1813P - Phase I/II trial of oral EPI-7386 in combination with enzalutamide (enz) compared to enz alone in metastatic castration-resistant prostate cancer (mCRPC) subjects: Current phase I (PI) results

Background

EPI-7386 is a next generation aniten designed to inhibit androgen receptor (AR) activity by binding the N-terminal domain and blocking transcription despite resistance driven by point mutations and splice variants in the ligand-binding domain. In preclinical models, the combination of EPI-7386 with Enz results in a deeper blockade of the AR pathway and greater antitumor activity, prompting this trial.

Methods

This phase I/II multicenter, open-label clinical trial (NCT05075577) is enrolling mCRPC patients on androgen deprivation therapy and naïve to second-generation antiandrogens (1 line of prior chemotherapy in the metastatic hormone sensitive setting allowed). PI examines escalating doses of EPI-7386 with Enz. Primary and secondary endpoints of PI evaluate the safety and pharmacokinetics (PK) of EPI-7386 and Enz when co-administered to establish recommended phase II combination doses (RP2CDs) and address possible drug-drug interactions (DDIs). Once RP2CDs are established, phase II (PII) will commence as a two arm, 2:1 randomized trial evaluating antitumor activity of EPI-7386 in combination with Enz versus Enz alone.

Results

To date, 11 patients have been enrolled in cohorts 1-3 (cohort 4 is currently enrolling). Safety is consistent with second-generation antiandrogens (e.g., Grade 1 or 2 AEs of fatigue and hot flashes). PK results demonstrate Enz exposure is minimally impacted by EPI-7386, allowing testing of the full dose of Enz (160 mg) in the current cohort 4. EPI-7386 exposure is strongly reduced by Enz (CYP3A4 inducer that metabolizes EPI-7386) but remains in the clinically relevant range seen in xenograft studies. EPI-7386 BID dosing shows an increase in EPI-7386 exposure and mitigates DDI caused by Enz. Data from the first 10 evaluable patients show 9/10 achieve a PSA90, and 7/10 patients reach PSA <0.2 ng/mL.

Conclusions

With no safety concerns from cohorts 1-3, cohort 4 is currently enrolling at EPI-7386 BID + 160 mg QD Enz to evaluate optimal RP2Ds before the P2 component of the trial. Updated results, including cohort 4, will be presented.

Clinical trial identification

NCT05075577.

Editorial acknowledgement

Legal entity responsible for the study

ESSA Pharma.

Funding

ESSA Pharma.

Disclosure

A.L. Laccetti: Financial Interests, Personal, Expert Testimony: Guidepoint; Financial Interests, Personal, Invited Speaker: ESSA Pharmaceuticals, Bayer Pharmacetuicals, ESSA Pharmaceuticals; Financial Interests, Personal, Research Grant: Johnson & Johnson. C. Kyriakopoulos: Financial Interests, Personal, Advisory Board: Exelixis, AVEO, Sanofi-Aventis, EMD Serono, Janssen Pharmaceuticals; Financial Interests, Personal, Invited Speaker: Pfizer; Financial Interests, Personal, Stocks/Shares: Biogen, Epic Systems; Financial Interests, Institutional, Invited Speaker: Gilead, Incyte Corporation, Sanofi-Aventis, AstraZeneca. S.J. Hotte: Financial Interests, Personal, Advisory Board: AAA/Novartis, AstraZeneca, Astellas, Bayer, BMS, Eisai, Ipsen, Janssen, Merck, Pfizer, SeaGen; Financial Interests, Institutional, Local PI: AAA/Novartis, AstraZeneca, Ayala, Bayer, BMS, Eisai, Exilixis, Ipsen, Merck, Roche, SeaGen, SignalChem; Financial Interests, Institutional, Research Grant: Astellas, BMS, Janssen; Financial Interests, Personal, Research Grant: Bayer; Financial Interests, Personal, Steering Committee Member: Janssen. R. Pili: Financial Interests, Personal, Advisory Board: Allarity; Financial Interests, Institutional, Research Grant: Genentech. J. Vuky: Financial Interests, Institutional, Local PI: Merck, Arvinas, Seattle Genetics, AstraZeneca, Fortis Therapeutics, IO Biotech, Essai Pharmaceuticals, Novartis. J. Zhang: Financial Interests, Personal, Advisory Board, I was also on speaker program before 2023: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer, Dendroen; Financial Interests, Personal, Invited Speaker: Sanofi. F. Saad: Financial Interests, Personal, Advisory Board: Astellas, Bayer, BMS, Janssen, Sanofi, Pfizer, Myovant, Novartis; Financial Interests, Institutional, Invited Speaker: Novartis, Astellas, Bayer, Janssen, Sanofi, BMS, Amgen, Pfizer. K. Villaluna, B. Younginger, R. Le Moigne, A. Cesano: Financial Interests, Personal, Stocks/Shares: ESSA Pharma; Financial Interests, Personal, Full or part-time Employment: ESSA Pharma. All other authors have declared no conflicts of interest.