Background: PRL-02 is a novel long-acting intramuscular (IM) depot injection prodrug of abiraterone (AA) that was designed to provide better safety through lower and less variable plasma exposures. Clinical results show that PRL-02 has a potentially superior therapeutic index compared to oral AA due to preferential inhibition of CYP17 lyase and lack of induction of progesterone, a known oncogenic driver, and tissue and lymphatic distribution. PRL-02 markedly depressed testosterone (T) through 14 wks in a castrate monkey model treated with a single dose. We present an interim report of data from an ongoing phase 1 study that includes the provisional RP2D and data from patients (pts) with prior exposure to enzalutamide (enza) recruited in either dose escalation or a dedicated expansion cohort. Methods: The study has a standard 3+3 dose escalation design (dose limiting toxicity [DLT] period = 28 days) with IM PRL-02 depot administered every 84 days. Pts with biochemical relapse, mCSPC, or mCRPC and ongoing GnRH analogue therapy (in absence of orchiectomy) with screening T < 50 are included. Pts with prior treatment with a CYP17 inhibitor and concurrent treatment with an AR blocking agent are excluded. Two expansion cohorts are recruiting: prior exposure to AA or enza. Results: Dose escalation: 22 pts (9 mCRPC, 12 mCSPC, 1 CSPC), median age 68, were treated at 5 dose levels: 180/360/720/1260/1800 mg (n=3/3/4/6/6) with median time on treatment (TOT) in months (mo) of 2.17 (1.88-2.20), 2.93 (2.37-23.52), 19.97 (1.91-21.48), 16.18 (11.81-19.87), and 10.66 (4.74-17.11), respectively. At 720 and 1260 mg, the median baseline T was 6.7 ng/dL and T suppression without significant changes in cortisol due to inhibition of CYP17 hydroxylase was observed in all pts. Minor transient progesterone elevations were observed at 1800 mg only. 3 of 4 pts at 720 and all pts at 1260 mg achieved a prostate specific antigen (PSA) response and had either a 90% reduction in T or values ≤ 1. One pt (1800 mg, CRPC heavily pretreated) progressed on treatment. No DLTs, treatment related serious adverse events (SAEs), or AEs related to PRL-02 with severity greater than CTCAE G2 were observed. In the prior enza expansion cohort 8 pts have been treated. Of the 10 pts with prior enza across both the escalation and expansion cohort, 8 had no prior chemo. Median TOT is currently 4.34+ mos. 3 pts progressed. All 7 active pts demonstrated either a PSA decrease from baseline or a flattening of PSA trajectory, including 2 with early PSA50s. Conclusions: PRL-02 was well tolerated. The RP2D of 1260 mg was selected over 1800 mg due to the absence of progesterone rises at 1260 mg. PRL-02 produces durable dose dependent T suppression and associated PSA response. The phase 1 data encourages continued investigation of PRL-02 for pts who have developed androgen receptor pathway inhibitor (ARPI) resistance. Clinical trial information: NCT04729114.