Phase 1/2a study of PRL-02, a long-acting IM depot injection of abiraterone decanoate, in patients with prostate cancer including those previously treated with enzalutamide.
Authors: Jose W. Avitia, Neal D. Shore, Luke T. Nordquist, Ryan J. Malone, David Morris, Cody J. Peer, William Richardson, Keith Thomas Schmidt, William Douglas Figg, Jacqueline M. Walling, Katherine McDougall, Joel Robert Eisner, William R. Moore, Ronald F. Tutrone
Journal: Journal of Clinical Oncology (2024)

140 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 &lt; 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 .