Background: ⁶⁸Ga-PSMA-11 PET/CT (PSMA-PET) was approved by the U.S. Food and Drug Administration in patients with prostate cancer (PCa) at primary staging or biochemical recurrence. A head-to-head comparison between PSMA-PET and conventional imaging (99mTc-MDP bone scan [BS] and CT) in men with advanced prostate cancer was not performed. We aimed to compare the detection rate of bone disease for PSMA-PET vs BS in men with PCa and with biochemical progression during androgen deprivation therapy (ADT). Methods: This was a prospective single-center, open-label, single-arm, head-to-head comparison, prospective phase 2 study (NCT04928820). A sample size of 102 men was required to achieve an 80.3% power to detect a difference of 12% positivity rate of bone disease in favor of PSMA-PET vs BS (35% vs 23%). Men with i) biopsy-proved PCa, ii) who had rising PSA levels on 2 successive occasions ≥1 week apart, iii) were receiving treatment with hormonal therapy, iii) and had an absolute PSA value ≥1 ng/ml were eligible. Men who were enrolled received PSMA-PET and bone scan within 30 days. The primary endpoint was detection rate of bone disease for PSMA-PET vs BS. Secondary endpoint was the number of bone lesions detected by PSMA-PET vs BS. Number of lesions was categorized into: 0 vs 1 vs 2 vs 3 vs 4 vs 5 vs > 5. A p value < 0.05 was considered statistically significant. Results: 22 men were enrolled between July 8, 2021 and June 9, 2022. The median patients age was 71 years (range: 56-94). The median time between scans was 12 days (range: 1-29). The median PSA value was 9.5 ng/ml (range: 1.2 – 1717). 11/22 (11%) patients had hormone-sensitive PCa, while 11/22 (50%) had castration-resistant PCa prior to receiving the scans. The positivity rate for bone disease was equal for PSMA-PET and BS in all cases: 7/22 (32%) patients had negative scans on both imaging modalities and 15 (68%) had ≥1 bone lesion detected on both imaging modalities (p = 1.00). In 15/22 (68%) men, both imaging modalities showed equal number of bone lesions: 0 lesions in 7/22 (32%) men and > 5 lesions in 8/22 (36%) men. In 3/22 (14%) men BS showed higher number of lesions, while in 4/22 (18%) men PSMA-PET showed higher number of lesions. No statistical difference was noticed between PSMA-PET and BS in number of bone lesions detected (p > 0.05). The trial was terminated early since these preliminary results gave already a 95% confidence interval of 81-100% for equivalent positivity rate of bone disease between PSMA-PET and BS. Conclusions: In this prospective study of patients with prostate cancer with rising PSA levels under hormonal therapy, ⁶⁸Ga-PSMA-11 PET and ⁹⁹mTc-MDP bone scan had similar detection rate for bone disease. Further studies investigating similar comparison between PSMA-PET and BS in clinically-relevant selected patient population are warranted. Clinical trial information: NCT04928820.