Deletions of PTEN are common in metastatic CRPC, particularly as early driver events, and lead to constitutive activation of PI3K/AKT/mTOR signaling pathways. Such activation not only readily feeds forward to drive cellular proliferation and survival, but, in prostate cancer specifically, can permit evasion of AR-targeted therapies. Consequently, the authors completed a phase I study to evaluate safety and preliminary activity in the rescue of sensitivity to enzalutamide, a potent AR inhibitor, by the addition of an inhibitor of PI3Kβ (GSK2636771) specifically in mCRPC tumors deficient in PTEN (via IHC).

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