ASCO 2018: A Phase II Trial of Enzalutamide, Docetaxel and Androgen Deprivation Therapy (ENZADA) in Patients with Metastatic Castrate Sensitive Prostate Cancer (mCSPC)

Chicago, IL (UroToday.com) The management of advanced prostate cancer continues to change on an almost daily basis. From a time when docetaxel was the only management option for metastatic prostate cancer that had failed androgen deprivation therapy (ADT), we now have multiple treatment options (docetaxel/chemotherapy and androgen-receptor targeted therapies) that are competing for the same disease space. The shift now has moved towards combined therapies to overcome treatment resistance and improve survival outcomes greater than individual or sequenced therapies can.

To that effect, the current trial, called ENZADA, combines enzalutamide, an oral androgen-receptor targeting therapy, and docetaxol, in the hormone sensitive metastatic prostate cancer disease space. This is combined with ADT. Preclinical data supports the use of enzalutamide (Enz) in combination with docetaxel (Doc). Enz inhibits the ABCB1 drug efflux pump implicated in Doc resistance, and Doc may eradicate Enz-resistant clones harboring the androgen receptor splice variant 7 (ARv7). The combination of Enz with Doc at standard doses was safe in the phase I setting.

Study Design: Phase II single-arm open-label study

Inclusion Criteria:
Men with metastatic prostate adenocarcinoma with confirmed soft tissue and/or skeletal metastasis
ECOG 0-2
PSA ≥ 5
Men who previously received 0-3 years of ADT with radiation for localized disease are eligible if ADT was discontinued > 6 months before diagnosis of mCSPC and testosterone recovery is confirmed
Prior treatment with cytotoxic chemotherapy or next generation endocrine therapy is not allowed
Other exclusion criteria: seizure history, major cardiovascular incident within 3 months, Grade 2-4 peripheral neuropathy, additional malignancy within 12 months

Goal Accrual: 39 patients – 26 patients in the high volume cohort and 13 in the low-volume cohort

Treatment Protocol:
Patients will be treated with:
• Doc 75 mg/m2 IV every 3 weeks for 6 cycles
• Enz 160 mg daily commencing at enrollment and continued until radiographic progression or study withdrawal
• Continuous ADT is required during the study period

Outcomes:
Primary endpoint is 12-month PSA complete response rate
Secondary endpoints include adverse events, best PSA response, radiographic objective response, time to castration resistance, progression free and overall survival
Exploratory biomarker analysis includes sequential measurement of circulating tumor cell (CTC) levels and CTC ARv7 status during study treatment
Blood and pathology will be collected during the study

Based on prior CHAARTED data, the null hypothesis has been set at 25% at 12-months.

Trial status:
As of May 2018, 13 patients have been initiated. Expected completion of accrual is Q2 of 2019.

We suspect this, and other combination studies, will likely yield very promising results as the biologic rationale is strong.

Presented by: Earle Frederick Burgess, MD

Written by: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Twitter: @tchandra_uromd at the 2018 ASCO Annual Meeting - June 1-5, 2018 – Chicago, IL USA
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