Prostate cancer is the most common solid tumour in men in Western countries. If it remains confined to the primary site it can be cured by a radical prostatectomy or radiotherapy, with a very high survival rate for low risk tumours, even untreated. However, because it is often diagnosed late, the cancer is already metastatic in around one in seven of all prostate cancer patients.
On top of this, the disease will become metastatic in about 20% of the remainder. Most prostate cancers are hormone dependent, so drug therapy has typically relied on antiandrogenic hormone treatment if the cancer returns or cannot be removed via surgery. However, resistance to therapy with gonadotropin releasing hormone analogue drugs develops quickly, and the prognosis for prostate cancer patients if their disease is castration-resistant is poor – of the order of a year to 18 months.
Many different alternative strategies have been investigated. One being looked at by companies including Takeda is to inhibit 17,20-lyase, which is involved in the synthesis of androgens from cholesterol, and this activity is believed to be highly upregulated in metastases from castration-resistant prostate tumours. Orteronel is a potent and selective non-steroidal inhibitor of this enzyme, which is currently in Phase III trials for metastatic prostate cancer.1
In one Phase II trial, 39 patients with non-metastatic, castration-resistant prostate cancer and rising prostate-specific antigen who had undergone surgical or chemical castration were given 300g twice daily doses of orteronel, and treatment continued until PSA progression, metastases or unacceptable toxicity occurred.2 Eight patients discontinued because of adverse events, of which the most common were dyspnoea, hypertension, fatigue, hypokalaemia and pneumonitis.
After three months, six patients achieved a PSA level below 0.2ng/ml (all subjects had a PSA level above 2ng/ml before the start of the trial), and the median PSA declined by 83%. Median time to PSA progression was 15 months, and treatment continued for more than six months in 17 patients.
In another trial, 38 patients were given 300mg doses of orteronel twice a day, and more than half remained on the treatment regimen for at least a year.3 Overall, 12 discontinued because of adverse events, and six had dose reduction. The median levels of testosterone declined by 89%, and a third of patients achieved PSA levels below 0.2ng/mg. The median progression free survival was 14 months, and estimated one- and two-year metastases-free rates were 94% and 69% respectively.
It has also been studied in combination with docetaxel in prednisone in patients with metastatic, castration-resistant prostate cancer who had received no prior chemotherapy or ketoconazole/abiraterone therapy.4 At the data cut-off point, 24 men had received treatment, and 12 of these remained on the study. Subjects were given 400mg orteronel twice a day, plus 5mg prednisone twice a day, and 75mg/m2 doses of docetaxel in three-week cycles.
Nine men discontinued because of adverse events, including neutropoenia, white blood count reduction and fatigue. Two subjects died during the study because of disease progression and respiratory distress, which were not considered related to treatment.
Median testosterone levels decreased to below 0.2ng/dl at three months. The median time to PSA progression was six months, and the median time to radiologic progression had not been reached.
There was no evidence of any drug-drug interactions between orteronel and the other components of the therapy, and the regime appeared to be tolerable while providing androgen lowering activity.
References
1. T. Kaku et al. Bioorg. Med. Chem. 2011, 19, 6383
2. D.J. George et al. J. Clin. Oncol. 2012, 30 (Suppl.), Abst. 4549
3. M. Hussain et al. J. Clin. Oncol. 2013, 31 (Suppl.), Abst. 5076
4. D. Petrylak et al. J. Clin. Oncol. 2013, 31 (Suppl.), Abst. 59
