Men with castration-resistant prostate cancer (CRPC) that was not mediated by androgen suppression experienced better outcomes when treated with an antifungal agent, according to a small clinical study reported here.
Men treated with the maximum recommended dose of itraconazole had a median progression-free survival (PFS) of 36 weeks, and 61% of the patients were alive without disease progression at 6 months.
Half of patients on high-dose therapy remained alive without prostate-specific antigen (PSA) PFS at 6 months. Three-fourths of the patients had stable disease or a partial response, Emmanuel S. Antonarakis, MD, said at the American Association for Cancer Research meeting.
“We think these results support a role for this nonhormonal treatment in castration-resistant prostate cancer,” Antonarakis, of Johns Hopkins, told MedPage Today. “We also observed changes in a marker of Hedgehog pathway activity, which correlated with modulation of PSA response and PSA PFS.”
Commercially available for treatment of fungal infections, itraconazole (Sporanox) has novel functional traits that suggested potential applicability in cancer. Specifically, preclinical studies showed evidence of angiogenesis inhibition and inhibition of the Hedgehog signaling pathway, Antonarakis said.
New Treatments for Castration-Resistant Prostate Cancer
Most of us were taught in medical school that prostate cancer was exquisitely dependent on circulating androgens and that castration, whether surgical or medical, resulted in significant decrease in tumor mass, associated pain in the setting of metastatic disease, and reduction in acid phosphates and prostate-specific antigen (PSA).
However, we were told, the cancer would inevitably adapt to the androgen- deprived milieu and progress. Socalled androgen-independent (androgenresistant) prostate cancer (now more often referred to as castration-resistant prostate cancer [CRPC]) was the reason that prostate cancer represents the second most common cause of cancer mortality.
For the treatment of moderate pain or moderately severe pain including arthralgia, headache, myalgia, dental pain following oral surgery such as extraction of impacted molars or chronic conditions such as low-back pain, bone pain and cancer-related pain.
- Adults: 100 mg/dose PO or 400 mg/day PO.
- Elderly >= 75 years: 100 mg/dose PO or 300 mg/day PO.
- Elderly 65 – 74 years: 100 mg/dose PO or 400 mg/day PO.
- Adolescents >= 16 years: 100 mg/dose PO or 400 mg/day PO.
- Adolescents 13 – 15 years: Maximum dosage has not been determined.
- Children: Maximum dosage has not been determined.
We should have questioned this concept more vigorously. Certainly there were clues that the role of androgens in prostate cancer was not “all or none.” We know, for example, that once a man had progressed to the socalled androgen-independent state, cessation of castration (made possible with diethylstilbestrol but more completely with the advent of luteinizing hormone-releasing hormone agonists) most often resulted in more rapid tumor progression. Even before this we had learned from pioneering studies by Willett Whitmore at Memorial Sloan- Kettering Cancer Center that giving testosterone to men previously castrated in an attempt to improve cytotoxic chemotherapeutic response was disastrous, with severe exacerbation of the tumor and patient death.
Investigators hypothesized that itraconazole would slow PSA and disease progression in men with metastatic CRPC and no prior exposure to chemotherapy. They also hypothesized that the drug would be safe for long-term use, given its favorable toxicity profile during extended use in patients with chronic fungal infections and its lack of adrenal androgen suppression (as compared with antifungal agent ketoconazole).
Antonarakis and colleagues randomized 46 patients with CRPC to one of two doses of itraconazole: 200 or 600 mg/d. Treatment continued until clinical or radiographic progression or development of unacceptable toxicity.
The primary endpoint was the proportion of patients without PSA progression at 24 weeks. Progression was defined as ≥25% and 2 ng/mL rise from baseline or nadir PSA, based on two PSA measurements 4 weeks apart.
Initially, the trial had an enrollment target of 58 patients. However, the low-dose arm closed after 17 patients because of futility. The high-dose arm continued accrual to the planned 29 patients, 25 of whom were evaluable for the primary endpoint.
The study population had a median age of about 72, an average of 6.5 metastases, and exposure to an average of 2.5 hormonal therapies. About a third of patients in each arm had a history of treatment with ketaconazole.
The median follow-up duration was 11.9 weeks in the low-dose arm and 21.6 weeks in the high-dose arm.
The high-dose itraconazole group had a 24-week PPFS of 48.4% versus 11.8% for the 200-mg group and median PPFS of 17 weeks and 11.9 weeks, respectively.
The low-dose group had PFS and median PFS of 18.8% and 11.9 weeks, respectively, about one-third the rates for the 600-mg arm.
Antonarakis reported that eight (28.6%) patients the 600-mg group had PSA declines ≥30%, including declines exceeding 50% in four (14.3%) patients. Tumor assessments showed that 2 (11.1%) patients in the high-dose arm had partial responses and 13 (72.2%) had stable disease.
Assessment of androgen synthesis showed that testosterone levels did not change significantly from baseline to week 12 in patients in the 600-mg itraconazole arm. Aldosterone declined significantly at 4 (P=0.002) and 12 weeks (P=0.001).
BMI correlates to risk for biochemical recurrence post-surgery
According to data presented on Tuesday at the American Association for Cancer Research annual meeting in Chicago, body mass index (BMI) at the time of surgery correlates with risk for biochemical recurrence of prostate cancer after first-line treatment with radical prostatectomy.
Most prior studies that have suggested a connection between excess weight/body mass and risk for progression of prostate cancer have been retrospective in nature. The new data presented by Freeman et al. this week are based on a prospective assessment of the projected outcomes of men awaiting radical prostatectomies for clinically localized prostate cancer at four urology clinics in the Chicago area.
The investigators carefully assessed the pre-treatment risk of biochemical progression (using the D’Amico risk criteria) and the body mass status of this cohort of patients and then sought to understand the correlation between D’Amico risk score and BMI.
Levels of dihydroepiandosterone increased from baseline at 4 and 12 weeks (P=0.03, P=0.001), as did adrenocorticotropin hormone levels (P=0.005, P=0.002).
To assess effects of treatment on Hedgehog pathway signaling, investigators measured GLI1 response in skin punch biopsies. They found that GLI1 was downregulated in 17 of 25 evaluable patients in the 600-mg itraconazole group.
Modulation of GLI1 correlated significantly with PPFS (P=0.028) and PSA response (P=0.01) but not PFS.
Investigators have discussed the possibility of conducting a larger, placebo-controlled evaluation of itraconazole in CRPC, Antonarakis said.
Antonarakis had no disclosures.
Primary source: American Association for Cancer Research
Source reference: Antonarakis ES, et al “A randomized phase II study of two doses of itraconazole in men with metastatic castration-resistant prostate cancer (mCRPC)” AACR 2012; Abstract LB-224.