The Company expects to complete the dose escalation portion of the trial and initiate the dose expansion portion of the Phase 1/2 clinical trial of ARV-471 in the first half of 2021 and anticipates sharing interim data from the dose expansion portion in 2022.
The Company also expects to initiate a Phase 1b cohort expansion of ARV-471 in combination with Ibrance® (palbociclib) in December 2020. This trial will evaluate the safety and tolerability of ARV-471 in combination with palbociclib and seek to identify a recommended combination dose.
The Company expects to begin two additional studies of ARV-471 in the second half of 2021: a combination trial of ARV-471 and another targeted therapy in second line and/or third line metastatic breast cancer, and a window of opportunity study in adjuvant breast cancer.
The combined data from these studies will inform the Company’s global development strategy and path forward toward the goal for ARV-471 to become the leading endocrine therapy in ER+/HER2- breast cancer.
ARV-110 Clinical Update
On December 14, 2020, the Company also announced updated interim data from the dose escalation portion of its ongoing Phase 1/2 clinical trial of ARV-110 in men with metastatic castrate resistant prostate cancer (“mCRPC”). The dose escalation portion of the Company’s Phase 1/2 clinical trial of ARV-110 is designed to assess safety, tolerability and PK of ARV-110 in men with mCRPC who have progressed on standard of care therapies, as well as to identify a recommended Phase 2 dose.
The Company believes that ARV-110 continues to show promising activity in a very late-line population, with prostate specific antigen (“PSA”) reductions equal to or greater than 50% (a “PSA50 response”) observed at doses greater than 280 mg, the last cohort for which the Company had previously disclosed data.
ARV-110 exposures have risen dose proportionally, and at 420 mg oral daily dosing, exposures in nearly all patients have surpassed a threshold the Company associated with tumor responses with ARV-110 in enzalutamide-resistant preclinical models of prostate cancer.
In the dose escalation portion of the trial, 76% of patients had been treated with prior chemotherapy, and 82% previously received both abiraterone and enzalutamide. Patients had a median of five prior lines of therapy. Multiple lines of therapy in nonmetastatic and metastatic castrate resistant prostate cancer are associated with a decreased responsiveness to androgen receptor (“AR”)-directed therapies and an increase in tumor heterogeneity, including in genetic mutations, which reduce the tumor’s dependence on the AR signaling axis. Genetic profiling of trial patient tumors showed genetic variability, with 84% of patients in the trial having non-AR gene mutations. As such, these patients would not be expected to respond to AR-directed agents such as ARV-110. In addition, the Company found that rates of specific AR mutations have been found to be higher than the Company anticipated based on previously published studies of men with mCRPC.
The Company has identified a molecularly defined, late-line population with a particularly strong response to ARV-110. Two of five patients (40%) with T878 or H875 mutations in AR had a PSA50 response, including one patient with a tumor size reduction of 80%.
In addition, two of 15 patients (13%) with wild-type AR also had a PSA50 response, representing activity in a broader patient population. In the full group of patients with exposures above the minimum threshold the Company predicted to be efficacious by preclinical studies, four of 28 (14%) had PSA reductions greater than 50%. The Company believes that this PSA50 response rate is substantially higher than would be expected from approved AR-directed therapies in such late line patients. Specifically, PSA50 response rates from standard-of-care AR-directed therapies generally decrease to 8%—15% in mCRPC patients with fewer prior therapies.