Background: The management of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved significantly in recent years due to the introduction of androgen receptor-targeted agents (ARTAs). When used alongside androgen deprivation therapy (ADT), these treatments have shown improved oncological results and enhanced survival rates for patients with this condition. Objectives: The objective of this study was to describe the decline in prostate-specific antigen (PSA), the oncological outcomes, and the toxicity profile of mHSPC patients treated with apalutamide. Materials and Methods: Clinical data obtained from seven national hospitals were utilized between March 2021 and July 2024. PSA responses were collected at 3, 6, 12, 18, and 24 months, along with adverse effects reported by patients, dose reductions, or drug discontinuations. The association between PSA decline and progression-free survival (PFS) was evaluated with respect to metastasis volume, location, and timing of diagnosis. Results: A total of 432 patients were included, of whom 40% were de novo cases, and the greater part were classified as M1b. After one year, a reduction of more than 90% in PSA levels was observed in 88.2% of cases, with undetectable levels (≤0.2 ng/mL) achieved in 81.7% of them. The drug was discontinued in 76 patients (15.6%), with adverse effects reported in 7.8% (grade 3) and 1.9% (grade 4). Regarding PSA levels <0.02 ng/mL, promising results were observed, with ultralow PSA (UL2) achieved in 43% of cases at 6 months. Conclusions: This study revealed strong oncological outcomes, with rapid and profound PSA declines and drug safety consistent with emerging evidence. The distinctive finding of this study underscores the importance of a rapid and profound response (UL PSA) as a predictor of better oncological outcomes.

Background: The management of metastatic hormone-sensitive prostate cancer (mHSPC) has evolved with the integration of androgen receptor signaling inhibitors (ARSIs) and metastasis-directed therapies (MDTs). Stereotactic body radiotherapy (SBRT) offers precise local control, yet real-world data on its combination with apalutamide remain limited. Methods: We conducted a multicenter retrospective cohort study including 134 patients with mHSPC treated with apalutamide and SBRT between February 2021 and December 2024. The primary endpoints were progression-free survival (PFS), local control (LC), and treatment safety. PSA kinetics and radiologic response were evaluated, and outcomes were analyzed according to PSA thresholds and treatment timing. Results: Most patients (93.3%) had low-volume disease; 97.1% presented with ≤5 metastases. At a median follow-up of 28 months, LC was 99.3% and 95.5% of patients were progression-free. Complete radiological response was achieved in 87.5% of patients, and 68.4% attained ultralow PSA levels (≤0.02 ng/mL). Undetectable PSA and radiologic complete response were independently associated with improved PFS (p = 0.010 and p = 0.011, respectively). Treatment was well tolerated, with grade ≥3 toxicity occurring in only 2.2% of patients. Conclusions: The combination of apalutamide and SBRT in mHSPC is associated with high local and systemic disease control and minimal toxicity in a real-world setting. This approach may delay systemic treatment intensification and the onset of castration resistance. Prospective studies are warranted to confirm these findings.