Outcomes of prechemotherapy (pCHT) abiraterone (AA) or enzalutamide (E) for metastatic castration-resistant prostate cancer (mCRPC) after androgen deprivation therapy (ADT) + docetaxel (D) or ADT alone for metastatic hormone sensitive prostate cancer (mHSPC) in a hospital-based registry.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e16515-e16515
Author(s):  
Edoardo Francini ◽  
Kathryn P. Gray ◽  
Carolyn Evan ◽  
Marina D. Kaymakcalan ◽  
Grace Katherine Shaw ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
De Novo ◽  
Small Sample Size ◽  
Small Sample ◽  
Castration Resistant Prostate Cancer ◽  
Start Time ◽  
Time To Death ◽  
Castration Resistant ◽  
Kaplan Meier ◽  
Hormone Sensitive

e16515 Background: The E3805: CHAARTED trial noted use of D at time of commencing ADT for mHSPC was associated with an improvement in time to CRPC (PSA rise or clinical progression [CP]) or time to CP and resulted in a prolongation of overall survival (OS). Therefore, we postulated that pCHT AA or E maintained activity after ADT+D. Methods: A cohort of CRPC patients (pts) treated with pCHT AA or E for CRPC between 2010 and 2016 was selected from the Dana-Farber Cancer Institute IRB approved database. Patients were grouped by use of D and whether they had prior localized therapy (PLT) or de novo (DN) metastatic disease, at time of ADT start for mHSPC. The analysis endpoints included OS (time to death from all causes) from ADT start, time to AA/E start from ADT start, OS from AA/E start. Kaplan-Meier method estimated the time to events distribution with median (95% CI). Results: Of the 147 pts selected, 134 (91.2%) had previously received ADT alone, while 13 (8.8%) had ADT+D. Once stratified by PLT or DN, the distributions of the 4 groups are 33.3% (ADT/PLT), 57.8% (ADT/DN), 0.7% (ADT+D/PLT), and 8.2% (ADT+D/DN). In the ADT alone group, the median OS with pCHT AA or E for CRPC was approximately 3 years from the AA/E start, regardless of PLT or DN. In the smaller cohort of pts selected for treatment with ADT+D, both the OS from ADT start and from AA/E start were shorter than the ADT alone cohort. However, even in this group with shorter time to AA/E start, the median OS from AA/E start was still 1.5 years despite prior chemotherapy. Conclusions: Within limitations of a hospital-based registry, small sample size for ADT+D and lack of volume of metastases data, pts selected for ADT+D show poorer outcomes but still have an OS of 1.5 yrs from AA/E start. [Table: see text]

scholarly journals Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial

2020 ◽  
Author(s):  
Hiroji Uemura ◽  
Hisashi Matsushima ◽  
Kazuki Kobayashi ◽  
Hiroya Mizusawa ◽  
Hiroaki Nishimatsu ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Small Sample Size ◽  
Group Analysis ◽  
Specific Antigen ◽  
Japanese Patients ◽  
Small Sample ◽  
Phase Iii ◽  
Efficacy And Safety ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant

Abstract Background Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. Methods In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. Results In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11–0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. Conclusions Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

A phase III trial of capivasertib and abiraterone versus placebo and abiraterone in patients with de novo metastatic hormone-sensitive prostate cancer characterized by PTEN deficiency (CAPItello-281).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS178-TPS178
Author(s):  
Karim Fizazi ◽  
Daniel J. George ◽  
Maria De Santis ◽  
Noel Clarke ◽  
Andre P. Fay ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Radiographic Progression ◽  
De Novo ◽  
Castration Resistant Prostate Cancer ◽  
Akt Inhibitor ◽  
Phase 3 ◽  
Free Survival ◽  
Pten Loss ◽  
Castration Resistant ◽  
Hormone Sensitive

TPS178 Background: In metastatic hormone-sensitive prostate cancer (mHSPC), abiraterone combined with androgen deprivation therapy (ADT) is highly effective in improving patient outcomes. However, around 20% of patients progress to castration-resistant disease within 12 months of treatment; these patients have shorter survival and limited treatment options. Aberrant activation of the PI3K/AKT pathway, predominately due to PTEN loss, is common in prostate cancer, especially in later-stage disease. The androgen receptor signaling and AKT pathway are reciprocally cross-regulated such as that inhibition of one leads to upregulation of the other. Therefore, combining abiraterone therapy with AKT inhibition may be beneficial in patients with mHSPC who have PTEN deficiency. In preclinical studies, capivasertib, a selective oral pan-AKT inhibitor, inhibited proliferation of models of hormone-sensitive and castration-resistant prostate cancer with PTEN loss. The results of the IPATential150 phase 3 study (NCT03072238) demonstrated that another oral AKT inhibitor, ipatasertib, prolonged radiographic progression-free survival (rPFS) when combined with abiraterone compared with placebo plus abiraterone in metastatic castration-resistant prostate cancer, particularly among patients with PTEN loss. CAPItello-281 (NCT04493853) is a global, multicenter, phase 3 trial to evaluate capivasertib in combination with abiraterone, on a background of ADT, as a treatment for de novo mHSPC patients with PTEN-deficient tumors. Methods: Eligible patients for this double-blind, randomized trial are men aged 18 years or older with confirmed newly diagnosed previously untreated metastatic hormone-sensitive prostate adenocarcinoma with immunohistochemically confirmed PTEN deficiency and Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1. Following screening, approximately 1000 patients will be randomized 1:1 to receive either capivasertib (400 mg) or placebo (twice daily; 4 days on, 3 days off) in combination with abiraterone (1000 mg once daily) and ADT until radiographic progression or intolerable toxicity. The primary endpoint is rPFS. Secondary endpoints include overall survival, time to start of first subsequent therapy or death, symptomatic skeletal event-free survival, time to pain progression and safety profile. Enrolment started in July 2020. Acknowledgments: We thank Julia Grigorieva, PhD, of Oxford PharmaGenesis, Philadelphia, USA, for providing medical writing assistance. Funding: The CAPItello-281 trial is funded and overseen by AstraZeneca. Clinical trial information: NCT04493853.

scholarly journals Metasztatikus hormonérzékeny prosztatadaganat korszerű kezelése

2018 ◽  
Vol 159 (41) ◽  
pp. 1664-1671
Author(s):  
Zsófia Küronya ◽  
Krisztina Bíró ◽  
Lajos Géczi ◽  
Anikó Maráz
Keyword(s):  
Prostate Cancer ◽  
Metastatic Prostate Cancer ◽  
De Novo ◽  
Androgen Deprivation ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Radium 223 ◽  
Sensitive Phase ◽  
Hormone Sensitive ◽  
To Receive

Abstract: The treatment of metastatic prostate cancer can be divided into two pathophysiological phases: hormone-sensitive and castration-resistant phases. Huggins’ observation in the year 1941, which was awarded with the Nobel Prize in 1966, has a key role in treatment during the hormone-sensitive phase, stating that if the testicles are removed, the size of the prostate cancer decreases. Inducing androgen deprivation, i.e., testosterone depletion is the basic treatment of metastatic prostate cancer that patients have to receive life-long. In the past eight years, five new agents have been approved besides docetaxel in the treatment of metastatic castration-resistant prostate cancer: sipuleucel-T, cabazitaxel, abiraterone, enzalutamide, and radium-223. With the sequential application of these agents, significant improvement can be achieved in survival. Besides the latest developments, the hormone-sensitive phase has become the focus of attention, especially in the treatment of patients with de novo metastases and poor prognosis. Many studies have proven the outstanding efficacy of adding early docetaxel and abiraterone to androgen deprivation therapy. The authors give a detailed overview of clinical studies leading to a paradigm change in treatment during the hormone-sensitive phase, and call attention to the difficulties encountered in Hungarian practice. Orv Hetil. 2018; 159(41): 1664–1671.

CYP17A1 Polymorphisms and Clinical Outcome of Castration-Resistant Prostate Cancer Patients Treated with Abiraterone

2016 ◽  
Vol 31 (3) ◽  
pp. 264-269 ◽  
Author(s):  
Samanta Salvi ◽  
Valentina Casadio ◽  
Salvatore Luca Burgio ◽  
Vincenza Conteduca ◽  
Lorena Rossi ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Outcome ◽  
Small Sample Size ◽  
Progression Free Survival ◽  
Small Sample ◽  
Nucleotide Polymorphisms ◽  
Castration Resistant Prostate Cancer ◽  
Single Nucleotide ◽  
Castration Resistant

Background We evaluated the role of single nucleotide polymorphisms in the CYP17A1 gene for predicting clinical outcome in castration-resistant prostate cancer (CRPC) patients treated with abiraterone. Methods Sixty-four patients were genotyped for the selected polymorphisms (rs743572, rs10883783, rs17115100 and rs284849) in CYP17A1. We hypothesized that different genotypes could be associated with progression-free survival (PFS) and overall survival (OS). Results Statistical analyses highlighted no significant associations between these polymorphisms and clinical outcome. However, individuals with the most common TT genotype for rs10883783 had a 3 months’ longer PFS than individuals with the TA + AA genotype. Conclusions With the limitation of the retrospective study design and the small sample size, the analyzed polymorphisms do not seem to be correlated with clinical outcome of CRPC patients treated with abiraterone.

AR Copy Number and AR Signaling-directed Therapies in Castrationresistant Prostate Cancer

2018 ◽  
Vol 18 (9) ◽  
pp. 869-876
Author(s):  
Samanta Salvi ◽  
Vincenza Conteduca ◽  
Cristian Lolli ◽  
Sara Testoni ◽  
Valentina Casadio ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Copy Number ◽  
Clinical Trial Design ◽  
Complete Information ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Anti Cancer ◽  
Hormone Sensitive ◽  
Predictive And Prognostic Biomarker

Background: Adaptive upregulation of Androgen Receptor (AR) is the most common event involved in the progression from hormone sensitive to Castration-Resistant Prostate Cancer (CRPC). AR signaling remains the main target of new AR signalling-directed therapies such as abiraterone and enzalutamide in CRPC patients. Objective: In this review, we discuss general mechanisms of resistance to AR-targeted therapies, with a focus on the role of AR Copy Number (CN). We reported methods and clinical applications of AR CN evaluation in tissue and liquid biopsy, thus to have a complete information regarding its role as predictive and prognostic biomarker. Conclusion: Outcomes of CRPC patients are reported to be highly variable as the consequence of tumor heterogeneity. AR CN could contribute to patient selection and tumor monitoring in CRPC treated with new anti-cancer treatment as abiraterone and enzalutamide. Further studies to investigate AR CN effect to these agents and its potential combination with other prognostic or predictive clinical factors are necessary in the context of harmonized clinical trial design.

scholarly journals Three-month early change in prostate-specific antigen levels as a predictive marker for overall survival during hormonal therapy for metastatic hormone-sensitive prostate cancer

2021 ◽  
Author(s):  
Shotaro Nakanishi ◽  
Masato Goya ◽  
Mitsuyoshi Tamaki ◽  
Takuma Oshiro ◽  
Seiichi Saito
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Prostate Specific Antigen ◽  
Characteristic Curve ◽  
Specific Antigen ◽  
Predictive Marker ◽  
Castration Resistant Prostate Cancer ◽  
Pretreatment Level ◽  
Castration Resistant ◽  
Hormone Sensitive

Abstract Objective: To date, there are no useful markers for predicting the prognosis of metastatic hormone-sensitive prostate cancer (mHSPC). We evaluated the effect of early changes in prostate-specific antigen (PSA) levels after androgen deprivation therapy (ADT) on castration-resistant prostate cancer (CRPC) progression and overall survival (OS) in mHSPC patients. Results: In 71 primary mHSPC patients treated with ADT, the median times to CRPC and OS were 15 months and 92 months, respectively. In multivariate analysis, a Gleason score of ≥8 (p = 0.004), an extent of disease value (EOD) of ≥2 (p = 0.004), and a 3-month PSA level >1% of the pretreatment level (p = 0.017) were independent predictors of shorter time to CRPC. The area under the receiver operating characteristic curve was feasible at 0.822. For OS, a 3-month PSA level >1% of the pretreatment level was an independent predictor of time to CRPC (p = 0.004).Three factors were independent predictors of shorter time to CRPC. A 3-month PSA level >1% of the pretreatment level correlated with poor a prognosis.

scholarly journals Dietary Tomato or Lycopene Do Not Reduce Castration-Resistant Prostate Cancer Progression in a Murine Model

2020 ◽  
Vol 150 (7) ◽  
pp. 1808-1817
Author(s):  
Joe L Rowles ◽  
Joshua W Smith ◽  
Catherine C Applegate ◽  
Rita J Miller ◽  
Matthew A Wallig ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
De Novo ◽  
Control Diet ◽  
Tumor Detection ◽  
Castration Resistant Prostate Cancer ◽  
Tumor Weight ◽  
Castration Resistant ◽  
Mouse Prostate ◽  
Tomato Powder ◽  
Tramp Mice

ABSTRACT Background Dietary tomato products or lycopene protect against prostate carcinogenesis, but their impact on the emergence of castration-resistant prostate cancer (CRPC) is unknown. Objective We hypothesized that tomato or lycopene products would reduce the emergence of CRPC. Methods Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice were castrated at 12–13 wk and the emergence of CRPC was monitored by ultrasound in each study. In Study 1, TRAMP mice (n = 80) were weaned onto an AIN-93G-based control diet (Con-L, n = 28), a 10% tomato powder diet (TP-L, 10% lyophilized w/w, n = 26), or a control diet followed by a tomato powder diet after castration (TP-Int1, n = 26). In Study 2, TRAMP mice (n = 85) were randomized onto a control diet with placebo beadlets (Con-Int, n = 29), a tomato diet with placebo beadlets (TP-Int2, n = 29), or a control diet with lycopene beadlets (Lyc-Int, n = 27) following castration (aged 12 wk). Tumor incidence and growth were monitored by ultrasound beginning at an age of 10 wk. Mice were euthanized 4 wk after tumor detection or aged 30 wk if no tumor was detected. Tissue weights were compared by ANOVA followed by Dunnett's test. Tumor volumes were compared using generalized linear mixed model regression. Results Ultrasound estimates for the in vivo tumor volume were strongly correlated with tumor weight at necropsy (R2 = 0.75 and 0.94, P <0.001 for both Studies 1 and 2, respectively). Dietary treatments after castration did not significantly impact cancer incidence, time to tumor detection, or final tumor weight. Conclusions In contrast to studies of de novo carcinogenesis in multiple preclinical models, tomato components had no significant impact on the emergence of CRPC in the TRAMP model. It is possible that specific mutant subclones of prostate cancer may continue to show some antiproliferative response to tomato components, but further studies are needed to confirm this.

scholarly journals Prognostic Value of 18F-Choline PET/CT in Patients with Metastatic Castration-Resistant Prostate Cancer Treated with Radium-223

Biomedicines ◽  
2020 ◽  
Vol 8 (12) ◽  
pp. 555
Author(s):  
Luca Filippi ◽  
Gian Paolo Spinelli ◽  
Agostino Chiaravalloti ◽  
Orazio Schillaci ◽  
Francesco Equitani ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Emission Computed Tomography ◽  
Castration Resistant Prostate Cancer ◽  
Choline Pet ◽  
Castration Resistant ◽  
Kaplan Meier ◽  
Radium 223 ◽  
Standardized Uptake Values ◽  
Pet Ct ◽  
Clinical Records

We aimed to investigate the role of positron emission computed tomography (PET/CT) with 18F-choline for predicting the outcome of metastatic castration-resistant prostate cancer (mCRPC) submitted to treatment with Radium-223 (223Ra-therapy). Clinical records of 20 mCRPC patients submitted to PET/CT with 18F-choline before 223Ra-therapy were retrospectively evaluated. The following PET-derived parameters were calculated: number of lesions, maximum and mean standardized uptake values (SUVmax, SUVmean), lean body mass corrected SUV peak (SULpeak), metabolic tumor volume (MATV), and total lesion activity (TLA). After 223Ra-therapy, all patients underwent regular follow-up until death. The predictive power of clinical and PET-derived parameters on overall survival (OS) was assessed by Kaplan–Meier analysis and the Cox proportional hazard method. All the patients showed 18F-choline-avid lesions at baseline PET/CT. Among the enrolled subjects, eleven (55%) completed all the six scheduled cycles of 223Ra-therapy; seven (35%) were responders according to imaging and biochemical parameters. Mean OS was 12.7 ± 1.4 months: by Kaplan–Meier analysis, number of lesions, PSA level and TLA were significantly correlated with OS. In multivariate Cox analysis, TLA remained the only significant predictor of survival (p = 0.003; hazard ratio = 7.6, 95% confidence interval = 1.9–29.5 months). 18F-choline PET may be useful for patients’ stratification before 223Ra-therapy. In particular, high metabolically active tumor burden (i.e., TLA) was predictive of poor outcome.

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