ESMO @ ECC 2015: Anti-tumour Activity Demonstrated with Orteronel in Metastatic Castration Resistant Prostate Cancer

Prolonged event-free survival achieved with orteronel as switch maintenance therapy in patients with non-progressive disease following chemotherapy

Orteronel showed promising activity as switch maintenance therapy in patients with metastatic castration-resistant prostate cancer (CRPC) and non-progressive disease following first-line docetaxel, according to phase III study results reported at the European Cancer Congress (ECC 2015), convening in Vienna, Austria, 25 - 29 September, 2015.

Orteronel plus best supportive care (BSC) was initiated at 3 to 6 weeks after the final administration of docetaxel in patients with stable disease following chemotherapy. Patients on orteronel maintenance achieved event free survival (EFS) nearly three times longer than similar patients receiving BSC alone.

EFS was defined as the time from randomisation to death, or a combination of at least two outcomes that included radiographic, clinical or prostate specific antigen (PSA) progression.

Phase III trial met primary and secondary endpoints

Median EFS, the trial’s primary endpoint, was 8.5 months in the orteronel/BSC cohort (95% confidence interval [CI] 3.2, 16.0 months) versus 2.9 months in the placebo/BSC cohort (95% CI 2.7, 3.9 months); hazard ratio (HR) 0.32 (95% CI 0.15, 0.65). Patients receiving orteronel showed significantly improved EFS (p = 0.001).


Maintenance orteronel after prior disease stabilisation with docetaxel significantly prolongs event-free survival in mCRPC patients.

Credit for image: Richard Cathomas

Secondary endpoints included PSA decline >50%, time to PSA progression, radiographic PFS (rPFS), toxicity, quality of life (QoL) and overall survival (OS). 

PSA decline >50% was observed in 57% of patients receiving orteronel compared to just 4% of patients in the placebo cohort. The time to PSA progression was also significantly increased to 6.5 months with orteronel compared to 1.8 months with placebo (95% CI 0.18, 0.75); HR 0.37 (p = 0.004). rPFS was 8.5 versus 2.8 months with orteronel and placebo, respectively, (95% CI 0.20, 0.91); HR 0.42 (p = 0.02).

Lead investigators Silke Gillessen, of the Department of Medical Oncology Kantonsspital St. Gallen and Richard Cathomas, of the Department of Medical Oncology, Kantonsspital Graubünden in Chur, Switzerland presented findings during the Genitourinary Malignancies - Prostate Cancer segment of the Proffered Paper Session held on 26 September 2015.

Study terminated early 

Professor Gillessen explained that, although the multicentre randomised double-blind placebo-controlled phase III study (SAKK 08/11)was designed to enrol 96 patients, a total of 47 patients were randomised between November 2012 and June,2014. All patients had non-progressive disease after receiving a cumulative dose of ≥ 300 mg/m2 of first line docetaxel and the median age was 70 years (range: 51 to 85 years). In all, 23 patients were randomised to orteronel at 300 mg twice daily plus BSC and 24 to receive placebo plus BSC. 

The study was terminated prior to completing enrolment by the company, which discontinued the development of orteronel in prostate cancer. Takeda Pharmaceutical announced on June 19, 2014 that it had decided to end the development programme for orteronel (TAK-700) in prostate cancer after two phase III clinical trials in patients with metastatic CRPC found that orteronel plus prednisone extended the time to disease progression but not OS in these patients.

Orteronel is an investigational oral, non-steroidal, selective inhibitor of 17,20-lyase, a key enzyme in the production of steroidal hormones, including androgens. Efficacy and safety had been demonstrated in early phase trials.

In the study presented at the ECC, the median follow-up of patients was 17 months. Adverse events were reported in 61% of orteronel versus 83% of placebo patients during treatment. 

Higher, but manageable, toxicity was seen in the orteronel arm. Grade 2 toxicity events occurring with orteronel included fatigue in 17%, nausea in 26%, hypertension in 17%, and hypokalaemia in 17% of patients; whereas grade 2 fatigue, nausea, and hypertension each occurred in 4% and hypokalaemia was reported in 13% of patients receiving placebo.

Grade 3 fatigue, hypertension, and hypokalaemia were reported in 9%, 9%, and 4%, respectively, of patients receiving orteronel, whereas placebo patients reported grade 3 toxicities including nausea (4%) and hypertension (8%). Grade 2/3 elevation of liver enzymes occurred at similar rates; 17% and 4% in the orteronel arm versus 17% and 8% in the placebo arm.

With orteronel, one (4%) patient experienced transient adrenal insufficiency grade 3, which responded to prednisone therapy and one (4%) patient developed grade 4 pneumonitis, which also responded to treatment.


The investigators stated that this was the first trial, to their knowledge, using an active pharmaceutical ingredient as switch maintenance in this patient cohort and they stated that the concept of maintenance therapy after disease stabilisation with chemotherapy warrants further research in mCRPC.

According to the authors: “Orteronel showed important anti-tumour activity and is a generally well-tolerated switch maintenance therapy in patients with disease stabilisation after docetaxel.” They acknowledged that increased toxicity occurred with orteronel but maintained that it was manageable. 


2500. Orteronel (Ort) maintenance therapy in patients (pts) with metastatic castration resistant prostate cancer (mCRPC) and non-progressive disease after first-line docetaxel (Doc) therapy: Results of a multicenter randomized double-blind placebo-controlled phase III trial (SAKK 08/11)

The study was sponsored by the Swiss Group for Clinical Cancer Research