endpoint was prostate-specific antigen (PSA) response measured at the end of enzalutamide administration at the 6-month timepoint. Secondary endpoints included assessment of toxicity and changes in anthropomorphic body measurement, sexual function, and metabolism. The sample size was 64 patients. The hypothesis was that if ≥60% of the patients did not achieve a PSA nadir of ≤0.2 ng/mL, the study results would be deemed negative. RESULTS: The results met the prespecified endpoint for efficacy in that PSA values ≤0.2 ng/mL were observed in 49 of 64 patients (77%), and 60 of 64 patients (94%) had PSA values ≤0.5ng/mL. The most frequent adverse events were hypertension and gynecomastia. There were no changes in anthropomorphic body measurements and only modest erectile dysfunction. CONCLUSIONS: Using PSA response as an endpoint, enzalutamide monotherapy may be as effective as ADT in combination with external beam RT for patients with intermediate-risk prostate cancer, and it is associated with fewer side effects. Randomized trials comparing enzalutamide with ADT are justified.


Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Benzamidas/uso terapéutico , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/radioterapia , Antagonistas de Andrógenos/efectos adversos , Andrógenos/sangre , Benzamidas/efectos adversos , Composición Corporal/efectos de los fármacos , Distribución de la Grasa Corporal , Ginecomastia/inducido químicamente , Humanos , Hipertensión/inducido químicamente , Masculino , Nitrilos/efectos adversos , Feniltiohidantoína/efectos adversos , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Riesgo , Testosterona/sangre , Factores de Tiempo
6.
J Urol ; 205(6): 1689-1697, 2021 06.
Artículo en Inglés | MEDLINE | ID: mdl-33502237

RESUMEN

PURPOSE: We report on the post-radical prostatectomy outcomes of patients enrolled in 3 randomized, multicenter, clinical trials of intense neoadjuvant androgen deprivation therapy prior radical prostatectomy. MATERIALS AND METHODS: All patients included were enrolled in trials evaluating intense androgen deprivation therapy followed by radical prostatectomy. The primary end point was time to biochemical recurrence, defined as the time from radical prostatectomy to prostate specific antigen >0.1 ng/ml or start of first post-radical prostatectomy therapy, stratified by pathological response at radical prostatectomy (presence or absence of exceptional pathological response defined as residual tumor at radical prostatectomy measuring 0-5 mm). Secondary end points included metastasis-free survival, overall survival, and time to testosterone recovery. RESULTS: Overall, 117 patients were included in the analysis, of whom 78.6% (92) had high risk disease. Following neoadjuvant therapy, 21.4% (25) had 0-5 mm of residual tumor, including 9.4% (11) with a pathological complete response. Overall, 49 patients (41.9%) experienced biochemical recurrence and the 3-year biochemical recurrence-free rate was 59.1% (95% CI 49.0-67.9). Of the 25 patients with an exceptional pathological response, 2 patients (8.0%) developed biochemical recurrence while 51.1% of nonresponders (47/92) developed biochemical recurrence. Testosterone recovery was observed in 93.8% of patients (106/113). PTEN loss and intraductal carcinoma were associated with shorter time to biochemical recurrence. CONCLUSIONS: In this pooled analysis of prospective trials, we demonstrate that exceptional pathological response following neoadjuvant therapy is associated with a favorable impact on biochemical recurrence. PTEN loss and intraductal carcinoma were associated with biochemical recurrence. Additional followup is warranted to evaluate the impact on long-term outcomes.


Asunto(s)
Androstenos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Benzamidas/uso terapéutico , Nitrilos/uso terapéutico , Feniltiohidantoína/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/cirugía , Anciano , Método Doble Ciego , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Estudios Prospectivos , Neoplasias de la Próstata/patología , Medición de Riesgo , Resultado del Tratamiento
7.
Cancer ; 127(6): 840-849, 2021 03 15.
Artículo en Inglés | MEDLINE | ID: mdl-33216356

RESUMEN

BACKGROUND: In this multicenter, single-arm, multicohort, phase 2 trial, the efficacy of nivolumab and ipilimumab was evaluated in patients with advanced rare genitourinary cancers, including bladder and upper tract carcinoma of variant histology (BUTCVH), adrenal tumors, platinum-refractory germ cell tumors, penile carcinoma, and prostate cancer of variant histology (NCT03333616). METHODS: Patients with rare genitourinary malignancies and no prior immune checkpoint inhibitor exposure were enrolled. Patients received nivolumab at 3 mg/kg and ipilimumab at 1 mg/kg intravenously every 3 weeks for 4 doses, and this was followed by 480 mg of nivolumab intravenously every 4 weeks. The primary endpoint was the objective response rate (ORR) by the Response Evaluation Criteria in Solid Tumors (version 1.1). RESULTS: Fifty-five patients were enrolled at 6 institutions between April 2018 and July 2019 in 3 cohorts: BUTCVH (n = 19), adrenal tumors (n = 18), and other tumors (n = 18). The median follow-up was 9.9 months (range, 1 to 21 months). Twenty-eight patients (51%) received 4 doses of nivolumab and ipilimumab; 25 patients received nivolumab maintenance for a median of 4 cycles (range, 1-18 cycles). The ORR for the entire study was 16% (80% confidence interval, 10%-25%); the ORR in the BUTCVH cohort, including 2 complete responses, was 37%, and it was 6% in the other 2 cohorts. Twenty-two patients (40%) developed treatment-related grade 3 or higher toxicities; 24% (n = 13) required high-dose steroids (≥40 mg of prednisone or the equivalent). Grade 5 events occurred in 3 patients; 1 death was treatment related. CONCLUSIONS: Nivolumab and ipilimumab resulted in objective responses in a subset of patients with rare genitourinary malignancies, especially those with BUTCVH. An additional cohort exploring their activity in genitourinary tumors with neuroendocrine differentiation is ongoing. LAY SUMMARY: Patients with rare cancers are often excluded from studies and have limited treatment options. Fifty-five patients with rare tumors of the genitourinary system were enrolled from multiple sites and were treated with nivolumab and ipilimumab, a regimen used for kidney cancer. The regimen showed activity in some patients, particularly those with bladder or upper tract cancers of unusual or variant histology; 37% of those patients responded to therapy. Additional studies are ongoing to better determine who benefits the most from this combination.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ipilimumab/administración & dosificación , Nivolumab/administración & dosificación , Neoplasias Urogenitales/tratamiento farmacológico , Femenino , Humanos , Ipilimumab/efectos adversos , Masculino , Persona de Mediana Edad , Nivolumab/efectos adversos , Enfermedades Raras , Neoplasias Urogenitales/mortalidad
8.
J Clin Invest ; 130(6): 3287-3298, 2020 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-32478682

RESUMEN

Despite widespread use of taxanes, mechanisms of action and resistance in vivo remain to be established, and there is no way of predicting who will respond to therapy. This study examined prostate cancer (PCa) xenografts and patient samples to identify in vivo mechanisms of taxane action and resistance. Docetaxel drug-target engagement was assessed by confocal anti-tubulin immunofluorescence to quantify microtubule bundling in interphase cells and aberrant mitoses. Tumor biopsies from metastatic PCa patients obtained 2 to 5 days after their first dose of docetaxel or cabazitaxel were processed to assess microtubule bundling, which correlated with clinical response. Microtubule bundling was evident in PCa xenografts 2 to 3 days after docetaxel treatment but was decreased or lost with acquired resistance. Biopsies after treatment with leuprolide plus docetaxel showed extensive microtubule bundling as did biopsies obtained 2 to 3 days after initiation of docetaxel or cabazitaxel in 2 patients with castration-resistant PCa with clinical responses. In contrast, microtubule bundling in biopsies 2 to 3 days after the first dose of docetaxel was markedly lower in 4 nonresponding patients. These findings indicate that taxanes target both mitotic and interphase cells in vivo and that resistance is through mechanisms that impair drug-target engagement. Moreover, the findings suggest that microtubule bundling after initial taxane treatment may be a predictive biomarker for clinical response.


Asunto(s)
Hidrocarburos Aromáticos con Puentes , Resistencia a Antineoplásicos , Microtúbulos/metabolismo , Neoplasias de la Próstata/metabolismo , Taxoides , Animales , Hidrocarburos Aromáticos con Puentes/farmacocinética , Hidrocarburos Aromáticos con Puentes/farmacología , Línea Celular Tumoral , Docetaxel/farmacocinética , Docetaxel/farmacología , Humanos , Masculino , Ratones , Ratones Desnudos , Microtúbulos/patología , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/patología , Taxoides/farmacocinética , Taxoides/farmacología
9.
Artículo en Inglés | MEDLINE | ID: mdl-31528835

RESUMEN

PURPOSE: Despite decreased screening-based detection of clinically insignificant tumors, most diagnosed prostate cancers are still indolent, indicating a need for better strategies for detection of clinically significant disease before treatment. We hypothesized that patients with detectable circulating tumor DNA (ctDNA) were more likely to harbor aggressive disease. METHODS: We applied ultra-low-pass whole-genome sequencing to profile cell-free DNA from 112 patients diagnosed with localized prostate cancer and performed targeted resequencing of plasma DNA for somatic mutations previously identified in matched solid tumor in nine cases. We also performed similar analyses of data from patients with metastatic prostate cancer. RESULTS: In all cases of localized prostate cancer, even in clinically high-risk patients who subsequently had recurrent disease, ultra-low-pass whole-genome sequencing and targeted resequencing did not detect ctDNA in plasma acquired before surgery or before recurrence. In contrast, using both approaches, ctDNA was detected in patients with metastatic prostate cancer. CONCLUSION: Our findings demonstrate clear differences between localized and advanced prostate cancer with respect to the dissemination and detectability of ctDNA. Because allele-specific alterations in ctDNA are below the threshold for detection in localized prostate cancer, other approaches to identify cell-free nucleic acids of tumor origin may demonstrate better specificity for aggressive disease.

11.
J Clin Oncol ; 37(11): 923-931, 2019 04 10.
Artículo en Inglés | MEDLINE | ID: mdl-30811282

RESUMEN

PURPOSE: Patients with locally advanced prostate cancer have an increased risk of cancer recurrence and mortality. In this phase II trial, we evaluate neoadjuvant enzalutamide and leuprolide (EL) with or without abiraterone and prednisone (ELAP) before radical prostatectomy (RP) in men with locally advanced prostate cancer. PATIENTS AND METHODS: Eligible patients had a biopsy Gleason score of 4 + 3 = 7 or greater, prostate-specific antigen (PSA) greater than 20 ng/mL, or T3 disease (by prostate magnetic resonance imaging). Lymph nodes were required to be smaller than 20 mm. Patients were randomly assigned 2:1 to ELAP or EL for 24 weeks followed by RP. All specimens underwent central pathology review. The primary end point was pathologic complete response or minimal residual disease (residual tumor ≤ 5 mm). Secondary end points were PSA, surgical staging, positive margins, and safety. Biomarkers associated with pathologic outcomes were explored. RESULTS: Seventy-five patients were enrolled at four centers. Most patients had high-risk disease by National Comprehensive Cancer Network criteria (n = 65; 87%). The pathologic complete response or minimal residual disease rate was 30% (n = 15 of 50) in ELAP-treated patients and 16% (n = four of 25) in EL-treated patients (two-sided P = .263). Rates of ypT3 disease, positive margins, and positive lymph nodes were similar between arms. Treatment was well-tolerated. Residual tumors in the two arms showed comparable levels of ERG, PTEN, androgen receptor PSA, and glucocorticoid receptor expression. Tumor ERG positivity and PTEN loss were associated with more extensive residual tumors at RP. CONCLUSION: Neoadjuvant hormone therapy followed by RP in locally advanced prostate cancer resulted in favorable pathologic responses in some patients, with a trend toward improved pathologic outcomes with ELAP. Longer follow-up is necessary to evaluate the impact of therapy on recurrence rates. The potential association of ERG and PTEN alterations with worse outcomes warrants additional investigation.


Asunto(s)
Adenocarcinoma/terapia , Antagonistas de Andrógenos/administración & dosificación , Androstenos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Leuprolida/administración & dosificación , Terapia Neoadyuvante , Feniltiohidantoína/análogos & derivados , Prostatectomía , Neoplasias de la Próstata/terapia , Adenocarcinoma/sangre , Adenocarcinoma/diagnóstico , Adulto , Anciano , Antagonistas de Andrógenos/efectos adversos , Androstenos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas , Quimioterapia Adyuvante , Humanos , Calicreínas/sangre , Leuprolida/efectos adversos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Clasificación del Tumor , Neoplasia Residual , Nitrilos , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/efectos adversos , Prednisona/administración & dosificación , Antígeno Prostático Específico/sangre , Prostatectomía/efectos adversos , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/diagnóstico , Factores de Tiempo , Resultado del Tratamiento , Estados Unidos
12.
Cancer Res ; 78(16): 4716-4730, 2018 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-29921690

RESUMEN

Primary prostate cancer can have extensive microheterogeneity, but its contribution to the later emergence of metastatic castration-resistant prostate cancer (mCRPC) remains unclear. In this study, we microdissected residual prostate cancer foci in radical prostatectomies from 18 men treated with neoadjuvant-intensive androgen deprivation therapy (leuprolide, abiraterone acetate, and prednisone) and analyzed them for resistance mechanisms. Transcriptome profiling showed reduced but persistent androgen receptor (AR) activity in residual tumors, with no increase in neuroendocrine differentiation. Proliferation correlated negatively with AR activity but positively with decreased RB1 expression, and whole-exome sequencing (WES) further showed enrichment for RB1 genomic loss. In 15 cases where 2 or 3 tumor foci were microdissected, WES confirmed a common clonal origin but identified multiple oncogenic alterations unique to each focus. These findings show that subclones with oncogenic alterations found in mCRPC are present in primary prostate cancer and are selected for by neoadjuvant-intense androgen deprivation therapy. In particular, this study indicates that subclonal RB1 loss may be more common than previously appreciated in intermediate- to high-risk primary prostate cancer and may be an early event, independent of neuroendocrine differentiation, in the development of mCRPC. Comprehensive molecular analyses of primary prostate cancer may detect aggressive subclones and possibly inform adjuvant strategies to prevent recurrence.Significance: Neoadjuvant androgen deprivation therapy for prostate cancer selects for tumor foci with subclonal genomic alterations, which may comprise the origin of metastatic castration-resistant prostate cancer. Cancer Res; 78(16); 4716-30. ©2018 AACR.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Resistencia a Antineoplásicos/genética , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Acetato de Abiraterona/administración & dosificación , Anciano , Antagonistas de Andrógenos/administración & dosificación , Hidrocarburo de Aril Hidroxilasas/genética , Biomarcadores de Tumor , Carcinogénesis , Evolución Clonal , Familia 2 del Citocromo P450/genética , Humanos , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Prostatectomía , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Receptores Androgénicos/genética , Esteroide 16-alfa-Hidroxilasa/genética
13.
Prostate Cancer Prostatic Dis ; 21(3): 364-372, 2018 09.
Artículo en Inglés | MEDLINE | ID: mdl-29263420

RESUMEN

BACKGROUND: Patients with high-risk prostate cancer have an increased likelihood of experiencing a relapse following radical prostatectomy (RP). We previously conducted three neoadjuvant androgen-deprivation therapy (ADT) trials prior to RP in unfavorable intermediate and high-risk disease. METHODS: In this analysis, we report on the post-RP outcomes of a subset of patients enrolled on these studies. We conducted a pooled analysis of patients with available follow-up data treated on three neoadjuvant trials at three institutions. All patients received intense ADT prior to RP. The primary endpoint was time to biochemical recurrence (BCR). BCR was defined as a PSA ≥ 0.2 ng/mL or treatment with radiation or androgen-deprivation therapy for a rising PSA < 0.2 ng/mL. RESULTS: Overall, 72 patients were included of whom the majority had a Gleason score ≥ 8 (n = 46, 63.9%). Following neoadjuvant therapy, 55.7% of patients (n = 39/70) had pT3 disease, 40% (n = 28) had seminal vesicle invasion, 12.9% (n = 9) had positive margins, and 11.4% (n = 8) had lymph node involvement. Overall, 11 (15.7%) had tumor measuring ≤ 0.5 cm, which included four patients (5.7%) with a pathologic complete response and seven (10.0%) with residual tumor measuring 0.1-0.5 cm. Compared to pretreatment clinical staging, 10 patients (14.3%) had pathologic T downstaging at RP. The median follow-up was 3.4 years. Overall, the 3-year BCR-free rate was 70% (95% CI 57%, 90%). Of the 15 patients with either residual tumor ≤ 0.5 cm or pathologic T downstaging, no patient experienced a recurrence. CONCLUSION: In this exploratory pooled clinical trials analysis, we highlight that neoadjuvant therapy prior to RP in unfavorable intermediate and high-risk patients may potentially have a positive impact on recurrence rates. Larger studies with longer follow-up periods are warranted to evaluate the impact of neoadjuvant hormone therapy on pathologic and long-term outcomes.


Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Calicreínas/sangre , Terapia Neoadyuvante/métodos , Recurrencia Local de Neoplasia/epidemiología , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata/terapia , Anciano , Supervivencia sin Enfermedad , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Recurrencia Local de Neoplasia/sangre , Recurrencia Local de Neoplasia/prevención & control , Estadificación de Neoplasias , Próstata/patología , Próstata/cirugía , Prostatectomía , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento
14.
Clin Cancer Res ; 24(2): 306-315, 2018 01 15.
Artículo en Inglés | MEDLINE | ID: mdl-29113986

RESUMEN

Purpose: MuscadinePlus (MPX), a commercial preparation of pulverized muscadine grape skin, was evaluated as a therapeutic option for men with biochemically recurrent (BCR) prostate cancer wishing to defer androgen deprivation therapy.Experimental Design: This was a 12-month, multicenter, placebo-controlled, two-dose, double-blinded trial of MPX in 125 men with BCR prostate cancer, powered to detect a PSA doubling time (PSADT) difference of 6 months (low dose) and 12 months (high dose) relative to placebo. Participants were stratified (baseline PSADT, Gleason score) and randomly assigned 1:2:2 to receive placebo, 500 mg MPX (low), or 4,000 mg MPX (high) daily. Correlates included superoxide dismutase-2 (SOD2) genotype, lipid peroxidation, and polyphenol pharmacokinetics.Results: The evaluable population included 112 patients, all treated for at least 6 months and 62% treated for 12 months. No significant difference was found in PSADT change between control and treatment arms (P = 0.81): control 0.9 months (n = 20; range, 6.7-83.1), low dose 1.5 months (n = 52; range, 10.3-87.2), high dose 0.9 months (n = 40; range, 27.3-88.1). One high-dose patient experienced objective response. No drug-related CTCAE grade 3-4 adverse events were seen. In a preplanned exploratory analysis, PSADT pre-to-post increase was significant in the 27 (26%) genotyped patients with SOD2 Alanine/Alanine genotype (rs4880 T>C polymorphism) on MPX (pooled treatment arms; 6.4 months, P = 0.02), but not in control (1.8 months, P = 0.25).Conclusions: Compared with placebo, MPX did not significantly prolong PSADT in BCR patients over two different doses. Exploratory analysis revealed a patient population with potential benefit that would require further study. Clin Cancer Res; 24(2); 306-15. ©2017 AACR.


Asunto(s)
Extractos Vegetales/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Vitis/química , Anciano , Anciano de 80 o más Años , Biomarcadores , Estudios de Casos y Controles , Genotipo , Humanos , Peroxidación de Lípido/efectos de los fármacos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Extractos Vegetales/química , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/metabolismo , Neoplasias de la Próstata/patología , Recurrencia , Superóxido Dismutasa/genética
15.
Clin Cancer Res ; 23(22): 6812-6822, 2017 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-28893901

RESUMEN

Purpose: Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer, with poor immunogenicity and subsequent low PD-L1 expression in prostate cancer being proposed as an explanation. However, recent studies indicate that a subset of prostate cancer may express significant levels of PD-L1. Furthermore, the androgen antagonist enzalutamide has been shown to upregulate PD-L1 expression in prostate cancer preclinical models. In this study, we evaluated the effect of neoadjuvant androgen deprivation therapy with abiraterone acetate plus prednisone and leuprolide (Neo-AAPL) on PD-L1 expression in prostate cancer.Experimental Design: Radical prostatectomy (RP) tissues were collected from 44 patients with intermediate- to high-risk prostate cancer who underwent RP after Neo-AAPL treatment. Untreated prostate cancer tissues were collected from 130 patients, including 44 matched controls for the Neo-AAPL cases. Tumor PD-L1 expression was detected by IHC using validated anti-PD-L1 antibodies. Tumor-infiltrating CD8+ cells were analyzed in trial cases and matched controls. Expression of DNA mismatch repair genes was examined in PD-L1-positive tumors.Results: Neo-AAPL-treated tumors showed a trend toward decreased PD-L1 positivity compared with matched controls (7% vs. 21% having ≥1% positive tumor cells; P = 0.062). Treated tumors also harbored significantly fewer tumor-infiltrating CD8+ cells (P = 0.029). In 130 untreated prostate cancers, African American ethnicity, elevated serum PSA, and small prostate independently predicted tumor PD-L1 positivity. Loss of MSH2 expression was observed in 1 of 21 PD-L1-positive tumors.Conclusions: A subset of prostate cancer expresses PD-L1, which is not increased by Neo-AAPL treatment, indicating that combining Neo-AAPL treatment with PD-L1/PD-1 blockade may not be synergistic. Clin Cancer Res; 23(22); 6812-22. ©2017 AACR.


Asunto(s)
Antígeno B7-H1/metabolismo , Neoplasias de la Próstata/metabolismo , Acetato de Abiraterona/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Antígeno B7-H1/genética , Reparación de la Incompatibilidad de ADN , Expresión Génica , Humanos , Inmunohistoquímica , Leuprolida/administración & dosificación , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Masculino , Terapia Neoadyuvante , Clasificación del Tumor , Estadificación de Neoplasias , Prednisona/administración & dosificación , Neoplasias de la Próstata/diagnóstico , Neoplasias de la Próstata/tratamiento farmacológico , Neoplasias de la Próstata/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
17.
Clin Cancer Res ; 23(9): 2169-2176, 2017 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-28151719

RESUMEN

Purpose: Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride (dut) and leuprolide (enza/dut/luteinizing hormone-releasing hormone analogues [LHRHa]).Experimental Design: Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enzalutamide or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of PSA and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa.Results: In the enzalutamide arm, none of the 25 patients achieved pCR or MRD. In the enza/dut/LHRHa arm, one of 23 patients (4.3%) achieved pCR and 3 of 23 (13.0%) achieved MRD. Median RCB was higher in the enzalutamide arm than in the enza/dut/LHRHa arm (0.41 cm3 vs. 0.06 cm3, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported.Conclusions: Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable with historical controls. Evidence of continued AR activity in residual tumor suggests that AR signaling may contribute to survival. Strategies to more effectively ablate AR activity are warranted to determine whether more substantial antitumor effects are observed. Clin Cancer Res; 23(9); 2169-76. ©2016 AACR.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Feniltiohidantoína/análogos & derivados , Neoplasias de la Próstata/tratamiento farmacológico , Receptores Androgénicos/genética , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Benzamidas , Terapia Combinada , Dutasterida/administración & dosificación , Humanos , Leuprolida/administración & dosificación , Masculino , Persona de Mediana Edad , Terapia Neoadyuvante/efectos adversos , Neoplasia Residual/sangre , Neoplasia Residual/inducido químicamente , Neoplasia Residual/patología , Nitrilos , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/efectos adversos , Antígeno Prostático Específico/sangre , Prostatectomía , Neoplasias de la Próstata/sangre , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/cirugía
18.
Clin Cancer Res ; 23(14): 3823-3833, 2017 Jul 15.
Artículo en Inglés | MEDLINE | ID: mdl-28119368

RESUMEN

Purpose: The molecular features that account for the distinct histology and aggressive biological behavior of Gleason pattern 4 (Gp4) versus Gp3 prostate cancer, and whether Gp3 tumors progress directly to Gp4, remain to be established.Experimental Design: Whole-exome sequencing and transcriptome profiling of laser capture-microdissected adjacent Gp3 and cribiform Gp4 were used to determine the relationship between these entities.Results: Sequencing confirmed that adjacent Gp3 and Gp4 were clonal based on multiple shared genomic alterations. However, large numbers of unique mutations in the Gp3 and Gp4 tumors showed that the Gp4 were not derived directly from the Gp3. Remarkably, the Gp3 tumors retain their indolent-appearing morphology despite acquisition of multiple genomic alterations, including tumor suppressor losses. Although there were no consistent genomic alterations that distinguished Gp3 from Gp4, pairwise transcriptome analyses identified increased c-Myc and decreased p53 activity in Gp4 versus adjacent clonal Gp3 foci.Conclusions: These findings establish that at least a subset of Gp3 and aggressive Gp4 tumors have a common origin, and support a branched evolution model wherein the Gp3 and Gp4 tumors emerge early from a common precursor and subsequently undergo substantial divergence. Genomic alterations detectable in the Gp3 may distinguish these tumors from truly indolent Gp3. Screening for a panel of these genomic alterations in men who have prostate biopsies showing only Gp3 (Gleason score 6, Gs6) may allow for more precise selection of men who can be safely managed by active surveillance versus those who may benefit from further intervention. Clin Cancer Res; 23(14); 3823-33. ©2017 AACR.


Asunto(s)
Secuenciación del Exoma , Proteínas de Neoplasias/genética , Neoplasias de la Próstata/genética , Transcriptoma/genética , Adulto , Anciano , Biopsia , Regulación Neoplásica de la Expresión Génica , Genoma Humano/genética , Humanos , Captura por Microdisección con Láser , Masculino , Persona de Mediana Edad , Mutación , Clasificación del Tumor , Próstata/patología , Neoplasias de la Próstata/clasificación , Neoplasias de la Próstata/patología , Proteína p53 Supresora de Tumor/genética
19.
Clin Cancer Res ; 23(4): 935-945, 2017 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-27683182

RESUMEN

Purpose: Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride.Experimental Design: Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this time, high-dose dutasteride (3.5 mg daily) was added. Patients continued therapy until study withdrawal or radiographic progression. Repeat metastasis biopsy was obtained at progression. The primary endpoint was to assess mechanisms of resistance. Serum hormone and abiraterone levels were assessed. Tissue was assessed for androgen receptor (AR) and AR splice variant-7 (ARV7) expression.Results: Forty patients were enrolled. Sixty percent (n = 24) achieved a ≥50% reduction in prostate-specific antigen (PSA). The median time to radiographic progression was 11 months. Nearly all baseline (n = 29 of 31) and posttreatment (n = 16 of 16) tumors tested for AR nuclear expression were positive. Of those tested, ARV7 expression was present in 48% (n = 10 of 21) of baseline and 42% (n = 5 of 12) of treatment discontinuation specimens. Compared with patients with higher serum abiraterone levels at treatment discontinuation, patients with lower levels had higher circulating androgens.Conclusions: Despite increased androgen synthesis inhibition, we demonstrate that tumor AR axis remains important in disease progression. We highlight that abiraterone metabolism and pharmacokinetics may play a role in resistance. The noncomparative design limits conclusions on the efficacy of dual therapy with abiraterone and dutasteride, but the results support development of further multifaceted approaches toward AR inhibition. Clin Cancer Res; 23(4); 935-45. ©2016 AACR.


Asunto(s)
Androstenos/administración & dosificación , Dutasterida/administración & dosificación , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Receptores Androgénicos/genética , Anciano , Andrógenos/biosíntesis , Andrógenos/genética , Androstenos/sangre , Progresión de la Enfermedad , Resistencia a Antineoplásicos/genética , Humanos , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Neoplasias de la Próstata Resistentes a la Castración/diagnóstico por imagen , Neoplasias de la Próstata Resistentes a la Castración/genética , Neoplasias de la Próstata Resistentes a la Castración/patología , Radiografía
20.
Clin Genitourin Cancer ; 15(4): 463-471, 2017 08.
Artículo en Inglés | MEDLINE | ID: mdl-27890446

RESUMEN

BACKGROUND: Galeterone is a multi-targeted agent with activity as a CYP17 inhibitor, androgen receptor antagonist, and also causes androgen receptor degradation. It has shown meaningful anti-tumor activity with a well-tolerated safety profile in patients with castration-resistant prostate cancer (CRPC) in phase I and II studies; however, the efficacy of currently approved CRPC therapies after treatment with galeterone is unknown. In this study, we evaluate prostate specific antigen (PSA) response of non-protocol therapies following galeterone in a subset of patients treated on the Androgen Receptor Modulation Optimized for Response (ARMOR) 2 study. PATIENTS AND METHODS: Patients who received any subsequent treatment were included. PSA response and treatment duration were summarized by line and type of subsequent therapy. RESULTS: Overall, 27 of 40 patients received ≥ 1 post-galeterone treatment, of whom 18 (67%) discontinued galeterone for progression, 14 (52%) received ≥ 2 treatments, and 6 (22%) received ≥ 3 treatments. PSA changed by a median of -36%, -35%, and +60% in patients receiving first-line, second-line, and third-line therapy, respectively. Overall, 18 (67%) received subsequent enzalutamide, 12 (44%) received docetaxel, 9 (33%) received abiraterone, and 5 (19%) received cabazitaxel. PSA changed by a median of -27%, -34%, -39%, and 17% for patients receiving subsequent enzalutamide, docetaxel, abiraterone, and cabazitaxel, respectively, at any line. CONCLUSION: We demonstrate that CRPC therapies exhibit differential anti-tumor activity following galeterone. In this small cohort, abiraterone demonstrates the highest PSA response post-galeterone, whereas enzalutamide and chemotherapy have more modest activity. Larger clinical studies are warranted to fully evaluate the efficacy and safety of second-generation hormonal agents and chemotherapy post-galeterone. Predictive biomarkers will be critical to optimizing patient selection for sequential therapies.


Asunto(s)
Androstadienos/administración & dosificación , Androstenos/administración & dosificación , Bencimidazoles/administración & dosificación , Calicreínas/sangre , Antígeno Prostático Específico/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Anciano , Androstadienos/farmacología , Androstenos/farmacología , Benzamidas , Bencimidazoles/farmacología , Quimioterapia , Humanos , Calicreínas/efectos de los fármacos , Masculino , Persona de Mediana Edad , Nitrilos , Feniltiohidantoína/administración & dosificación , Feniltiohidantoína/análogos & derivados , Feniltiohidantoína/farmacología , Antígeno Prostático Específico/efectos de los fármacos , Neoplasias de la Próstata Resistentes a la Castración/sangre , Análisis de Supervivencia , Resultado del Tratamiento
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