The effect of circadian rhythm–based medication timing adjustments on the efficacy and safety of novel hormonal therapy.

TPS277 Background: Neoadjuvant hormonal therapy (NHT) serves as the primary treatment approach for metastatic hormone-sensitive prostate cancer (mHSPC) by either inhibiting androgen synthesis or blocking androgen receptor binding, thereby suppressing tumor growth. Despite its effectiveness, patients with mHSPC inevitably develop resistance to NHT over time, advancing to metastatic castration-resistant prostate cancer (mCRPC), which is associated with a poor prognosis. Androgen synthesis and secretion exhibit a prominent circadian rhythm, with accelerated synthesis in the early morning, peaking around 8:00 AM, followed by a decline to nadir by approximately 8:00 PM. Administrating NHT agents during nighttime may enhance therapeutic efficacy by preemptively inhibiting androgen synthesis and receptor binding before the peak secretion period. Consequently, we have designed a prospective study to evaluate and compare the efficacy and safety of daytime versus nighttime administration of NHT agents in patients with mHSPC. Methods: This prospective, open-label, phase II study will enroll 70 patients with mHSPC. Key eligibility criteria include histologically or pathologically confirmed prostate cancer, classified as mHSPC, without prior NHT or chemotherapy. Patients currently receiving other systemic antitumor therapies, those who have undergone organ transplantation within the past 3 months, or been diagnosed with autoimmune disease will be excluded. Eligible patients will be randomized in a 1:1 ratio to receive NHT agents either between 7:00 and 9:00 AM or between 10:00 and 12:00 PM. Treatment is continued until disease progression. The primary objective is to evaluate the effect of nighttime administration of NHT agents by assessing PSA response rate (PSA-RR), defined as the proportion of patients achieving > 90% reduction in PSA from baseline after 3 months of NHT. Secondary endpoints include circulating tumor cell (CTC) clearance rate, clinical benefit rate, objective response rate (ORR), duration of response (DoR), time to objective response, radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs). Differences in response rates between the 2 groups will be analyzed using the Chi-square test. Survival endpoints will be estimated using the Kaplan-Meier method, with between-group comparisons conducted by the log-rank test. Currently, 14 of a planned total of 70 participants have been enrolled. Clinical trial information: NCT06505278 .