Becky McCall

March 07, 2012

March 7, 2012 (Paris, France) — An oral investigational agent leads to significant and durable declines in prostate-specific antigen (PSA) levels in patients with nonmetastatic castration-resistant prostate cancer, investigators reported here at the European Association of Urology 27th Annual Congress.

Orteronel (TAK-700, Millennium Pharmaceuticals) is a nonsteroidal selective inhibitor of 17,20 lyase. It suppresses androgen production and appears to have less of an effect on cortisol synthesis, allowing steroid-free dosing.

According to phase 2 interim results, presented by Maha Hussain, MD, FACP, professor of medicine and urology in the Departments of Internal Medicine and Urology at the University of Michigan in Ann Arbor, orteronel has manageable toxic effects, making it attractive for long-term use.

The primary end point of the study was a PSA level of 0.2 ng/mL or less. Secondary end points included safety, PSA response rates at 3 and 6 months, time to disease progression, time to metastases, and duration of progression-free survival.

In addition, changes in endocrine markers — serum testosterone, adrenocorticotropic hormone, dehydroepiandrosterone, luteinizing hormone, corticosterone, and cortisol concentrations — were assessed.

Dr. Hussain reported that 38 patients received orteronel 300 mg twice a day without prednisone in 28-day treatment cycles. That regimen was continued until PSA progression, metastases, or unacceptable toxic effects occurred. At 6 months, 44% of men remained on treatment.

At 3 months, 16% of men achieved the primary end point of a PSA level of 0.2 ng/mL or less, and 32% had experienced a reduction in PSA of 90% and 76% achieved a reduction of 50%.

"Practically, everyone had a PSA decline to some degree, but the important aspect of this is durability of response, as reflected by the percentage of patients maintaining their response at 6 months," Dr. Hussain explained.

At 6 months, 8 men had a decline in PSA level of at least 90%, 9 had a decline of 50% to 89%, and 3 had a decline of 30% to 49%. Two men had undetectable PSA levels.

Median time to PSA progression was 14.8 months. "You do not see this rate and durability of response...with other agents, such as steroids and ketoconazole," Dr. Hussain told Medscape Medical News.

"When the cancer is so advanced, as in the case of metastatic castration-resistant disease, the effect of these agents on survival is generally modest. The question is whether using these agents earlier, when the tumor is smaller and likely to be less resistant, will lead to better outcomes," noted Dr. Hussain.

At the 6- and 12-month assessments, 97% of patients were free from metastasis. "The follow-up time is short at the moment, but this result is important because we selected patients we felt were at a higher risk of developing metastasis sooner," said Dr. Hussain.

Adverse events were reported in 36 of the 38 men. According to Dr. Hussain, the most frequent adverse effects were fatigue and low-grade events. The most common high-grade events were hypertension (in 13% of patients), shortness of breath (in 8%), and pneumonitis (in 5%). Two patients discontinued treatment because of grade 2 adrenal insufficiency, but upon review, only 1 was found to have laboratory values consistent with a hypoadrenal state and required corticosteroid supplementation, but no patient required corticosteroid supplementation because of mineralocorticoid excess. "The vast majority of side effects were lower grade," she reported.

Most notably, orteronel had little impact on corticosteroid production. Cortisol levels dropped slightly because orteronel inhibits the enzyme that makes it, but Dr. Hussain pointed out that the drop in cortisol level was within the normal range.

Other drugs with a similar mechanism of action, such as abiraterone, require steroid use because of the effect on 17α-hydroxylase activity. "This is an important difference at the doses and durations tested," explained Dr. Hussain. "Researchers will need to ask whether the selectivity of orteronel is reduced with higher doses and whether higher doses are actually needed."

"The idea of having people tied to a drug plus a steroid over the long term is not medically very attractive, especially in elderly patients who have comorbidities," she added.

Dr. Hussain cautioned that it is necessary to wait for the results of the phase 3 trials of orteronel in metastatic prostate cancer, which are now being conducted, before drawing any conclusions about its use as a single agent in metastatic disease.

In an interview with Medscape Medical News, Ferdinand Labrie, MD, PhD, director of the Molecular Endocrinology, Oncology and Genomics Research Center and Laval University Hospital Research Center, in Québec City, Quebec, Canada, explained how the antiandrogen effect of orteronel can be explored further.

"Since it is well recognized that androgens are the prostate before and after medical (by gonadotropin-releasing hormone agonists) or surgical castration, and that responsiveness plays a significant role at all stages of prostate would seem important to compare the effect of orteronel with an antiandrogen, such as flutamide or bicalutamide, at appropriate doses, to achieve the best possible blockade of androgens and ultimately possibly combine the 2 drugs."

"Since, after castration, very low serum levels of testosterone result from variable leakage from intracellular testosterone made locally in peripheral tissues, a much better estimate of the androgen pool left after castration plus orteronel would be measurement of androsterone and 3α-androstanediol glucuronide [levels]," Dr. Labrie added.

This study received funding from Millennium Pharmaceuticals. Dr. Hussain reports being a consultant to Johnson & Johnson, Astellas, Lilly, and Merck. Dr. Labrie has disclosed no relevant financial relationships.

European Association of Urology (EAU) 27th Annual Congress: Abstract 124. Presented February 25, 2012.