A phase Ib open-label, dose escalation and expansion study to investigate the safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK525762 in combination with abiraterone or enzalutamide in metastatic castrate-resistant prostate cancer.

Abstract

TPS391 Background: Metastatic castrate-resistant prostate cancer (mCRPC) remains an incurable illness as resistance develops after androgen deprivation therapy (ADT) and/or androgen receptor (AR) axis targeted therapies. The bromodomain (BRD) and extraterminal (BET) proteins are critical for transcription. Preclinically, one of these proteins, BRD4, acts in complex with AR to mediate androgen signaling that leads to prostate cell growth and proliferation. GSK525762 is an oral pan-BET inhibitor that suppresses BET dependent activated AR-driven transcription. Combined with androgen production or receptor targeted agents like abiraterone or enzalutamide, GSK525762 may enhance efficacy of or overcome resistance to either agent. Methods: This is a Phase Ib open-label, dose-escalation study to evaluate the safety and efficacy of oral administration of GSK525762 in combination with either abiraterone plus prednisone (Arm A) or enzalutamide (Arm B) in mCRPC patients whose disease has progressed on prior abiraterone or enzalutamide. Patients must have documented prostate cancer progression as assessed by rising PSA or radiographic progression of soft tissue by PCWG3-modified RECIST 1.1 criteria or bone metastasis. Dose escalation is designed to identify safe doses to move into dose expansion. Dose expansion will explore safety and efficacy in patients who failed in first line (L2 population) or after multiple lines of prior therapy (LX population). Primary objectives include defining the safety, tolerability and clinical activity of GSK525762 when combined with products in Arm A or Arm B. Primary clinical activity endpoint is defined as the response rate of subjects achieving a 50% or more reduction from baseline of PSA at 12 weeks or thereafter. Dose escalation will employ a modified Toxicity Probability Interval (mTPI) design. Dose expansion will use a Bayesian adaptive design, which will calculate posterior probability that utility of the dose is clinically significant at interim futility analysis for each dose level. Funding: GSK Clinical trial information: NCT03150056.

Potential of histone deacetylase inhibitors in the control and regulation of prostate, breast and ovarian cancer

“…In mCRPC patients whose disease has progressed on prior abiraterone or enzalutamide, a phase Ib open-label, doseescalation study was conducted to assess the safety and efficacy of oral administration of GSK525762 in combination with either abiraterone plus prednisone (Arm A) or enzalutamide (Arm B) (Vaishampayan et al, 2018). In metastatic CRPC, a phase Ib/IIa clinical trial combining the BETi PLX2853 with abiraterone or olaparib has recently been begun (NCT04556617).…”

AR Splicing Variants and Resistance to AR Targeting Agents

“…Thus, disrupting this interaction with BET inhibitors hampers PCa growth [ 74 ]. Several BET inhibitors are under development (e.g., GSK525762, ODM-207, ABBV-075, JQ1, OTX015, ZEN-3694, GS-5829, PFI-1) [ 67 , 74 , 75 , 76 , 77 , 78 , 79 ], most of which have been shown to suppress AR-V7 in preclinical studies [ 76 , 77 , 78 , 80 ]. Among them, ZEN-3694 in combination with enzalutamide demonstrated acceptable tolerability and potential efficacy in phase Ib/IIa clinical trial (NCT02711956) [ 67 ].…”

Chemogenomics for drug discovery: clinical molecules from open access chemical probes

“…47 It is also being evaluated as part of a combination therapy for breast cancer (NCT02964507, expected completion August 2021) 48 and prostate cancer (NCT03150056, expected completion August 2021). 49 OTX015/MK-8628. OTX015 (Fig.…”