A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer

Abstract

Purpose Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride. Experimental Design Eligible metastatic CRPC patients underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this time, high-dose dutasteride (3.5mg daily) was added. Patients continued therapy until study withdrawal or radiographic progression. Repeat metastasis biopsy was obtained at progression. The primary endpoint was to assess mechanisms of resistance. Serum hormone and abiraterone levels were assessed. Tissue was assessed for androgen receptor (AR) and AR splice variant-7 (ARV7) expression. Results Forty patients were enrolled. 60% (n=24) achieved a ≥50% reduction in PSA. The median time to radiographic progression was 11 months. Nearly all baseline (n=29/30) and post-treatment (n=16/16) tumors tested for AR nuclear expression were positive. Of those tested, ARV7 expression was present in 48% (n=10/21) of baseline and 42% (n=5/12) of treatment discontinuation specimens. Compared to patients with higher serum abiraterone levels at treatment discontinuation, patients with lower levels had higher circulating androgens. Conclusions Despite increased androgen synthesis inhibition, we demonstrate that tumor AR axis remains important in disease progression. We highlight that abiraterone metabolism and pharmacokinetics may play a role in resistance. The non-comparative design limits conclusions on the efficacy of dual therapy with abiraterone and dutasteride, but the results support development of further multifaceted approaches towards AR inhibition.

Circulating steroid hormone variations throughout different stages of prostate cancer

“…The reported values in subjects with BPH or PC appear to be similar to those in healthy controls (1.5-2.5 nM) (Hammond et al 1977, 1978, Belanger et al 1994. Elevated pregnenolone levels were observed in abiraterone-treated CRPC patients (16.3 nM, IQR 9.85-27.77 nM) using LC-MS/MS, and it was also noted that patients with high serum abiraterone levels (>35 ng/mL) had higher pregnenolone levels than patients with low abiraterone concentrations (McKay et al 2017). This can be explained by impaired conversion of pregnenolone to 17OH-pregnenolone because of CYP17A1 inhibition by abiraterone, resulting in the accumulation of the former steroid.…”

“…In one trial, median serum testosterone in CRPC patients declined from 0.35 nM at baseline to 0.02 nM after 12 weeks treatment with 1000 mg abiraterone and 5 mg prednisone daily (McKay et al 2017). This is lower than the in vitro activation thresholds observed in literature, although intracellular levels may differ (Sonneveld et al 2005, Campana et al 2016.…”

“…In each of these studies, however, abiraterone treatment strongly reduced DHEAS levels by 80-90%, with on-treatment values between 0.14 and 0.4 µM. Even lower post-abiraterone treatment levels (median <0.03 µM) have been reported using highly sensitive LC-ESI-MS/MS by McKay and coworkers after 24 weeks of treatment (McKay et al 2017). Importantly, not only abiraterone but also administration of prednisone contributes to this effect through attenuation of ACTH levels.…”

“…Like androstenedione, serum DHEA levels are reduced upon treatment with abiraterone with reported values between 0.08 and 2.7 nM in several LC-MS/MS studies (Attard et al 2008, McKay et al 2017. A possible explanation for circulating DHEA levels not 24:11 being reduced as strongly as testosterone may be the continued presence of high (albeit diminished) levels of DHEAS after abiraterone treatment.…”

“…Even lower levels (<0.086 nM and <0.44 nM) were achieved in two studies using LC-MS/MS (Kim et al 2014, McKay et al 2017 in which CRPC patients were treated with abiraterone and prednisone. DHT concentrations necessary to activate the AR in vitro are estimated to be between 0.05 and 0.5 nM, and in some mammaliancell-based luciferase assays EC 50 values as low as 0.01 nM were measured (Sonneveld et al 2005, Dennis et al 2008, Campana et al 2016, Lallous et al 2016.…”