Background: Despite the approval of life prolonging treatments, metastatic prostate cancer remains incurable and the annual estimated death from this disease is rising. We hypothesize the survival from metastatic prostate cancer can be improved through a sequential therapeutic approach modeled on the eco-evolutionary dynamics of Anthropocene extinctions. The eradication of a species typically results from a sequence of perturbations, that applied individually could not achieve the same outcome. The 1st strike greatly reduces the size, spatial distribution, and diversity of an initially large and heterogeneous population. The 2nd strike produces destructive, amplifying feedbacks to further increase the small surviving population’s vulnerability to extinction (PMC7771333). The key to maximize tumor killing is the timely switch from 1st strike to the 2nd strike despite the high level of efficacy with the initial treatment regimen, otherwise resistance will inevitably emerge. Here we report an ongoing phase IIA single-institution study testing a first-strike, second-strike strategy in high-risk metastatic castration sensitive prostate cancer (mCSPC). Methods: High risk mCSPC patients with adequate organ function and no prior radical prostatectomy are eligible. High risk mCSPC is defined as having 2 of the 3 risk factors: a Gleason score of 8 or more, at least 3 bone metastases, or the presence of measurable visceral metastasis. Because androgen deprivation therapy (ADT) remains the cornerstone for mCSPC treatment, we start the 1st strike with luteinizing hormone-releasing hormone (LHRH) analog plus abiraterone, apalutamide or enzalutamide. Based on our mathematical modeling of Anthropocene extinctions in mCSPC, the 1st strike will be completed on day 1 of week 13 if >90% PSA decline is achieved. The remaining subjects will complete their 1st strike with a total of 18 weeks of combined ADT, regardless of PSA levels. 2nd strike will start within 3 weeks of completing 1st strike, which involves continuing the LHRH analog while adding 4 cycles of docetaxel 75 mg/m² intravenously (IV) once every 3 weeks. Patients with <0.1 ng/ml PSA and a negative post treatment prostate biopsy will continue the LHRH analog monotherapy beyond the 2nd strike. For patients with positive prostate biopsy or >0.1 ng/ml PSA, the 2nd strike will be consolidated with 2 additional cycles of docetaxel plus 6 doses of anti-programmed cell death (PD)-1 agent, tislelizumab, given IV once every 3 weeks. The primary objective is to improve overall survival, which will be measured at year 3 from initiation of the 1st strike. Twenty of the 31 patients have been enrolled and the study has passed the predefined interim analysis for futility. We aim to complete accrual before June 2024. Clinical trial information: NCT05189457.