A Phase Ib Trial Of Enzalutamide With Venetoclax In Metastatic Castration-Resistant Prostate Cancer (Mcrpc).

TPS5599 Background: Androgen receptor (AR) signaling plays an important role in prostate cancer (PCa) cell survival and proliferation. Xenograft and PDX models demonstrate that untreated PCa harbors AR−/lo stem cells not critically dependent on androgens for survival.1 Furthermore, castration and enzalutamide (enza) leads to expansion of both AR−/lo and AR+/hi resistant clones in xenograft tumors, resulting in two distinct CRPC-propagating populations.2 However, most current CRPC treatments are directed towards AR+/hi cells. RNAseq revealed that BCL-2 is highly up-regulated in AR−/lo tumors post-castration and in AR+/hi CRPC tumors post-enza.2 Strikingly, BCL-2, but not BCL-XL and MCL-1, was selectively up-regulated in these xenograft tumors. These results were subsequently validated in patient CRPC datasets.2,3 Venetoclax (ven), a potent and selective BCL-2 inhibitor, inhibits enza resistance in AR+/hi CRPC and tumor growth in AR−/lo xenograft models.2 A recent phase I trial of ven combined with tamoxifen showed promising activity in ER+ and BCL2+ metastatic breast cancer.4 We hypothesize that co-targeting AR−/lo and AR+/hi PCa clones with ven and enza will prevent the emergence of enza resistance in human mCRPC. Methods: This is a phase Ib, single-center, single-arm trial of enza (160mg/d) with ven in patients with mCRPC that has progressed on previous therapies which may include anti-androgens. Three dose-levels of ven (400mg, 600mg and 800mg/d q28d) will be evaluated using a 3+3 study design. Fifteen to 18 patients will be enrolled in this phase to assess dose-limiting toxicities, maximum tolerated dose, and recommended phase II dose. Aims of correlative studies include (1) assessing the pharmacokinetic interaction between enza and ven, (2) identification of potentially predictive blood and tissue biomarkers (including pre- and post-treatment CTC levels, expression of BCL2, AR, ARv7 in pre-and post-treatment biopsies and CTCs), (3) measurement of pre- and post-treatment BCL2 expression in peripheral blood mononuclear cells as a surrogate for ven activity, and (4) the development of 3D organoid models from CTCs and biopsies. The trial is open with 3 patients enrolled to dose-level 1, and 2 patients currently at dose-level 2. Correlative studies are ongoing. References: (1) Qin J, et al. Cell Stem Cell. 10(5): 556-69, 2012 (2) Li Q, et al. Nat Commun. 9(1): 3600, 2018 (3) Rajan P, et al. Eur Urol. 66 (1):32-9, 2014 (4) Lok SW, et al. Cancer Discov. 9(3):354-69, 2019. Clinical trial information: NCT03751436 .