Phase I trial of apalutamide (Apa) with abiraterone acetate (AA) plus prednisone (P) and docetaxel (Doce) in patients with metastatic castration-resistant prostate cancer (mCRPC).
Authors: Nauseef Jones T. , Christos Paul J. , Thomas Charlene , Nordquist Luke T. , Sternberg Cora N. , Beltran Himisha , Guervil Sabrina , Galletti Giuseppe , Giannakakou Paraskevi , Nanus David M. , Tagawa Scott T. , Molina Ana M. 
Published: March 2021

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Background: The combination of AR inhibition plus taxane chemotherapy has demonstrated clinical benefit in PC ( i.e. CHAARTED, STAMPEDE), indicating efficacy when targeting the AR signaling pathway at different points. We launched a phase I study to test the hypothesis that the combination of Apa (AR signaling inhibitor), AA (CYP17 inhibitor) + P, and Doce (inhibitor of AR translocation to the nucleus) is safe and effective. Previously we reported that the full doses of all drugs were tolerated in combination and the recommended phase II dose (R2PD). Here we present addition of the expansion cohort and longer follow up. Methods: Men were enrolled with progressive mCRPC, intact organ function, and without prior exposure to Doce (within 3 years) or Apa. In the initial dose-escalation portion, standard doses of AA (1000 mg daily), Doce (75 mg/m2 q3 weeks), and P (5 mg BID) were administered initially with different doses of Apa. Cohort 1 = 120 mg/d, Cohort 2 = 240 mg/d in modified 3+3 design. No GCSF was permitted during dose escalation phase. Following initial combo therapy, men could continue Apa/AA+P without Doce. The expansion cohort added men at full doses of all drugs to narrow confidence intervals around efficacy/toxicity. Results: Sixteen men (4 Apa 120 mg, 12 Apa 240 mg) with mCRPC and median age 70 and median PSA 3.45 ug/mL (range 0.07 – 188.97) were treated. Sites of metastases included bone (50%), lymph node (56%), lung and liver (6% each), and other sites (13%). Seven (44%) were low, 5 (31%) were intermediate, and 4 (25%) were high CALGB (Halabi) risk group. During dose escalation, there was 1 DLT of grade (Gr) 3 hypertension. In the overall study including expansion, non-heme AEs included Gr 3 hypertension (2/16), hyperglycemia (1/16), and rash (1/16), and Gr 2 hypertension (3/16), fatigue (3/16), rash (2/16), neuropathy (2/16), and nausea (1/16). Heme AEs included Gr 3 anemia (1) and Gr 4 neutropenia (10/16, 1 febrile neutropenia). 15/16 (93.8%) of subjects had a PSA50, of whom 12 achieved PSA90 (12/16, 75%) and 4 (25%) had PSA decline > 99%. Of 7 evaluable with measureable disease, all had RECIST response. Median rPFS was not reached with median 22.8 month follow up (range 2.8-46.6 mo). 2-year rPFS was 70.1% (95% CI = 32.3%, 89.5%). 9 of 10 evaluated had undetectable CTCs at 12 weeks; 5 of 5 with baseline detectable CTCs converted to undetectable at 12 weeks. Conclusions: The combination of apa, AA+P, and doce at full doses is tolerable. The combination is associated with a high proportion with PSA decline, measurable disease response, CTC count control, and favorable rPFS. Pre-treatment tumor tissue and pre-and post-treatment plasma ctDNA and CTC characterization are being analyzed. [NCT02913196]. Clinical trial information: NCT02913196.