Abstract CT418: A Phase Ib study of BKM120 combined with abiraterone acetate for castrate-resistant, metastatic prostate cancer

Introduction: There is significant cross-talk between PI3-kinase (PI3K) and androgen receptor (AR) signaling pathways, respectively, which are both critical for cell survival in castrate-resistant prostate cancer (CRPC). The primary study objective (NCT01741753) is to determine the safety profile and maximum tolerated dose (MTD) of BKM120 (pan-PI3K inhibitor) in combination with abiraterone/prednisone (A/P) in CRPC patients. The secondary study objectives are to assess the impact of PTEN status on duration of response/time to progression in the expansion cohort, and to evaluate the impact of BKM120 on a PI3-kinase activation fingerprint in metastatic bone or lymph node tissue samples. An exploratory objective of the study is to assess the effect of BKM120 on transcription of a set of AR-regulated genes in metastatic bone biopsy samples. Methods: The trial design involves a 14 day lead-in phase with BKM120 alone, to assess single-agent toxicity and perform correlative studies. A/P is combined with BKM120 at the end of 14 days using the standard 3+3 dose-escalation design with 3 dose levels of BKM120 (80 mg, 100 mg, 120 mg, respectively), and participants are assessed for safety and MTD on the combination therapy. To determine pharmacodynamic impact of single agent BKM120 on the PI3K activation signature at a metastatic site, a mandatory CT-guided bone or lymph node biopsy is performed prior to BKM120 initiation and at the end of 2 weeks on BKM120 single-agent therapy. Immunohistochemical (IHC) stains for three markers (p-AKT, p-S6 and PTEN) are used to obtain a semi-quantitative PI3K activation score, based on the quartile levels of continuous staining scores of each marker. Results: The clinical, PSA biochemical responses, immunohistochemical and molecular RT-PCR data for three enrolled patients are summarized here. The first patient had symptomatic bone pain with limited functional mobility at baseline, and was treated with the first BKM120 dose level of 80 mg daily. He had a decline in PSA from 156.5 to 129.6 during the lead-in phase with single-agent BKM120 treatment with partial symptomatic pain relief. Interestingly, comparison of pre- and post-treatment metastatic bone tumor IHC staining on single-agent BKM120 showed inhibition of phospho-S6 staining. Upon adding A/P to BKM120 treatment, he had a striking decline in his PSA to 23.3 within 1 week, which reached a nadir of 9.2 within 4 weeks of combination therapy treatment. This striking biochemical improvement corresponded to a marked decline in narcotic pain requirements, increased mobility and quality-of-life. However, he developed clinical, biochemical and radiographic disease progression after 4 cycles of combination therapy treatment, so had to withdraw from study. The second and third patient had a >90% biochemical improvement within 4 weeks of combination therapy treatment and remain on study to date. To evaluate cross-talk between AR and PI3K signaling in the bone microenvironment, RT-PCR analyses on pre- and BKM120-treated bone biopsy samples were performed. The results showed that the feedback relationship between PI3K and AR signaling are heterogeneous, and dependent on the PTEN status of the tumor. Conclusion: The pan-PI3K inhibitor/abiraterone combination is well-tolerated, and demonstrates promising anti-tumor activity in CRPC patients. Citation Format: Akash Patnaik, Massimo Loda, Justin Kung, Jim Wu, MaryEllen Taplin, Philip Kantoff, Lewis Cantley, Steven Balk, Glenn Bubley. A Phase Ib study of BKM120 combined with abiraterone acetate for castrate-resistant, metastatic prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT418. doi:10.1158/1538-7445.AM2014-CT418