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Supplementary Table 2

Supplementary Table 1

Purpose:ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).Patients and Methods:Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).Results:Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post–ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6–12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0–7.8). Median duration of treatment was 3.5 months (range, 0–34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).Conclusions:ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.

Supplementary Figure 1

Supplementary Figure 2

Purpose:ZEN-3694 is a bromodomain extraterminal inhibitor (BETi) with activity in androgen-signaling inhibitor (ASI)-resistant models. The safety and efficacy of ZEN-3694 plus enzalutamide was evaluated in a phase Ib/IIa study in metastatic castration-resistant prostate cancer (mCRPC).Patients and Methods:Patients had progressive mCRPC with prior resistance to abiraterone and/or enzalutamide. 3+3 dose escalation was followed by dose expansion in parallel cohorts (ZEN-3694 at 48 and 96 mg orally once daily, respectively).Results:Seventy-five patients were enrolled (N = 26 and 14 in dose expansion at low- and high-dose ZEN-3694, respectively). Thirty (40.0%) patients were resistant to abiraterone, 34 (45.3%) to enzalutamide, and 11 (14.7%) to both. ZEN-3694 dosing ranged from 36 to 144 mg daily without reaching an MTD. Fourteen patients (18.7%) experienced grade ≥3 toxicities, including three patients with grade 3 thrombocytopenia (4%). An exposure-dependent decrease in whole-blood RNA expression of BETi targets was observed (up to fourfold mean difference at 4 hours post–ZEN-3694 dose; P ≤ 0.0001). The median radiographic progression-free survival (rPFS) was 9.0 months [95% confidence interval (CI), 4.6–12.9] and composite median radiographic or clinical progression-free survival (PFS) was 5.5 months (95% CI, 4.0–7.8). Median duration of treatment was 3.5 months (range, 0–34.7+). Lower androgen receptor (AR) transcriptional activity in baseline tumor biopsies was associated with longer rPFS (median rPFS 10.4 vs. 4.3 months).Conclusions:ZEN-3694 plus enzalutamide demonstrated acceptable tolerability and potential efficacy in patients with ASI-resistant mCRPC. Further prospective study is warranted including in mCRPC harboring low AR transcriptional activity.

1023 Background: Metastatic triple negative breast cancer (mTNBC) is an aggressive and heterogeneous cancer with limited therapeutic options. PARP inhibitors (PARPi), approved to treat patients with HER2- breast cancer with a germline BRCA1/2 (gBRCA1/2) mutation, have not shown efficacy in homologous recombination repair (HRR) proficient tumors. In pre-clinical models, the BET inhibitor (BETi) ZEN-3694 sensitizes wild-type (WT) BRCA1/2 tumors to PARPi through downregulation of HRR gene expression, providing a rationale for combination therapy. We previously reported results from the Ph 1b portion of the trial evaluating the combination of ZEN-3694 plus talazoparib, in TNBC patients without gBRCA1/2 mutations; here we present results from the completed Ph 1b/2 study. Methods: A Ph 1b dose finding portion (n = 15) was followed by a single arm Ph 2 Simon 2-stage portion (n = 17+20 (37)). The primary endpoint of the Ph 1b portion of the study was safety and recommended Ph 2 dose (RP2D). The secondary endpoints were pharmacokinetics (PK), pharmacodynamics (PD), and clinical benefit rate (CBR = confirmed objective response rate (ORR) + stable disease > 16 weeks). Ph 2 measured CBR as the primary endpoint, ORR and duration of response (DOR) as key secondary endpoints. Eligibility criteria for Ph 1b included TNBC (ER/PR < 10%, HER2-), WT gBRCA1/2, and > 1 prior cytotoxic regimen for mTNBC, and in the Ph2 portion ER/PR < 1% and < 2 prior cytotoxic regimens for mTNBC. Patients were dosed daily in continuous 28 day cycles until disease progression or unacceptable toxicity. Adverse events, PK, and PD in whole blood and tissue biopsies were assessed. Response endpoints were assessed per RECIST 1.1 every 2 cycles. Results: RP2D was determined to be 48mg qd ZEN-3694 plus 0.75mg qd talazoparib. The most common AE for the Ph 1b/2 study was thrombocytopenia (TCP) (55% any grade, 34% G3/4), which was managed with dose holds and reductions. Dose intensity analysis showed average daily doses of ZEN-3694 and talazoparib could be maintained above 40mg and 0.5mg, respectively, over 8 cycles. Robust target engagement was demonstrated using BET-dependent and HRR transcripts assessed in paired tumor biopsies. Ph 2 portion of the trial met its primary endpoint with a CBR of 30% (11/37). For the Ph 1b/2 trial, investgator assessed ORR was 22% (11/50), including 2 CR, CBR was 35% (18/51) and the median DOR was 24 weeks. For the subset of TNBC at diagnosis patients (no history of HR+ disease), ORR was 32% (11/34), and CBR was 44% (15/34). Conclusions: Combination of ZEN-3694 and talazoparib demonstrated anti-cancer activity in pretreated mTNBC WT gBRCA1/2 patients. All confirmed responses were observed in TNBC at diagnosis patients, whose tumors are expected to be more sensitive to the combination due to their basal-like properties. The trial is being expanded to Ph. 2b to accrue an additional 80 TNBC at diagnosis patients. Clinical trial information: NCT03901469.

TPS201 Background: Androgen receptor signaling inhibitors (ARSI), such as enzalutamide (Enza), and abiraterone (Abi), are standard therapies for metastatic hormone-sensitive and metastatic castration-resistant prostate cancer (mHSPC, mCRPC). Patients who respond to the initial ARSI are frequently prescribed a second ARSI upon progression. However, a suboptimal response to first line ARSI, including the ̃ 20% treated with an ARSI for mHSPC who progress within 12 months of treatment initiation, may enrich for cancers harboring AR-independent mechanisms of resistance including treatment-emergent neuroendocrine prostate cancer (t-NEPC). Recently, BETi have been shown pre-clinically to block the neuroendocrine prostate cancer lineage plasticity program through modulating E2F1, a transcription factor involved in stemness and cell differentiation. Prior results from a mCRPC Ph. 1b/2a trial of ZEN-3694+ Enza support this notion, as lower AR transcriptional activity in baseline tumor biopsies was associated with longer radiographic progression-free survival (rPFS). Additionally, mCRPC patients who were primary refractory to first-line abiraterone had prolonged rPFS with ZEN-3694 + Enza, suggesting that the patients with primary resistance may benefit from the combination. To test this hypothesis, a Ph. 2b randomized trial has been initiated, enriching for mCRPC with suboptimal response to first-line ARSI. Methods: This is a multi-national, open-label, randomized, two cohort, Ph. 2b study of ZEN-3694 + Enza vs. Enza in mCRPC patients who have progressed on Abi (NCT04986423). Cohort A (N = 150): Patients with poor response to Abi defined either as progression in < 12 months or failure to achieve PSA nadir of 0.2 ng/mL while taking Abi in HSPC setting, or progression in < 6 months and/or failure to achieve a PSA50 response while taking Abi in the CRPC setting. Cohort B (N = 50): Patients who responded to Abi, defined as > 12 months duration without progression while on Abi in the HSPC setting and achieving a nadir PSA < 0.2 ng/mL, or > 6 months duration without progression while on Abi in the CRPC setting and confirmed PSA50 response. The primary endpoint is radiographic progression-free survival (rPFS) by blinded independent central review (BICR) in Cohort A evaluated by PCWG3. Key secondary endpoints include rPFS by BICR for Cohorts A + B, PFS by investigator assessment, overall survival, PSA50 response rate, objective response rate by RECIST 1.1, and patient-reported health status and quality of life, evaluated in Cohorts A, and Cohorts A + B together. The trial, conducted in collaboration with Newsoara is expected to enroll 200 participants, and the first patient was dosed in October 2021. Astellas is providing the enzalutamide for this study. Clinical trial information: NCT04986423.

Background: Metastatic triple-negative breast cancer (TNBC) is an aggressive and heterogeneous cancer with limited therapeutic options. PARP inhibitors (PARPi) are approved to treat breast cancer harboring germline BRCA1/2 (gBRCA1/2) mutations and have not shown efficacy in homologous recombination DNA repair (HRR) proficient tumors. In pre-clinical models, the BET inhibitor (BETi) ZEN003694 sensitizes wild-type BRCA1/2 tumors to PARPi through downregulation of HRR gene expression, providing a rationale for combination therapy. We report initial results from a Ph 1b/2 trial evaluating the combination of ZEN003694 and the PARPi, talazoparib, in TNBC patients without gBRCA1/2 mutations. Methods: A Ph 1b dose-finding segment will be followed by a single-arm Ph 2 Simon 2-stage segment. Ph 1b evaluated several dose combinations of ZEN003694 and talazoparib, with safety and recommended Ph 2 dose (RP2D) as primary endpoints and pharmacokinetics (PK), pharmacodynamics (PD), and clinical benefit rate (CBR = Objective response rate (ORR) + stable disease > 4 months) as secondary endpoints. The Ph 2 segment has CBR as the primary endpoint and progression free survival (PFS) and duration of response as secondary endpoints. Eligibility criteria included TNBC (ER/PR < 10% and not a candidate for endocrine therapy), HER2-, wild-type gBRCA1/2, and > 1 prior chemotherapy regimen for metastatic disease. Patients were dosed daily in continuous 28-day cycles until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) period was one cycle. Adverse events (AE), PK, and PD in whole blood and tissue biopsies were assessed. Response endpoints were assessed per RECIST 1.1 every 2 cycles. Results: Findings of the Ph 1b are reported. 15 patients with a median 3 lines of prior therapy in the metastatic setting were enrolled in 3 dose-finding cohorts. RP2D was determined to be 48mg ZEN003694 plus 0.75mg talazoparib. Across the cohorts, the most common AE was thrombocytopenia (TCP) (73%) with 53% G3/4 (Table 1). G4 TCP was the DLT and 1 DLT patient required a platelet transfusion. TCP could be managed to G1/2 levels with intermittent dose holds and reductions. Other G1/2 AEs included fatigue, anorexia, neutropenia, nausea, dysgeusia, and photophobia. Dose intensity analysis showed average daily doses of ZEN003694 and talazoparib could be maintained above 40mg and 0.5mg, respectively, over 4 cycles. Exposures of ZEN003694 and talazoparib were dose proportional with no drug-drug PK interactions. At RP2D, PD assessment by a whole blood mRNA assay for BET-dependent genes demonstrated robust down-regulation of CCR1, IL1RN, and IL8 to < 50% of baseline for > 8 h. Expression of HRR genes, RAD51 and BRCA1, in whole blood also decreased for > 8 h. Analysis of an on-treatment biopsy showed robust and durable BET target modulation assessed by comparing RNA sequence data with a reference BET dependent signature. Across the 3 cohorts, ORR by Investigator was 38% (5/13), including 1 CR and 4 PRs, and CBR was 57% (8/14). 6 of the 15 patients are ongoing as of data analysis date (2-9 cycles), with 1 patient responding for > 6 months. Conclusions: Combination of ZEN003694 and talazoparib demonstrated anti-cancer activity in pretreated metastatic TNBC patients without gBRCA1/2 mutations. TCP is frequent but manageable with dose adjustments. PK is predictable, and PD data show meaningful target engagement. The Ph 2 part of the trial is currently ongoing. Grade 3/4 Adverse EventsCohort 1(1mg talazoparib + 48mg ZEN003694)N=6Cohort 2(0.75 mg talazoparib + 48mg ZEN003694)N=6Cohort 3(1mg talazoparib + 36mg ZEN003694)N=3Thrombocytopenia3 (G3), 2 (G4, DLT)1 (G3), 1 (G4, DLT)1 (G3)Diarrhea1 (G3)00Neutropenia01 (G3)0 Citation Format: Philippe Aftimos, Mafalda Oliveira, Kevin Punie, Valentina Boni, Erika Hamilton, Ayca Gucalp, Payal Shah, Lida Mina, Priyanka Sharma, Lisa Bauman, Eric Campeau, Sarah Attwell, Margo Snyder, Karen Norek, Akos Czibere, Yanke Yu, Michael H Silverman, Sanjay Lakhotia, Susan Domchek, Jennifer Litton, Mark Robson. A Phase 1b/2 Study of the BET inhibitor ZEN003694 in combination with talazoparib for treatment of patients with TNBC without gBRCA1/2 mutations [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-10.

Background: Abiraterone (ABI) and enzalutamide (ENZ) have significant activity in mCRPC yet demonstrate frequent cross-resistance limiting efficacy of sequential androgen receptor (AR) targeting. Bromodomain extra terminal (BET) inhibitors (BETi) down-regulate the expression of putative drivers of ABI/ENZ resistance. ZEN-3694 is an orally bioavailable, potent, and selective BETi with significant anti-tumor activity in ENZ-resistant pre-clinical models. The safety and efficacy of ZEN-3694 in combination with ENZ was evaluated in a phase 1b/2a study in mCRPC (NCT02711956). Methods: Patients (pts) were required to have progressive mCRPC, prior resistance to ABI and/or ENZ, and no prior chemotherapy for mCRPC. A 3 plus 3 dose escalation schema was utilized, with a starting daily oral dose of ZEN-3694 36 mg plus ENZ 160 mg. Dose expansion was conducted in parallel cohorts at low and high-dose ZEN-3694 (48 and 96 mg daily, respectively). The primary objective was determination of maximally tolerated dose (MTD); key secondary endpoints included time to radiographic progression (TTP) and pharmacokinetic (PK) parameters. Pharmacodynamic (PD) markers included whole blood RNA expression of BETi targets including MYC, IL-8, CCR1, and IL1RN. Results: 64 pts were enrolled. The median age and PSA at study entry was 70 (range 47 - 89) and 25.9 (range 0.1 - 1701.8), respectively. At study entry, 24 (37.5%) of pts were resistant to ABI, 29 (45.3%) were resistant to ENZ, and 11 (17.2%) to both. ZEN-3694 dose levels ranged from 36 mg to 144 mg daily without reaching a MTD. The most common treatment-related adverse events (AEs) (any grade) included transient photophobia (66%), nausea (40%), fatigue (31%), decreased appetite (22%), and dysgeusia (16%). Grade ≥ 3 related AEs (N = 8) and dose-limiting toxicities (N = 1 at 96 mg dose level) were uncommon. No Grade ≥ 3 thrombocytopenia was observed. Exposure to ZEN-3694 increased with dose without significant drug-drug interaction with ENZ. PD analyses demonstrated exposure-dependent, up to 4-fold decrease in expression of BETi targets. RNA-Seq of paired tumor biopsies demonstrated suppression of BET-dependent genes. The overall median TTP was 44.4 weeks, and was similar in subgroups with prior ABI vs. ENZ resistance. Durable responses were observed, including 3 pts with disease primarily refractory to ABI on study treatment for 21.3 +, 20.8 +, and 17.3 months, respectively, with > 90% decline in serum PSA. Early transitory serum PSA increases were associated with longer TTP. Conclusions: ZEN-3694 demonstrates an acceptable safety and PK profile, robust target modulation, and encouraging disease stabilization in combination with ENZ in ABI/ENZ-refractory mCRPC. Analysis of paired metastatic tumor biopsies, circulating tumor cells and ctDNA is ongoing. Further investigation of the combination is warranted. Citation Format: Rahul Aggarwal, Wassim Abida, Michael Schweizer, Allan Pantuck, David Nanus, Elisabeth Heath, Sanjay Lakhotia, Henrik Hansen, Michael Silverman, Lisa Bauman, Margo Snyder, Eric Campeau, Karen Norek, Sarah Attwell, Marie O'Farrell, Steve Smith, Philip Wegge, Ravi Jahagirdar, Joshi Alumkal. A Phase Ib/IIa study of the BET bromodomain inhibitor ZEN-3694 in combination with enzalutamide in patients with metastatic castration-resistant prostate cancer (mCRPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT095.