Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Prostatic Neoplasms

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Antineoplastic Agents

All Drugs and Chemicals

Abiraterone Acetate

Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 Enzyme Inhibitors

Abiraterone acetate standard dose

Abiraterone acetate escalated dose

Jerome ALEXANDRE, MD PhD

The purpose of this study is to test whether a dose escalation up to 2000 mg per day of abiraterone acetate is feasible and lead to disease stabilization in castration-resistant metastatic prostate cancer patients who experience disease progression within the first 6 months of abiraterone actetate at standard dose (1000 mg/d) and have a plasma abiraterone concentration below 8.5 ng/mL.

It is a non-comparative phase 2 study in which patients will be included in two successive steps. Patients with mCRPC will be included in the first step and treated with standard dose (1000 mg/day) of ABI + prednisone /prednisolone (10 mg/d) according to the summary of product characteristics and monitored for trough ABI plasma level each month for 3 months.

In the second step intrapatient ABI dose escalation (2000 mg/day) + prednisone/prednisolone (10 mg/d) will be realized for patients from the first step experiencing progressive disease within 6 months of ABI standard dose and with mean ABI plasma level during the first three months \< 8.5 ng/mL

Metastatic castration-resistant prostate cancer (mCRPC) causes approximately 307,500 deaths annually worldwide. mCRPC has been defined as a clinical state in which, despite suppressed circulating testosterone levels lower than 50 ng/dL, the androgen receptor axis is reactivated. This reactivation is mainly due to the multiple signaling mechanisms in prostate cancer cells along with their microenvironment.

Thus, research efforts aimed at identifying new strategies to inhibit the androgen receptor axis. Abiraterone acetate (ABI) is a first-in-class inhibitor of cytochrome (CYP) 17A1, a critical enzyme for extra-gonadal and testicular androgen syntheses. ABI has shown impressive efficacy in treatment of mCRPC. ABI plus low-dose prednisone was first shown to improve survival in mCRPC patients pre-treated with docetaxel, and the combination therapy has since been approved for this purpose. Moreover, ABI plus low-dose prednisone resulted in prolonged overall survival (OS) as compared with placebo plus prednisone in docetaxel-naive patients. In these patients, ABI was associated with a median progression free survival of 16 months and median overall survival of 35 months. However, around 40% of patients do not experience PSA response to ABI therapy at 3 months. This parameter has been consistently identified as a surrogate parameter of time to progression.

As ABI is an oral agent that is subject to both inter- and intra-individual variability in bioavailability, its pharmacokinetics might be a critical parameter for its anticancer activity.

Investigators first established a simple method to mesure plasma ABI concentration by HPLC. They then conducted a prospective observational study in which they aimed to explore the relationship between ABI trough concentration and PSA response in mCRPC patients and to identify the critical determinants for its activity.

73 mCRPC patients, in whom treatment with ABI was indicated, were recruited from December 2012 to December 2014 in the oncology department of Cochin Hospital in Paris, France. The plasma concentration of ABI was determined at baseline, and then one (M1), two (M2) and three (M3) months after treatment initiation. The primary study objective was to investigate the relationship between ABI mean plasma trough concentration (ABI Cmin) and PSA response. PSA response was defined as a PSA decline of at least 50% after receiving ABI for 3 months.

In multivariate analysis, ABI Cmin was the only factor independently associated with PSA response: OR=1.12, \[1.0-1.3\], P=0.03. Based on these results, they established an optimal threshold of ABI C min by building a ROC curve. The treshold value of 8.45 ng/mL was associated with a specificity of and sensitivity of 70% \[49-84\] and 79% \[63-81\], respectively.

As plasma ABI exposure is a key element of PSA response, it supports the exploration of benefits of a pharmacokinetically-guided dosing strategy for ABI.

In a phase I trial, the recommended dose of ABI was 1000 mg per day as a plateau of endocrine effects was reported at doses greater than 750 mg. However, to their knowledge, no data regarding the effect of ABI on tissue androgens are available, and no dose limiting toxicity was identified up to 2000 mg per day which support the rational of a dose-escalation strategy. In a phase 2 study, 41 mCRPC patients received 1000 mg twice a day of ABI (2000 mg/day) and the tolerance profile appeared similar than with lower dose.

In this phase II trial, investigators aim to confirm the preliminary results presented above in a larger population. Moreover, their objective is to test whether a dose escalation up to 2000 mg per day is feasible and lead to disease stabilization in progressive patients within the first 6 months of treatment.

Study of Dose Escalation of Abiraterone Actetate in Prostate Cancer

Intra-individual Dose Escalation of Abiraterone Acetate According to Its Plasma Concentration in Patients With Progressive Castration-resistant Metastatic Prostate Cancer

The proportion of patients who do not experience progressive disease (defined by PSA and/or radiographic progression) among those receiving ABI at a dose of 2000 mg / day + prednisone/prednisolone after failure of standard dose (1000 mg/day).

Incidence of underexposure to ABI (mean plasma concentration \< 8.5 ng/mL) in patients treated at standard dose (1000 mg / day) and identification of inter- and intra-individual variability factors of plasma levels of ABI

The adherence will be evaluated using two tools: the french version of the Girerd survey filled by the patient at 12 weeks and a personal treatment log book indicating daily times of drug administration

The adherence will be evaluated using two tools: the french version of the Girerd survey filled by the patient at 24 weeks and a personal treatment log book indicating daily times of drug administration

PSA response rate is defined as the proportion of patients with a decrease of ≥ 50% in the PSA concentration from the pretreatment baseline value, confirmed after ≥ 3 weeks by an additional PSA evaluation

Time from inclusion to progression or death in patients treated at escalated dose Disease progression is defined as either PSA or radiologic progression as described above

Janssen, LP

Assistance Publique - Hôpitaux de Paris

Symptoms and General Pathology

Recurrence

Disease Progression

Disease Attributes

Lipid Regulating Agents

Androgens

Atorvastatin

Anticholesteremic Agents

Hypolipidemic Agents

Antimetabolites

Hydroxymethylglutaryl-CoA Reductase Inhibitors

Capsules of atorvastatin. Daily dose of 80 mg for max. 10 years or until development of castration resistance.

Identical capsules as in the atorvastatin arm, but including no active ingredient. Used daily for max. 10 years or until development of castration resistance

Atorvastatin 80mg

Similar capsules as in the atorvastatin arm, but without the active ingredient

Placebo oral capsule

Teemu Murtola, MD, PhD

Aino Siltari, PhD

Mikkel Fode, MD, PhD

Peter Oestergren, MD, PhD

Andres Kotsar, MD, PhD

Antti Rannikko, MD,PhD

Heikki Seikkula, MD, PhD

Arto Salonen, MD,PhD

Timo Marttila, MD,PhD

Otto Ettala, MD, PhD

Rasmus Nilsson, MD, PhD

Sven Lofferen, MD, PhD

Heikki Seikkula

This randomized double-blind placebo-controlled trial tests whether intervention with atorvastatin delays development of castration resistance compared to placebo during androgen deprivation therapy (ADT) for prostate cancer.

Cholesterol-lowering statin drugs have been reported to lower proliferation activity in prostate cancer, delay occurrence of castration resistance and reduce the risk of prostate cancer death. Therefore, it is important to test statins' efficacy in addition to conventional prostate cancer treatment in a randomized, placebo-controlled trial.

This phase 3 randomized double-blind placebo-controlled trial will explore whether intervention with atorvastatin delays prostate cancer progression i.e. development of castration resistance compared to placebo during androgen deprivation therapy (ADT) for metastatic or recurrent prostate cancer.

Secondary objectives include exploring whether atorvastatin lowers prostate cancer-specific or overall mortality compared to placebo, and to demonstrate whether changes in serum lipid parameters predict disease recurrence and occurrence of adverse genomic changes predicting castration resistance among prostate cancer patients during ADT.

The study recruitment target is 400 participants who start ADT as management of metastatic or recurrent prostate cancer. These men will be randomized 1:1 (200 + 200) to receive blinded study drug, either 80 mg of atorvastatin daily or placebo until disease recurrence i.e. development of castration resistance or for a maximum of five years.

The study will be carried out in collaboration between urological departments of University Hospitals in Finland as a project of the national FinnProstata study group, Herlev University Hospital in Denmark, Vestfold and Telemark hospitals in Norway and the Tartu University Hospital in Estonia.

Follow-up is continued until the primary end-point, development of castration resistance. After this the participants will be given the opportunity to voluntarily carry on with the blinded intervention for maximum time of ten year to observe effects on survival after development of castration resistance. Blinding will be lifted after the follow-up is complete for all study participants.

Castration resistance is defined as prostate-specific antigen (PSA) progression (three consecutive rises of PSA measured at least 1 week apart with two \> 50% increases over the nadir and PSA \> 2 ng/ml) or radiological disease progression (appearance of two or more lesions in bone scan or soft tissue enlargement as per RECIST criteria) with serum testosterone at castrate level (\< 1.73 nmol/l; 50 ng/dl) during ADT.

Impact of Atorvastatin on Prostate Cancer Progression During ADT

Impact of Atorvastatin on Prostate Cancer Progression After Initiation of Androgen Deprivation Therapy - Lipid Metabolism as a Novel Biomarker to Predict Prostate Cancer Progression

Sharing of individual-level data is not allowed by ethics board

Castration resistance is defined as PSA progression (three consecutive PSA rises measured at least 1 week apart with two \> 50% increases over the nadir and PSA \> 2 ng/ml) or radiological disease progression (appearance of two or more lesions in bone scan or soft tissue enlargement as per RECIST criteria) with serum testosterone at castrate level (\< 1.73 nmol/l; 50 ng/dl) during ADT.

Change in serum lipid levels during the intervention. Measured at baseline and in every follow-up visit. Results are blinded from the investigators and participants before the final analysis

Followed through Finnish national registries after reaching the primary end-point

Occurrence of adverse tumor traits predicting development of castration resistance in circulating cell free DNA

To see how ADT affects glucose tolerance and whether atorvastatin intervention has any effect on it

Any cardiovascular events as described by the participant or evident from the patient files during the course of follow-up. Followed via national registries after meeting the primary end-point.

Score from validated QOL questionnaire EORTC QLQ-C30 (range 0-100, with 100 denoting highest quality of life)

Score from validated QOL questionnaire EORTC QLQ-PR25 (range 0-100, with 100 denoting highest quality of life)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Study of Dose Escalation of Abiraterone Actetate in Prostate Cancer	NCT03458247	Prostate Cancer	Abiraterone ace... Abiraterone ace...	18 Years -	Assistance Publique - Hôpitaux de Paris
Impact of Atorvastatin on Prostate Cancer Progression During ADT	NCT04026230	Metastatic Pros... Recurrent Prost...	Atorvastatin 80... Placebo oral ca...	18 Years -	Tampere University Hospital

Spots Global Cancer Trial Database for castration resistance