PD32-06 Long-Term Safety and Antitumor Activity of ODM-201 in Chemotherapy and CYP17-INHIBITOR Naïve Patients from the Arades and the Arafor Trials (original) (raw)
Related papers
Urology, 2011
Introduction: Continuation of docetaxelbased chemotherapy significantly associated with overall survival beyond progression. However, a number of long-term adverse events associated with continuous docetaxel. The aim of this study was to determine predictive factors for premature discontinuation of docetaxel-based chemotherapy in men with castrationresistant prostate cancer (CRPC). Materials and Methods: We retrospectively reviewed the medical records of men who treated with docetaxel based chemotherapy for CRPC in single institution between May 2005 and April 2010. After screening, 30 patients fit eligibility for inclusion in this study. The group 1 included 12 patients who treated with 5 or less cycles of docetaxel-based chemotherapy, and group 2 included 18 patients who treated with 6 or more cycles of docetaxel-based chemotherapy for CRPC. The treatment consisted of 5mg prednisolone twice daily and 75mg/m 2 docetaxel once every 3 weeks. Results: Median age was 72 years, and median ECOG performance status was 0. Median baseline prostate specific antigen (PSA) was 33.8 ng/ml. Median cycle of docetaxel-based chemotherapy was 5.8. Of 30 patients, 13 patients (48.2%) had Ͼ 50% PSA decline from baseline. 22 patients had measurable metastasis, revealed by imaging study. 3 patients (13.6%) had achieved partial response. There is no difference in age, ECOG performance status, hemoglobin, serum creatinine, PSA response. The body mass index is significantly low in group 1 (21.8kg/m 2 vs. 23.6kg/m 2 , pϭ0.034). Group 1 included more patients with prior systemic chemotherapy (50% vs. 11%, pϭ0.039.) And group 1 showed a shorter overall survival (pϭ0.039). Conclusions: Premature discontinuation of docetaxel-based chemotherapy is associated with low body mass index and prior systemic chemotherapy. And the continuation of docetaxel-based chemotherapy is associated with overall survival.
Hormonal Therapies for Patients with Advanced Prostate Cancer
European medical journal, 2016
Prostate cancer (PCa) is the second most common cancer in men, comprising 15% of new cancer cases. While most cases are diagnosed at an early stage and can be managed conservatively or by local treatment alone, up to 30% of patients will receive androgen deprivation therapy (ADT). Indeed, high-risk localised and locally advanced PCa require either surgery or ADT in combination with radiation as a local strategy. On the other hand, metastatic patients are treated upfront with ADT, eventually combined with docetaxel, as suggested by recent studies. ADT has been in use for more than 60 years and during this time it has undergone considerable evolution. Gonadotropin-releasing hormone (GnRH) agonists have supplanted surgical castration and oestrogens, and are now challenged by GnRH antagonists. ADT induces profound but often short-lasting responses. In a low serum testosterone environment, the androgen receptor (AR) pathway may be reactivated either by overexpression, by mutation of the AR itself, or by adrenal or intracrine production of androgens. These mechanisms underlie the development of the majority of castration-resistant prostate cancers (CRPCs). In addition to AR adaptation, several AR-independent mechanisms may also underlie progression of these cancers on ADT. A new generation of AR-pathway inhibitors have succeeded first-generation anti-androgens and steroids, and are proven to extend survival in patients with metastatic CRPC. This review aims to summarise the current standard of care and available hormonal strategies in advanced PCa and future therapeutic perspectives that could change treatment paradigms in the coming years.
The Journal of Steroid Biochemistry and Molecular Biology, 2018
We report the discovery of a novel nonsteroidal dual-action compound, ODM-204, that holds promise for treating patients with castration-resistant prostate cancer (CRPC), an advanced form of prostate cancer characterised by high androgen receptor (AR) expression and persistent activation of the AR signaling axis by residual tissue androgens. For ODM-204, has a dual mechanism of action. The compound is anticipated to efficiently dampen androgenic stimuli in the body by inhibiting CYP17A1, the prerequisite enzyme for the formation of dihydrotestosterone (DHT) and testosterone (T), and by blocking AR with high affinity and specificity. In our study, ODM-204 inhibited the proliferation of androgen-dependent VCaP and LNCaP cells in vitro and reduced significantly tumour growth in a murine VCaP xenograft model in vivo. Intriguingly, after a single oral dose of 10-30 mg/kg, ODM-204 dose-dependently inhibited adrenal and testicular steroid production in sexually mature male cynomolgus monkeys. Similar results were obtained in human chorionic gonadotropintreated male rats. In rats, leuprolide acetate-mediated (LHRH agonist) suppression of the circulating testosterone levels and decrease in weights of androgen-sensitive organs was significantly and dose-dependently potentiated by the co-administration of ODM-204. ODM-204 was well tolerated in both rodents and primates. Based on our data, ODM-204 could provide an effective therapeutic option for men with CRPC.
Targeted Oncology
Background Androgen deprivation therapy (ADT), a cornerstone of prostate cancer treatment, is commonly co-prescribed as combination therapy. Objective To better understand the safety and tolerability profile of relugolix, an oral non-peptide gonadotropin-releasing hormone (GnRH) receptor antagonist, in combination with abiraterone acetate (abiraterone) and apalutamide, a phase I study was undertaken. Patients and Methods This is an ongoing, 52-week, open-label, parallel cohort study of relugolix in combination with abiraterone in men with metastatic castration-sensitive prostate cancer (mCSPC) or metastatic castration-resistant prostate cancer (mCRPC) [Part 1] and apalutamide in men with mCSPC or non-metastatic castration-resistant prostate cancer (nmCRPC) [Part 2]. Eligible patients treated with leuprolide acetate or degarelix with abiraterone or apalutamide prior to baseline, at which time they were transitioned to relugolix. Assessments included reporting of adverse events, clinical laboratory tests, vital sign measurements, electrocardiogram (ECG) parameters, and testosterone serum concentrations. In this interim report, patients completing ≥12 weeks were included. Results Overall, 15 men were enrolled in Part 1 and 10 in Part 2. Adverse events were mostly mild-to-moderate in intensity and were consistent with the known safety profiles of the individual medications. No transition (from prior ADT treatment)-or time-related trends in clinical laboratory tests, vital sign measurements, or ECG parameters were observed. Mean testosterone concentrations remained below castration levels. Conclusions Combination therapy of relugolix and abiraterone or apalutamide was associated with a favorable safety and tolerability profile consistent with the known profiles of the individual medications. Castration levels of testosterone were maintained after transitioning to relugolix from other ADTs. Clinical Trial Registration ClinicalTrials.gov identifier: NCT04666129
European Urology Focus
Background: ODM-201, a new androgen receptor antagonist for treatment of metastatic castration-resistant prostate cancer (mCRPC), demonstrated antitumour activity and acceptable tolerability in phase 1/2 trials. Objective: To determine the antitumour activity and safety profile of extended treatment with ODM-201 in men with mCRPC. Design, setting, and participants: ARADES and ARAFOR trials with ODM-201 enrolled chemotherapy-naïve and CYP17 inhibitor (CYP17i)-naïve mCRPC patients. Both trials had extended follow-up. Here we report results for chemotherapy-naïve and CYP17i-naïve patients from both trials (data cutoff October 2014 for ARADES and April 2015 for ARAFOR) after extended follow-up. Intervention: A total of 41 chemotherapy-naïve and CYP17i-naïve patients received oral ODM-201 twice daily (total daily dose of 1200, 1400 or 1800 mg). Outcome measurements and statistical analysis: Antitumour activity was assessed in terms of prostate-specific antigen (PSA) declines and PSA/radiographic progression. Safety was assessed until disease progression and/or drug discontinuation due to any intolerable adverse event (AE). Results and limitations: ODM-201 safety data after a median treatment time of 13.5 mo (95% confidence interval [CI] 9.7-15.6, interquartile range [IQR] 7.5-22.0) were similar to those reported in the main ARADES and ARAFOR trials. The overall AE incidence was 80.5% (n = 33/41), with 58.5% (n = 24/41) of patients experiencing only grade 1-2 AEs. The most common AEs were fatigue, back pain, diarrhoea, nausea, and pain in extremity. The median times to PSA and radiological progression were 12.4 mo (95% CI 6.3-18.2, IQR 5.5-22.0) and 15.3 mo (95% CI 9.5-not reached [NR], IQR 6.3-NR), respectively. Conclusions: Extended treatment with ODM-201 (1200-1800 mg/d) was well tolerated, with no new safety concerns, and provided evidence of sustained antitumour activity in chemotherapynaïve and CYP17i-naïve patients with mCRPC. Patient summary: Prolonged treatment with high doses of ODM-201 was well tolerated and provided long-lasting disease control in patients with mCRPC. ODM-201 represents a therapeutic treatment option for mCRPC. The ARAFOR trial (including the follow-up stage) and the follow-up component of the ARADES trial are registered with ClinicalTrials.gov as trial numbers NCT01784757 and NCT01429064.
BMC Cancer
Background: Testosterone suppression is the standard treatment for advanced prostate cancer, and it is associated with side-effects that impair patients' quality of life, like sexual dysfunction, osteoporosis, weight gain, and increased cardiovascular risk. We hypothesized that abiraterone acetate with prednisone (AAP) and apalutamide, alone or in combination, can be an effective hormonal therapy also possibly decreasing castration-associated side effects. Methods: Phase II, open-label, randomized, efficacy trial of abiraterone acetate plus prednisone (AAP) and Androgen Deprivation Therapy (ADT) versus apalutamide versus the combination of AAP (without ADT) and apalutamide. Key eligibility criteria are confirmed prostate adenocarcinoma; biochemical relapse after definitive treatment (PSA ≥ 4 ng/ml and doubling time less than 10 months, or PSA ≥ 20 ng/ml); newly diagnosed locally advanced or metastatic prostate cancer; asymptomatic to moderately symptomatic regarding bone symptoms. Patients with other histology besides adenocarcinoma or previous use of hormonal therapy or chemotherapy were excluded. Discussion: There is an urgent need to study and validate regimens such as new hormonal agents that may add benefit to castration with an acceptable safety profile. We aim to evaluate if apalutamide in monotherapy or in combination with AAP is an effective and safety hormonal treatment that can spare patients of androgen deprivation therapy. Trial registration: This trial was registered in ClinicalTrials.gov on October 16, 2017, under Identifier: NCT02867020.
Hormonal treatment and quality of life of prostate cancer patients: new evidence
Minerva urologica e nefrologica = The Italian journal of urology and nephrology, 2018
Androgen deprivation therapy (ADT) is the mainstay of treatment of patients with relapsed or metastatic hormone-sensitive prostatic carcinoma. The dramatic reduction of serum testosterone levels induced by ADT produces multiple side effects as vasomotor flushing, sexual dysfunction, fatigue, impairment of cognitive function, reduced quality of sleep, gynecomastia and anemia, that are able to decrease health-related quality of life (QoL). In addition, hormonal therapy can interfere with bone metabolism and induce metabolic and cardiovascular complications. Recently, new-generation hormonal therapies, such as abiraterone and enzalutamide, have been tested and approved in castration resistant prostatic cancer patients and current studies are moving forward to the earlier use of these two drugs. In this evolving scenario, the management of hormonal therapy toxicity, given the long duration of treatment and the potentially high impact of side effects on patients' functional status an...
Hormonal Therapy for Prostate Cancer: Modalities and Evaluation of Results
2018
Th is was a retrospective study carried out from September 1 st , 2010 to October 31 st , 2012. It collected all patients who had hormone therapy for prostate cancer confi rmed histologically. Th e parameters studied were: patient's age at diagnosis, patient's general condition (ECOG performance status), Gleason score, tumor status (TNM 2009), type of treatment and treatment complications. Hormone therapy was: • Either medical, using analogs of LHRH (Goserelin, Triptorelin), non-steroidal antiandrogens (bicalutamide), steroidal anti-androgen (cyproterone acetate) • Or surgically, using bilateral testicular pulpectomy or orchiectomy. Body hygiene measure (stop all smoking, regular physical activities) were recommended for all patients. Calcium and vitamin D3 prescription was made for all osteopenic or osteoporotic patients on bone densitometry. Patients were reviewed at three, six and 12 months with a PSA control, liver function tests and Complete Blood Count (CBC). Th us, the appreciation criteria of treatment outcomes were total PSA level, overall survival, progression free survival. Th e original date was the date of the initiation of hormonal therapy. Th e data were analyzed and exploited by excel 2010 and SPSS 19.0. Survival was measured according to Kaplan Meier method. Th e comparative analysis of the parameters was made with a signifi cance