Abstract Background: Prostate cancer is driven by the androgen receptor (AR) pathway, which may be targeted by inhibition of androgen synthesis (e.g. abiraterone = Abi), AR signaling (e.g. apalutmide = Apa), and/or translocation of AR to the nucleus (e.g. docetaxel = Doce). The combination of AR inhibition plus taxane chemotherapy has already demonstrated clinical benefit (CHAARTED, STAMPEDE), lending weight to the theory that combining drugs targeting different points in the AR signaling pathway is effective. We hypothesize that the combination of Apa, Abi, and Doce will be safe and efficacious. Methods: Men with progressive mCRPC, intact organ function, and no prior exposure to Apa (ever) or Doce within 3 years were enrolled. Standard Abi 1000 mg daily, Doce 75 mg/m2 q3 weeks, and prednisone 5 mg BID was administered with different doses of Apa. Cohort 1 = Apa 120 mg daily, Cohort 2 = Apa 240 mg daily, Cohort 3 (if necessary) = Apa 180 mg daily in modified 3+3 design. The primary endpoint of the Phase I dose-escalation portion of the study was determination of dose-limiting toxicity (over 6 weeks) and recommended Phase II dose (RP2D). Results: Nine men (3 Apa 120 mg, 6 Apa 240 mg) with mCRPC and median age 69, median PSA 8.18 (range 0.07 - 278.5) were treated. 67% with bone, 78% LN, 11% lung, 11% other metastases. No DLT occurred with Apa 120 mg and 1 of 6 with Apa 240 mg had possibly related grade 3 hypertension. All had >95% PSA decline (78% with > 99% decline). Of 5 with measureable disease, 100% had RECIST response. 6 of 7 with post-treatment CTC counts were undetectable. Conclusions: The combination of apalutamide plus abiraterone, docetaxel, and prednisone at full doses is tolerable, with the RP2D of the regimen Apa 240 mg daily, Abi 1000 mg daily, docetaxel 75 mg/m2 q3 wks, and prednisone 5 mg BID. The combination appears to be associated with a high rate of PSA decline, measurable disease response, and CTC count control. Tumor tissue, plasma ctDNA, and CTCs are being collected for analysis. Enrollment to the expansion phase of study to further refine efficacy and toxicity at PCCTC sites is ongoing including assessment of response and resistance biomarkers [NCT02913196] Citation Format: Ana Molina, Paul Christos, Amy Hackett, Luke Nordquist, Edward Gelmann, Mark Stein, Cora Sternberg, Himisha Beltran, Lauren Gracey, Giuseppe Galletti, Paraskevi Giannakakou, David M. Nanus, Scott T. Tagawa. Phase I trial of apalutamide plus abiraterone acetate, docetaxel, and prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT097.