Background: Main approach for early biochemical relapse (BR) after radical prostatectomy (RP) is prostate bed salvage radiotherapy (SRT). PSICHE is a prospective trial aimed to explore oncological results of a 68Ga-PSMA-11 PET/CT tailored strategy based on a pre-defined treatment algorithm. We present results focusing on early biochemical outcomes after therapy. Biochemical response was defined as Complete (CBR) or Partial (PBR) if a PSA < 0.2 or <50% of baseline was reached. Methods: Enrolled patients were affected by BR (defined as PSA > 0.2 ng/ml) after RP +/- postoperative SRT. PSA >1 at recurrence or PSA persistence after surgery (PSA >0.2 ng within 16 weeks from RP) were exclusion criteria. All patients underwent centralized 68Ga-PSMA PET/CT and treatment approach was performed according to predefined criteria. Observation and re-staging at further PSA progression were proposed to patients with negative PSMA and previous postoperative RT. Prostate bed SRT was proposed to all patients with negative staging or positive imaging within the prostate bed. Stereotactic body radiotherapy (SBRT) to all sites of disease was proposed to patients with pelvic nodal recurrence (nodal disease <2 cm under aortic bifurcation) or oligometastatic disease (< 3 non visceral metastatic lesions). Non oligometastatic disease was treated with Androgen deprivation therapy +/- other systemic treatment. Results: Enrollment started on 19/03/2021 and 104 patients have been enrolled, with a median baseline PSA of 0.39 ng/ml. Overall, PSMA results were negative/positive in prostate bed in 75 patients (72.1%), while pelvic nodal or extrapelvic metastatic disease were detected in 23 (22.1%) and 6 (5.76%) patients, respectively. Twenty-two patients were observed after re-staging and were excluded from the current analysis. Treatment provided was SRT, SBRT or ADT in 50 (48.1%), 29 (27.8%) and 3 (2.9%) patients, respectively. Data about biochemical response at 3 months after treatment were available for 53 patients. Of these, 33 (62.3%) had a PBR, out of whom CBR was detected in 29 (54.7%). Any reduction in PSA if compared to baseline was detected in 44 patients, for an overall biochemical response rate of 83%. Five patients had biochemical progression and underwent a second PSMA re-staging with distant metastases detection. Only 2 patients experienced G2 Genitourinary toxicity, no G2 Gastrointestinal toxicity was recorded. Chi square test did not detect impact of ISUP score (< or >3) or time to recurrence (measured between surgery and biochemical relapse) on CBR rate. Conclusions: A PSMA targeted salvage treatment strategy offered promising results in terms of early biochemical response, with optimal toxicity profile, and avoided unnecessary overtreatment in this setting. Longer follow up is needed to explore biochemical relapse free and progression free survival after this approach. Clinical trial information: NCT05022914.