Patient Characteristics and Treatment
Between October 2007 and May 2008, 33 men with metastatic prostate cancer progressing despite a castrate level of testosterone were enrolled across five study centers within the U.S. lists the baseline patient demographics and clinical characteristics. The median baseline PSA level was 23 ng/mL and ranged from 5.9 to 1110 ng/mL. All patients had radiographic evidence of metastatic disease and 26/33 (79%) had bony metastases. All patients had received androgen deprivation therapy with an LHRH antagonist (n = 31) or orchiectomy (n = 2), and 32 (97%) had also received an antiandrogen and undergone antiandrogen withdrawal. All patients had castrate serum testosterone levels (median 8.5 ng/dL; range 0.9 to 24.1 ng/dL). The majority of patients (88%) had received two prior hormonal therapies, with three patients (9%) having received up to four hormonal therapies including estrogens or glucocorticoids. No patient had undergone prior treatment with abiraterone, ketoconazole, or chemotherapy. At the time of analysis (January 2010), the study population had received a median of 63 weeks (range 8 to 104 weeks) of treatment with abiraterone acetate plus prednisone, with 15 patients (46%) continuing to receive therapy. Treatment had been discontinued due to disease progression in 14 patients (42%) and adverse events in three patients (9%); two patients discontinued due to grade 3 adverse events (1 each for back pain and pathological fracture). Twenty-six patients were evaluable for the bone flare phenomenon. All 33 patients were evaluable for response and safety.
Baseline Demographic and Clinical Characteristics of 33 Patients Enrolled in a Phase II Trial of Abiraterone Acetate Plus Prednisone.
PSA Response and Durability
Changes in PSA, both after 3 months of therapy and maximal, for each patient are depicted in . A decline in PSA of ≥ 50% after 3 months, the primary study end point, was confirmed in 22 (67%) of 33 patients. Confirmed maximal declines in PSA of ≥ 50% and ≥ 90% were seen in 26 (79%) and 15 (46%) patients, respectively. In two patients, PSA levels became undetectable (≤ 0.1 ng/mL), declining from baseline values of 204 ng/mL and 9 ng/mL, respectively. These patients continue to receive study therapy after 20 and 21 months, both with continued stable bone scans and resolution of adenopathy in one patient.
Changes in prostate specific antigen (PSA) levels in castration-resistant prostate cancer (CRPC) patients treated with abiraterone acetate plus prednisone. Waterfall plots of maximal PSA change (top panel) and PSA change at week 12 (bottom panel).
Median follow-up time for this analysis was 19.3 months. The median time to PSA progression was 16.3 months (95% CI; 9.2 months, not estimable, ). Nineteen (58%) patients of have received study treatment for at least 12 months.
Time to prostate specific antigen (PSA) progression in castration-resistant prostate cancer (CRPC) patients treated with abiraterone acetate and prednisone (n = 33). CI, confidence interval; NE=Not Estimable
Objective Tumor Response
Of 13 patients with measurable disease consisting of lymphadenopathy, nine (69%) had a partial response and three (23%) had stable disease.
Bone Scan results and Bone Scan Flare
At baseline, 26 patients had positive bone scans. One had a solitary bone metastasis, seven patients had between two and four metastases, and 18 patients had more than four discrete metastases. Twenty three patients had the combination of a positive baseline bone scan, ≥50% decline in PSA after three months and bone scans at 3 and 6 months and thus are available for evaluation of bone scan flare. Reports are available on 92 total bone scans from 41 unique radiologists dispersed geographically amongst the study sites. Of the 23 eligible patients, bone scan progression was indicated in the radiologist's report in 12 (52 %) of the scans taken after 3 months of therapy. Four of the 12 patients had a report indicating “progression of disease” without new lesions whereas for 8/12 patients, progression of disease due to new lesions was noted. Imaging following 6 months of therapy, the radiologists report in 10/12 indicated subsequent improvement, thereby meeting the definition of bone flare. Thus, overall, bone scan flare was observed in 10 of 23 (43.5%) evaluable patients or 10 of 33 (30%) enrolled patients.
Two patients were not evaluable: one had persistent PSA declines (from baseline to the end of month 3 and from month 3 through month 6 of therapy) with a negative bone scan at baseline that was not repeated; the second discontinued study therapy after 4 months on therapy due to a pathological femoral neck fracture despite a PSA decline of 91.7%.
In the 10 patients with bone flare, median age was 72 (range 54 to 85) years, median PSA at baseline was 32.4 (range 6.8 to 204.3) ng/dL, and median alkaline phosphatase at baseline was 88.5 (range 49.0 to 372.0) units/L, not significantly different from the study population as a whole. Alkaline phosphatase did not change in patients experiencing flare: median baseline value was 88.5 units/L. After 3 months of therapy, 88.5 units/L and after 6 months, 83.5 units/L. Three patients had between two and four metastases and seven patients had multifocal disease. Patient disposition is summarized in .
Disposition of patients who did and did not experience a bone scan flare.
Radiologist interpretation of bone scan in these 10 patients was as follows, five patients had month 4 bone scans read as having increased intensity of existing lesions; the other five patients had bone scans that were read as having new lesions. Images in demonstrate this. Of these 10 patients with flare, six had continued declines in PSA, and four had modest increases in PSA (range 0.14–5.1 ng/dL). Of the two remaining patients with discordant results after 3 months of therapy, both continued to have PSA declines past 3 months but both had bone scans after 6 months of therapy that were interpreted as progressive disease. The first of these two patients came off study after 8 months of therapy (and thus never underwent another bone scan), while the other patient discontinued study therapy after 15 months.
Figure 4 Examples of bone scan flare in patients receiving abiraterone acetate. (A) Example of a patient with a declining prostate specific antigen (PSA) but a month 4 bone scan being read as having a new metastasis in the right pubic ramus, as indicated by the (more ...)
Adverse events were most often grade 1 or 2 (see ) and clinically manageable. The most common treatment-related adverse events were fatigue, hot flush, bone pain, peripheral edema, arthralgia, dizziness, and hypokalemia. In addition to those listed in , there was a single occurrence each of grade 3 supraventricular arrhythmia and atrial flutter. One incident each of grade 3 hypokalemia and hypertension each was observed.
Incidence of Most Frequent (≥ 10%) Treatment-related Adverse Events (n = 33)*