Phase I/II trial of oral masofaniten (EPI-7386) in combination with enzalutamide (Enz) compared to enz alone in metastatic castration-resistant prostate cancer (mCRPC) subjects

BackgroundMasofaniten (EPI-7386), as a next generation aniten, inhibits androgen receptor (AR) activity by binding the N-terminal domain and blocking transcription, irrespective of ligand-binding domain resistance mechanisms. Preclinically, combining masofaniten + Enz results in a deeper blockade of the AR pathway and greater antitumor activity than either agent alone.MethodsThis Phase 1/2 multicenter, open-label clinical trial (NCT05075577; EU CT 2023-509336-25-00) examines mCRPC pts on androgen deprivation therapy naïve to second-generation antiandrogens (1 line of prior chemotherapy in the metastatic hormone sensitive setting allowed). Phase 1 (P1) completed enrollment; evaluated escalating doses of masofaniten + Enz; reviewed safety and pharmacokinetics (PK) endpoints of the combination to establish the recommended Phase 2 combination dose (RP2CD); and assessed possible drug-drug interactions. Currently enrolling, phase 2 (P2) is a two arm, 2:1 randomized trial evaluating antitumor activity of masofaniten + Enz versus Enz alone.ResultsP1 enrolled 18 pts in 4 cohorts; 16 are evaluable for efficacy analysis per protocol and 12 are ongoing. 14/18 pts displayed 2+ parameters associated with Enz early treatment failure. The RP2CD was established at masofaniten 600 mg BID + Enz 160 mg QD. The RP2CD continues to be well tolerated and PK results demonstrated Enz exposure was not impacted by masofaniten while masofaniten exposure, despite being reduced by co-administration of Enz, remained in the active range seen in preclinical studies. To date, 13/16 pts achieved PSA90 (81%) regardless of previous chemotherapy status (44% pts received prior chemotherapy in the mHSPC setting). 5/16 evaluable pts showed measurable disease with 3/5 (60%) partial response and 2/5 (40%) stable disease. As data matures and the median time to PSA progression is not yet reached, the data compares favorably to historical P3 trials of Enz single agent.ConclusionsUpdated results, long term follow-up of P1 pts and a comparison to historical trials will be presented. P2 is currently enrolling in the USA, Canada, Australia, France, Belgium and Spain.Clinical trial identificationNCT05075577; EU CT 2023-509336-25-00.Legal entity responsible for the studyESSA Pharmaceuticals.FundingESSA Pharmaceuticals.DisclosureC. Kyriakopoulos: Financial Interests, Personal, Advisory Board: Exelixis, AVEO, Sanofi-Aventis, EMD Serono, Janssen Pharmaceuticals, Pfizer; Financial Interests, Personal, Writing Engagement: Pfizer; Financial Interests, Personal, Stocks/Shares: Biogen, Epic Systems; Financial Interests, Institutional, Local PI: Gilead Sciences, Incyte Corporation, Sanofi-Aventis, AstraZeneca, BMS, Madison Vaccines, Merck KGaA, ESSA Pharma, Pionyr Immunotherapeutics, Merck. A.L. Laccetti: Financial Interests, Personal, Advisory Board: Guidepoint; Financial Interests, Personal, Advisory Board, Health tech company. Advisory role on wearable devices in oncology care.: Musculo; Financial Interests, Personal, Invited Speaker: Dava Oncology; Financial Interests, Institutional, Invited Speaker, Travel stipend for abstract presentation: Bayer; Financial Interests, Personal, Stocks/Shares, Stock option.: Musculo; Financial Interests, Personal, Coordinating PI: ESSA Pharmaceuticals; Financial Interests, Personal, Steering Committee Member: Bayer Pharmacetuicals; Financial Interests, Personal, Local PI: ESSA Pharmaceuticals; Financial Interests, Personal, Research Grant: Johnson & Johnson. A.O. Sokolova: Financial Interests, Personal, Advisory Board: AstraZeneca; Financial Interests, Personal, Invited Speaker: Lantheus; Financial Interests, Personal and Institutional, Research Grant: AstraZeneca. S.J. Hotte: Financial Interests, Personal, Advisory Board: AAA/Novartis, 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, Institutional, Research Grant: Genentech. F. Saad: Financial Interests, Personal, Advisory Board: Astellas, Bayer, BMS, Janssen, Pfizer, Myovant, Novartis, AstraZeneca, Merck; Financial Interests, Institutional, Local PI: Novartis, Astellas, Bayer, Janssen, Sanofi, BMS, Amgen, Pfizer, Merck; Financial Interests, Institutional, Coordinating PI: AstraZeneca. J. Zhang: Financial Interests, Personal, Advisory Board, I was also on speaker program before 2023: AstraZeneca; Financial Interests, Personal, Advisory Board: Bayer, Dendroen, Sanofi. K. Villaluna, B. Younginger, R. Le Moigne, A. Cesano: Financial Interests, Personal, Member: ESSA Pharma. All other authors have declared no conflicts of interest.