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e17027 Background: Metastatic castration resistant prostate cancer (mCRPC) remains an incurable disease despite recent advances in therapy. In patients (pts) receiving the second-generation androgen receptor antagonist enzalutamide (enza), primary or adaptive resistance can occur due to upregulation of the steroidogenesis pathway, including aldo-keto reductase 1C3 (AKR1C3), which can also upregulate intratumoral androgen synthesis. Indomethacin, a non-steroidal anti-inflammatory drug and selective inhibitor of AKR1C3, demonstrates synergistic activity when combined with enza against enza-resistant CRPC in vitro and in vivo. We thus sought to study this combination in a clinical trial. Methods: This investigator-initiated Phase I/II trial enrolled pts with enza-naive mCRPC on androgen deprivation therapy. Prior abiraterone was allowed. Pts must have adequate organ function and ECOG performance status 0-2. In the phase I lead-in, a 3+3 dose de-escalation design was used to identify the recommended Phase II dose (RP2D) of indomethacin in combination with enza 160 mg oral (PO) once daily, after which a Phase II expansion proceeded. Pts continued treatment until disease progression or unacceptable toxicity. Co-primary endpoints were safety and PSA response, defined as 50% or more reduction from baseline. Secondary endpoints included overall response as determined by Prostate Cancer Working Group 2 criteria (PCWG2). Results: From 2017 - 2022, 26 pts were enrolled, with a median age of 71 (range 50-88), primarily white (n=16, 62%), median baseline PSA 19.45 (range 1.5-210), ECOG 1 (n=12, 46%), and most received prior abiraterone (n=24, 92%). In 6 pts enrolled to the phase I cohort, there were no grade 3 adverse events (AEs); RP2D of indomethacin was 50mg PO twice daily. All 26 pts were evaluable for safety and efficacy. Most common treatment-related AEs (n; %) were nausea (12; 46%), fatigue (11; 42%), diarrhea (8; 31%), hypertension (7; 27%), anorexia (6; 23%). Most common ≥ grade 3 treatment-related AEs were acute kidney injury (3; 12%), hypertension (3; 12%), and anemia (2; 8%). PSA response was observed in 8 pts (31%). By PCWG2, 14 pts (54%) experienced stable disease, while 10 pts (38%) had progressive disease. Conclusions: The combination of enza and indomethacin was safe, clinically feasible, and had clinical activity in pts with abiraterone-pretreated mCRPC. Further correlative studies are needed to identify pts who may benefit from AKR1C3 inhibition. Clinical trial information: NCT02935205 .
Leibrandt et al. (Sat,) studied this question.