Researchers at Johns Hopkins have, for a while, been investigating the potential of the antifungal agent itraconazole as a treatment for men with metastatic, castration-resistant prostate cancer (mCRPC). We last reported on this research nearly a year ago, based on a presentation at the annual meeting of the American Society of Clinical Oncology (ASCO) in 2011.
Anonarakis and his colleagues have now provided final results from the randomized Phase II trial of two different doses of itraconazole (either 200 or 600 mg/day). Their data were presented last week at the annual meeting of the American Association for Cancer Research (AACR) in Chicago.
According to the published abstract and a report on the MedPageToday web site:
- 46 men with mCRPC were randomized to be treated with one of two doses of itraconazole.
- 17 men received itraconazole at a dosage of 200 mg/day but enrolled ment of patients at this dosage was stopped “for futility” (i.e., because it was insufficiently effective).
- 29 men received itraconazole at a dosage of 600 mg/day.
- Patients were followed until clinical or radiographic progression was observed or until development of unacceptable toxicity.
- The primary study endpoint was the proportion of patients with PSA-based progression-free survival (PPFS) at 24 weeks (defined as a ≥25 percent increase in PSA level from baseline or nadir PSA, based on two PSA measurements taken 4 weeks apart).
- Secondary endpoints included
- Progression-free survival (PFS) at 24 weeks (based on clinical/radiographic progression or death, but not rising PSA)
- Median PFS
- Median PPFS
- Maximum decline in PSA levels
- Progression was defined as a ≥25 percent increase in PSA level and a 2 ng/mL rise from baseline or nadir PSA, based on two PSA measurements taken 4 weeks apart.
The study results reported by Antonarakis et al. are as follows:
- The average (median) age of the patients was about 72 years.
- Patients had an average of 6.5 metastases, and had previously received an average of 2.5 hormonal therapies.
- About 33 percent of patients in each arm had a history of treatment with ketaconazole.
- The average (median) follow-up on treatment with itraconazole was 11.9 weeks in the low-dose arm and 21.6 weeks in the high-dose arm.
- For men in the high-dose itraconazole group
- 4/29 patients (14 percent) had PSA decreases of > 50 percent.
- Another 4/29 patients (14 percent) had PSA decreases of ≥ 30 percent.
- 14/29 patients (48 percent) demonstrated PPFS at 24 weeks.
- 17/29 patients (62 percent) demonstrated PFS at 24 weeks.
- Median PPFS was 17 weeks.
- Median PFS was 36 weeks.
- For men in the low-dose itraconazole group
- No patients had PSA decreases of > 50 percent.
- 2/17 patients (12 percent) demonstrated PPFS at 24 weeks.
- 3/16 patients (19 percent) demonstrated PFS at 24 weeks.
- Median PPFS was 11.9 weeks.
- Median PFS was 11.9 weeks.
Antonarakis and his colleagues have suggested that itraconazole at a dose of 600 mg/d could potentially be used to delay disease progression in men with mCRPC and no prior exposure to chemotherapy. They also have noted that itraconazole does not suppress adrenal androgens (as compared with the similar antifungal agent ketoconazole).
The apparent clinical effects of itraconazole may not, however, be sufficient on their own to have major utility with the availability of drugs like abiraterone acetate and (potentially) enzalutimide (MDV3100). However, one is tempted to wonder whether combinations of abiraterone + itraconazole or enzalutimide + itraconazole might have significant impact in the management of men with chemotherapy-naive mCRPC.
Itraconazole is an oral, generically available, low-cost, antifungal agent. It therefore has the potential to be used easily and relatively cheaply in combination with drugs like abiraterone and enzalutimide. However, whether it is safe and effective to use in such combinations will need further exploratory trials. Data available to date suggest that itraconazole can be given with relative safety to men with mCRPC. However, itraconazole is not a benign drug. It has a well-understood history of side effects that can include fatigue, nausea, anorexia, rash, hypokalemia, hypertension, edema, and even heart failure in some patients.