85 Background: Androgen receptor (AR) targeting therapies prolong survival of patients with metastatic castration-resistant prostate cancer (mCRPC); however, in many cases, resistance develops, resulting in disease progression. Activation of the PI3K/AKT/mTOR signaling pathway is common in mCRPC and contributes to resistance, mostly due to loss of PTEN, which occurs in 40–60% of patients. Preclinical studies have demonstrated reciprocal regulation between the AR and PI3K/AKT/mTOR pathways and significant anti-tumor activity when both pathways are inhibited, particularly in models with PTEN-loss. Thus, a rationale exists to inhibit both pathways in mCRPC patients. We report interim results of a phase 1 multicohort study (NCT04087174) to confirm the acceptable dose of capivasertib, a potent, selective pan-AKT inhibitor in combination with the androgen synthesis inhibitor abiraterone acetate (AA) in mCRPC patients. Methods: Patients who had received at least one prior systemic therapy (chemotherapy or novel hormonal agent) for mCRPC were given AA (1000 mg, once daily) with capivasertib (400 mg, twice daily, 4 days on/3 days off) until unacceptable toxicity or disease progression. Dose-limiting toxicity in the first 28 days of treatment and adverse events were recorded. Results: 15 patients, median age 67 (range 49–82) years, were recruited in the USA and Spain. Twelve patients had received prior chemotherapy; 7 had two or more prior lines. Seven patients had received prior AA and 10 had received prior enzalutamide. No dose-limiting toxicities were recorded. Eight patients reported at least one grade ≥ 3 adverse event (AE). Grade ≥ 3 AEs in 7 patients were related to capivasertib: allergic reaction to medication, asthenia, type 2 diabetes mellitus, diarrhea and fatigue were each reported in 1 patient, maculopapular rash − in 2 patients, both hypokalemia and acquired Fanconi syndrome − in 1 patient. Acute kidney injury was reported in 4 patients but was not considered related to capivasertib. The most common AEs of any grade related to capivasertib were: diarrhea, 6/15 patients (40%); maculopapular rash, 5/15 (33%); fatigue, 4/15 (27%); hyperglycemia/type 2 diabetes mellitus, 4/15 (27%); nausea, 3/15 (20%); hypokalemia, 2/15 (13%); hypophosphatemia, 2/15 (13%). Capivasertib was discontinued in 4/15 patients (27%) due to AEs. Between initial screening and day 29 of treatment, 5 patients had reduced (> 20%) PSA levels, with 3 patients showing sustained falls in PSA over 12 weeks. Conclusions: In this phase 1 study combined capivasertib and AA exhibits an acceptable safety and tolerability profile. Further data on the clinical efficacy and safety of the combination are being collected in the phase 3 CAPItello-281 trial. Acknowledgments: We thank Adam Errington, PhD, of Oxford PharmaGenesis, for medical writing assistance. Funding: This trial is funded by AstraZeneca. Clinical trial information: NCT04087174.
A Phase 1/2 Study of At13387, a Heat Shock Protein 90 (Hsp90) Inhibitor in Combination with Abiraterone Acetate (Aa) and Prednisone (P) in Patients (Pts) with Castration-Resistant Prostate Cancer (Mcrpc) No Longer Responding to Aa
