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Orteronel Maintenance Therapy in Patients With Metastatic Castration Resistant Prostate Cancer and Non-progressive Disease After First-line Docetaxel Therapy: a Multicenter Randomized Double-blind Placebo-controlled Phase III Trial.

Phase 3
18 Years
Open (Enrolling)
Prostate Cancer

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Trial Information

Orteronel Maintenance Therapy in Patients With Metastatic Castration Resistant Prostate Cancer and Non-progressive Disease After First-line Docetaxel Therapy: a Multicenter Randomized Double-blind Placebo-controlled Phase III Trial.


One in six men will be diagnosed with cancer of the prostate during his lifetime.
Accordingly, prostate cancer is the most common cancer amongst men in the western world. In
Switzerland approximately 5'400 men are diagnosed with the disease and 1'300 die of prostate
cancer every year. Prostate cancer represents 30% of all cancer diagnoses in men. Despite
earlier detection and new treatments the life time risk to die of prostate cancer has
remained stable at 3% since 1980.

Metastatic prostate cancer is hormone-sensitive and therefore androgen deprivation therapy
(ADT) is the treatment of choice. Yet, virtually all patients with metastatic prostate
cancer progress on androgen deprivation therapy (so called castration-resistant prostate
cancer: CRPC). Further hormonal manipulations are often administered (e.g. maximal androgen
blockade with addition of a non-steroidal antiandrogen such as bicalutamide), however these
interventions have only modest impact. Metastatic CRPC (mCRPC) that progresses despite these
therapies is nowadays treated with docetaxel-based chemotherapy. In a phase III trial,
treatment of mCRPC patients with docetaxel in combination with low dose prednisone resulted
in a significant survival advantage in comparison to the previous standard of care of
mitoxantrone plus prednisone. Moreover docetaxel treatment improved response rate,
progression free survival and symptom control.

The current standard of care in patients with disease stabilization after first line
chemotherapy with docetaxel is a wait-and-watch strategy, where patients are regularly
examined in the hospital every 3-4 weeks. A second line chemotherapy in patients with mCRPC
was not standardized until recently. However, two trials presented in 2010 have changed the
landscape: the novel taxane cabazitaxel was tested in a phase III trial against mitoxantrone
as a second line chemotherapy in patients progressing under or after docetaxel. There was a
significant improvement in overall survival, progression free survival and response rate.
Most of the included patients had experienced disease progression during or within three
months of docetaxel first line treatment. Cabazitaxel was associated with increased toxicity
including 5% toxic deaths. Another randomized phase III trial using abiraterone in patients
with progression after docetaxel showed a significant improvement in overall survival and
pain palliation. Abiraterone belongs to a group of agents that very effectively inhibits the
androgen synthesis via blockade of the key enzyme cytochrome P-450c17 (CYP17).

The new drug orteronel (TAK-700) belongs to the same group of active substances as
abiraterone. Orteronel is currently the subject of a large international Phase III study in
patients with metastatic carcinoma of the prostate and progression of disease following
docetaxel. Initial results have shown that orteronel effectively inhibits testosterone
synthesis and, in contrast to abiraterone, has fewer side effects.


CYP17 inhibitors are active and well tolerated agents for treatment of patients with
castration-resistant prostate cancer. However, despite its activity patients become
resistant to this new form of antihormonal treatment and hence develop further progression
after a median of approximately 6 months. In that case, the options are very limited as
outlined above.

In all reported post-docetaxel trials and in the large phase III trials, patients start on
the CYP17 inhibitor treatment at the time of disease progression. Trials examining other
advanced malignant diseases such as lung cancer have shown that initiating an effective
treatment earlier in the disease course at the end of a first-line chemotherapy (so called
switch maintenance therapy) is beneficial in terms of progression free survival (PFS) but
also overall survival (OS). This may also hold true for early administration of antihormonal
agents in patients with mCRPC.

Therefore, the aim of this trial is to test the hypothesis that starting orteronel after
disease stabilization with docetaxel prolongs event-free survival (EFS), consequently
maintains a good quality of life (QL) and eventually also improves OS.

Inclusion Criteria:

- Patient has given voluntary written informed consent

- Male patient 18 years or older

- WHO performance status of ≤2

- Adenocarcinoma of the prostate

- Castration resistance: tumor progression after orchiectomy or during treatment with
GnRH analogues

- Metastatic disease, radiographically documented (

- Total testosterone ≤ 50 ng/dL

- Non-progressive disease after docetaxel first-line treatment with a cumulative dose ≥

- No evidence of progression on imaging according to PCWG2 and modified RECIST 1.1

- PSA levels not elevated ≥ 25% AND at least 2 ng/mL above the nadir since start
of docetaxel treatment

- Non-surgically castrated patient agrees on ongoing use of GnRH analogues (agonists or
antagonists) during the trial

- PSA ≥ 2 ng/mL; Potassium ≥ 3.5 mmol/L; Neutrophils ≥ 1.5 x 109/L; Platelets ≥ 100 x

- Normal kidney and liver function

- Planned start of trial treatment 3 to 6 weeks after last docetaxel administration

- Screening calculated ejection fraction of ≥ 50% or normal according to local standard
by echocardiogram or by multiple gated acquisition (MUGA) scan.

- Baseline QL questionnaire completed

- Patient is able and willing to swallow study drug as whole tablet

- Patient compliance and geographic proximity allow proper staging and follow-up

- Patient agrees to practice effective barrier contraception or to completely abstain
from intercourse

Exclusion Criteria:

- Prior therapy with aminoglutethimide, ketoconazole, orteronel, abiraterone or other
modern CYP17 inhibitors

- Prior chemotherapy for prostate cancer within 12 months before enrollment except from

- Retreatment with docetaxel after interruption of > 5 weeks

- Concurrent disease requiring higher doses of corticosteroid than the equivalent of 10
mg prednisone per day

- Known hypersensitivity to trial drug or hypersensitivity to any of its components

- Patient has received other investigational drugs within 30 days before enrollment

- Presence of a small cell component in histological specimen

- Radiotherapy within the last 2 weeks before expected start of the trial treatment

- Known history of central nervous system (CNS) or spinal cord metastases

- Current spinal cord compression

- Diagnosed or treated for another malignancy within 2 years of registration, with the
exception of complete resection of basal cell carcinoma or squamous cell carcinoma of
the skin, or any in situ malignancies

- History of myocardial infarction, unstable symptomatic ischemic heart disease,
ongoing arrhythmias of Grade ≥ 3 (NCI CTCAE version 4.0) or thromboembolic events
(e.g., deep vein thrombosis, pulmonary embolism, or symptomatic cerebrovascular
events) within 6 months prior to first dose of study drug. Chronic stable atrial
fibrillation on stable anticoagulant therapy is allowed

- New York Heart Association Class III or IV heart failure

- ECG abnormalities of:

- Q-wave infarction, unless identified ≥ 6 months prior to registration

- QTc interval > 460 msec

- Uncontrolled hypertension despite appropriate medical therapy

- Likely inability (e.g. due to a psychiatric disorder) to understand information on
trial related topics, to give informed consent, to comply with the protocol, to fill
in QL forms and to cooperate fully with the investigator and site personnel

- Known gastrointestinal (GI) disease or GI procedure that could interfere with the GI
absorption or tolerance of orteronel

- Known active chronic hepatitis B or C, life-threatening illness unrelated to cancer,
or any serious medical or psychiatric illness that could, in the investigator's
opinion, potentially interfere with participation in this study

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Outcome Measure:

Event free survival (EFS)

Outcome Time Frame:

At baseline; every 4 weeks until disease progression (estimated up to 1 year)

Safety Issue:


Principal Investigator

Richard Cathomas, MD

Investigator Role:

Study Chair

Investigator Affiliation:

Kantonsspital Graubünden


Switzerland: Swissmedic

Study ID:

SAKK 08/11



Start Date:

September 2012

Completion Date:

December 2020

Related Keywords:

  • Prostate Cancer
  • adenocarcinoma of the prostate
  • metastatic castration-resistant prostate cancer
  • maintenance therapy
  • orteronel
  • TAK-700
  • Prostatic Neoplasms