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.

Translational Relevance

Bromodomain extraterminal inhibitors (BETi) demonstrate in vivo activity in enzalutamide-resistant prostate cancer models via downregulation of bypass signaling pathways including MYC. Clinical translation of BETi as a therapeutic strategy in metastatic castration-resistant prostate cancer (mCRPC) has heretofore been limited by significant toxicity including risk of thrombocytopenia. In this phase Ia/IIb study of the pan-BETi, ZEN-3694, in combination with enzalutamide in 75 patients with abiraterone- and/or enzalutamide-resistant mCRPC, the combination was well-tolerated without reaching an MTD. Less than 5% of patients experienced a grade ≥3 thrombocytopenia. Robust, dose-dependent, and sustained downregulation of expression of BETi target genes including MYC was observed using a whole-blood RNA assay. Encouraging efficacy was observed including a median radiographic progression-free survival of more than 10 months in those with prior progression on enzalutamide monotherapy. Clinical benefit was particularly pronounced in high-risk subgroups including those with an aggressive variant clinical phenotype as well as those with lower androgen receptor transcriptional activity in baseline tumor biopsies. A randomized study is planned with ZEN-3694 at the recommended phase II dose of 96 mg orally once daily in combination with enzalutamide in mCRPC with prior progression on enzalutamide or abiraterone.

Prostate cancer is the most common malignancy and second leading cause of death among men in the United States (1). Androgen-signaling blockade with either androgen receptor (AR) antagonism or CYP17 inhibition improves long-term survival in both metastatic castration-resistant prostate cancer (mCRPC) and metastatic castration-sensitive disease (2–5). However, treatment resistance is universal, and cross-resistance between AR antagonists and CYP17 inhibitors limits the clinical utility of these agents when used sequentially (6–10).

Multiple mechanisms of therapeutic resistance to AR pathway inhibitors have been described, including amplification of the AR gene and its enhancers, upregulation of intratumoral androgen synthesis, generation of ligand-independent AR splice variants, activation of alternative oncogenic signaling pathways including MYC, transdifferentiation to an AR-independent, neuroendocrine phenotype, and cooption of alternative steroid hormone receptors including the glucocorticoid receptor (GR; refs. 11–16). A broad therapeutic approach capable of affecting expression/signaling of multiple pathways may provide a means to reverse resistance and restore sensitivity to AR-targeting therapy.

Proteins of the bromodomain extraterminal (BET) bromodomain family are epigenetic readers that bind to acetylated histones through their bromodomains to affect gene transcription (17). They preferentially localize at sites of enhancers of various oncogenes to promote tumorigenesis and progression. ZEN-3694 is an orally bioavailable, second-generation, potent pan-BET bromodomain inhibitor (BETi) that leads to downregulation of expression of AR signaling, AR splice variants, MYC, GR, and other oncogenes in multiple CRPC models, and has significant in vivo activity as single agents, with evidence of synergy when combined with enzalutamide (18).

We conducted a first-in-human phase Ib/II dose-escalation/expansion study of ZEN-3694 in combination with enzalutamide in patients with mCRPC and prior progression on one or more androgen-signaling inhibitor (ASI).

Patient population

Patients had histologically confirmed mCRPC with progression at study entry by Prostate Cancer Working Group 2 (PCWG2) criteria (19). Patients were required to have progression on prior abiraterone and/or enzalutamide treatment prior to study entry, no prior docetaxel for the treatment of mCRPC, serum testosterone <50 ng/dL with maintenance of androgen deprivation therapy during study treatment, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, adequate organ function including absolute neutrophil count >1.5 × 109/L, platelet count >100,000, total bilirubin <1.5 × ULN, and creatinine clearance >60 mL/minute. Patients with uncontrolled hypertension or New York Heart Association class II or higher congestive heart failure were excluded.

Study approval was obtained from the ethics committees at the participating institutions and regulatory authorities. All patients gave written informed consent. The study followed the Declaration of Helsinki and Good Clinical Practice guidelines (NCT02711956).

Study design and treatment schedule

This was a phase Ib/II, multicenter, open-label, combination dose-escalation study of ZEN-3694 in combination with the standard dose of enzalutamide, 160 mg daily. Lead-in treatment period with enzalutamide monotherapy (day −14 to day −1) was required in subjects not already receiving enzalutamide at the time of study enrollment. Patients continued treatment until radiographic progression by PCWG2 criteria, unequivocal clinical progression, or unacceptable toxicity. PSA progression alone was not used as a criterion for treatment discontinuation.

The starting dose of ZEN-3694 was 36 mg orally once daily. A 3+3 dose-escalation schema was utilized up to a maximum administered dose of 144 mg daily. Dose expansion was subsequently performed in two cohorts in parallel: (i) low dose, ZEN-3694 at 48 mg daily (N = 14), and (ii) high dose, ZEN-3694 96 mg daily (N = 26).

A formal interim analysis was not planned; however, interim data were reviewed on an ongoing basis. The final planned analyses were performed after 75 patients were enrolled and the database was locked on February 6, 2020.

The primary study endpoint was safety and the recommended phase II dose of ZEN-3694 in combination with enzalutamide. Secondary endpoints included pharmacokinetics assessment of ZEN-3694 and enzalutamide, PSA50 response (≥50% decline in PSA from baseline confirmed ≥4 weeks later) rate, duration of PSA50 response, and radiographic progression-free survival (rPFS). Soft-tissue radiographic progression and responses were assessed according to RECIST v1.1 criteria. Progression of bone metastases was assessed using PCWG2 criteria. Post hoc analyses were performed to assess composite progression-free survival (PFS), defined as first occurrence of radiographic or clinical progression or death, as well as PSA PFS by PCWG2 criteria. Correlative endpoints included pharmacodynamics assessment of ZEN-3694 in combination with enzalutamide and relationship between tumor genomic/transcriptional profile, protein expression, and clinical variables with clinical outcomes on treatment.

Safety and efficacy assessments

Clinical and laboratory assessments were conducted at baseline and weekly during cycles 1 and 2 (28-day cycle length), every 2 weeks in cycle 3, and then every 4 weeks thereafter. Tumor response monitoring was performed using whole-body bone scan and cross-sectional imaging of the chest/abdomen/pelvis at baseline and every 2 cycles thereafter. Adverse events were graded using Common Toxicity Criteria version 4.0.

Pharmacodynamic/exploratory assessments

Whole-blood RNA for assessment of BETi target gene expression (MYC, IL8, CCR1, GPR183, HEXIM1, and IL1RN) was collected predose, 2 hours, 4 hours, 6 hours, and 24 hours post–cycle 1, day 1 dose (20). Baseline and on-treatment metastatic tumor biopsies of bone or soft tissue were obtained whenever feasible, and were evaluated by RNA-sequencing (RNA-seq) and IHC for protein expression of AR. Quality of the FASTQ files was verified by FASTQC2, and reads were aligned on BaseSpace (https://basespace.illumina.com) using the RNA-Seq alignment App (version 1.1.1) with the default parameters (STAR aligner version 2.5.0b, UCSC hg19 reference genome). Gene expression levels (FPKM) for baseline biopsies were estimated using Cufflinks (version 2.2.1). For the paired biopsies, aligned reads were used as input for DESeq2 (version 1.1.0) to enable pairwise differential gene expression analysis using the default parameters. Gene set enrichment analysis (GSEA) was performed on transcriptional data when available, and previously validated AR, prostate cancer, and MYC transcriptional signatures were additionally applied to the transcriptional data (21, 22). For the BETi signature, significant genes (P < 0.05) that were >2-fold downregulated upon exposure of 0.5 μmol/L I-BET762 for 24 hours in LNCaP prostate cancer cells were selected (23). Archival tumor tissue was obtained whenever feasible for analysis of whole transcriptome and exome sequencing.

Pharmacokinetics assessments

Plasma levels of ZEN-3694, the bioactive first-order metabolite ZEN-3791, and enzalutamide were measured predose and up to 24 hours postdose on days 1 and 15 of cycle. Plasma concentrations were determined using validated LC/MS-MS analysis.

Study population and patient disposition

A total of 75 patients were enrolled from December 2016 to April 2019 across seven investigational sites. Baseline characteristics of the enrolled patients are shown in Table 1. At study entry, 30 (40.0%) patients had previously experienced disease progression on abiraterone, 34 (45.3%) on enzalutamide, and 11 (14.7%) on both. Twelve (16%) patients experienced prior primary resistance to first-line AR-targeted therapy, defined in post hoc fashion as treatment duration of less than 6 months. Forty-two (56%) patients had evidence of radiographic and/or clinical progression at study entry.

Table 1.

Baseline characteristics.

Study cohort
(N = 75)a
Median age (range), years 70 (47–89) 
ECOG score 
 0 42 (56%) 
 1 33 (44%) 
Opioid analgesic use 18 (24%) 
Visceral metastases at study entry (%) 21 (28%) 
Median PSA, ng/mL (range) 26.99 (0.15–1,701.8) 
Median ALP, U/L (range) 82 (33–487) 
Median LDH, U/L (range) 188 (98–543) 
Median hemoglobin, g/dL (range) 13.2 (6.4–20.2) 
Halabi risk category (ref. 24; %) 
 Low 50 (67) 
 Intermediate 16 (21) 
 High 8 (11) 
 Unknown 1 (1) 
Prior number of systemic cancer treatments (range) 3 (1–7) 
Prior resistance to AR-targeted therapy (%) 
 Abiraterone 30 (40) 
 Enzalutamide 34 (45) 
 Both 11 (15) 
Duration of prior AR-targeted therapy (range), months 14.3 (1.0–58.3) 
Reason for prior abiraterone or enzalutamide discontinuation 
 Radiographic progression 8 (11%) 
 Radiographic and PSA progression 31 (41%) 
 Clinical and PSA progression 3 (4%) 
 PSA progression 33 (44%) 
 Clinical progression 
Study cohort
(N = 75)a
Median age (range), years 70 (47–89) 
ECOG score 
 0 42 (56%) 
 1 33 (44%) 
Opioid analgesic use 18 (24%) 
Visceral metastases at study entry (%) 21 (28%) 
Median PSA, ng/mL (range) 26.99 (0.15–1,701.8) 
Median ALP, U/L (range) 82 (33–487) 
Median LDH, U/L (range) 188 (98–543) 
Median hemoglobin, g/dL (range) 13.2 (6.4–20.2) 
Halabi risk category (ref. 24; %) 
 Low 50 (67) 
 Intermediate 16 (21) 
 High 8 (11) 
 Unknown 1 (1) 
Prior number of systemic cancer treatments (range) 3 (1–7) 
Prior resistance to AR-targeted therapy (%) 
 Abiraterone 30 (40) 
 Enzalutamide 34 (45) 
 Both 11 (15) 
Duration of prior AR-targeted therapy (range), months 14.3 (1.0–58.3) 
Reason for prior abiraterone or enzalutamide discontinuation 
 Radiographic progression 8 (11%) 
 Radiographic and PSA progression 31 (41%) 
 Clinical and PSA progression 3 (4%) 
 PSA progression 33 (44%) 
 Clinical progression 

Abbreviations: ALP, alkaline phosphatase; LDH, lactate dehydrogenase.

aFor data recorded in the clinical database as of the data cut-off date of January 7, 2020.

The median duration of treatment was 3.5 months (range, 0–34.7+). As of date of data cutoff, seven patients (9%) remain on treatment without progression, with duration of therapy ranging from 15.0+ to 34.7+ months. Forty-eight patients (64%) discontinued for disease progression; nine patients (12%) discontinued for adverse events, and 11 (16%) withdrew from study.

Safety results

The proportion of patients who experienced grade ≥3 treatment-related adverse event was 18.7% (n = 14). The most common grade ≥3 adverse events (≥2 patients) included nausea (n = 3; 4%), thrombocytopenia (n = 3; 4%), anemia (n = 2; 2.7%), fatigue (n = 2; 2.7%), and hypophosphatemia (n = 2; 2.7%). There were no clinically significant bleeding events observed on treatment.

The most commonly reported ZEN-3694–related adverse events (any grade severity, occurring in ≥10% of patients, in order of incidence) were visual symptoms (described as a transitory perception of brighter lights and/or light flashes, with or without visual color tinges, as well as trouble navigating in dim light; 67%), nausea (45%), fatigue (40%), decreased appetite (25%), dysgeusia (20%), thrombocytopenia (15%), and weight decreased (11%; Table 2). Visual symptoms were grade 1 in all cases, resolved 60–90 minutes after dosing, were successfully mitigated with implementation of dosing before bedtime, and resulted in no functional consequences upon repeat eye exams throughout study participation.

Table 2.

Summary of all grades treatment-related adverse events by dose level of ZEN-3694.

36 mg QD48 mg QD60 mg QD72 mg QD96 mg QD120 mg QD144 mg QDTotal
n = 4n = 21n = 6n = 6n = 31n = 4n = 3N = 75 (%)
Blood creatinine increased      5 (6.7) 
Constipation      4 (5.3) 
Decreased appetite  10 20 (26.7) 
Diarrhea      6 (8) 
Dizziness      4 (5.3) 
Dysgeusia  10 16 (21.3) 
Dyspepsia      3 (4) 
Fatigue 13 29 (38.7) 
Nasal congestion       3 (4) 
Nausea  17 34 (45.3) 
Photopsia      4 (5.3) 
Photosensitivity      5 (6.7) 
Rash       3 (4) 
Rash maculopapular     5 (6.7) 
Taste disorder     5 (6.7) 
Thrombocytopenia   11 (14.7) 
Vision blurred      3 (4) 
Visual symptomsa 12 17 48 (64) 
Vomiting     5 (6.7) 
Weight loss and abnormal weight loss   8 (10.7) 
36 mg QD48 mg QD60 mg QD72 mg QD96 mg QD120 mg QD144 mg QDTotal
n = 4n = 21n = 6n = 6n = 31n = 4n = 3N = 75 (%)
Blood creatinine increased      5 (6.7) 
Constipation      4 (5.3) 
Decreased appetite  10 20 (26.7) 
Diarrhea      6 (8) 
Dizziness      4 (5.3) 
Dysgeusia  10 16 (21.3) 
Dyspepsia      3 (4) 
Fatigue 13 29 (38.7) 
Nasal congestion       3 (4) 
Nausea  17 34 (45.3) 
Photopsia      4 (5.3) 
Photosensitivity      5 (6.7) 
Rash       3 (4) 
Rash maculopapular     5 (6.7) 
Taste disorder     5 (6.7) 
Thrombocytopenia   11 (14.7) 
Vision blurred      3 (4) 
Visual symptomsa 12 17 48 (64) 
Vomiting     5 (6.7) 
Weight loss and abnormal weight loss   8 (10.7) 

Abbreviation: QD, every day.

aVisual symptoms defined as a transitory perception of bright lights and/or light flashes with or without visual color tinges.

Dose reductions and/or treatment discontinuation due to adverse events were required in 24 of 75 (32%) of patients. The percentage of patients requiring dose reduction and/or discontinuation ranged from 10% to 35% for doses from 36 to 96 mg/day, in contrast to 75% and 100% at ZEN-3694 dose levels of 120 and 144 mg/day, respectively (Supplementary Table S1). The class of adverse events leading to dose reduction and/or discontinuation were related to gastrointestinal (GI) toxicities in 83% of occurrences.

Determination of MTD and recommended phase II dose

In the dose escalation, 35 patients were enrolled across dose levels ranging from 36 to 144 mg daily. The MTD was not reached. One patient experienced a dose-limiting toxicity at the 96 mg/day dose level (grade 3 nausea necessitating missing >25% of scheduled doses in cycle 1). On the basis of the aggregate of pharmacodynamics data indicating dose exposure–dependent downregulation of BETi target gene expression with a plateau of effect at doses above 96 mg/day, the high percentage of patients requiring dose interruptions/reductions at doses above 96 mg/day, and a comparable pharmacokinetics/pharmacodynamics effect with preclinical models treated at efficacious doses, 96 mg/day was chosen as the recommended phase II dose of ZEN-3694 for dose expansion (N = 26). An additional dose-expansion cohort of 48 mg/day (N = 14) was also enrolled, to better characterize the exposure–effect relationship.

Pharmacokinetics analyses

The AUC0–24 and the Cmax of combined ZEN-3694 (parent compound) + ZEN-3791 (active metabolite), on day 1 and day 15 of cycle 1, are shown in Fig. 1A and B, respectively. Less than dose proportional increase in exposure was observed at doses higher than 96 mg daily. The estimated Tmax and half-life of ZEN-3694 + ZEN-3791 were 2 and 5–6 hours, respectively. The ratio of ZEN-3791 metabolite to parent compound, ZEN-3694, was increased on day 15 compared with day 1, likely related to enzalutamide-mediated induction of CYP3A4 metabolism (Fig. 1C). The observed plasma concentrations of ZEN-3694 + ZEN-3791 were similar to ZEN-3694 monotherapy pharmacokinetics reported previously (24). Likewise, there was no significant impact of ZEN-3694 on enzalutamide and desmethyl enzalutamide concentrations (Fig. 1D).

Figure 1.

Pharmacokinetics analyses. A and B, AUC from 0 to 24 hours (AUC0–24) and maximum serum concentration, respectively, of ZEN-3694 + ZEN-3791 (first-generation active metabolite) serum concentration on day 1 and day 15 of cycle 1 (red triangles). Overlaid AUC0–24 data from the monotherapy (mono) trial of ZEN-3694 (23) are shown for dose levels 48 and 72 mg daily (black circles). C, Ratio of ZEN-3791 (first-generation active metabolite) versus ZEN-3694 (parent compound) from the prior monotherapy trial (23) and in combination with enzalutamide (enza) on day 1 and day 15 of cycle 1. D, Steady-state serum concentration of enzalutamide and desmethyl enzalutamide following 14 day lead-in of enzalutamide (day −14 to day −1), by ZEN-3694 dose level. QD, every day.

Figure 1.

Pharmacokinetics analyses. A and B, AUC from 0 to 24 hours (AUC0–24) and maximum serum concentration, respectively, of ZEN-3694 + ZEN-3791 (first-generation active metabolite) serum concentration on day 1 and day 15 of cycle 1 (red triangles). Overlaid AUC0–24 data from the monotherapy (mono) trial of ZEN-3694 (23) are shown for dose levels 48 and 72 mg daily (black circles). C, Ratio of ZEN-3791 (first-generation active metabolite) versus ZEN-3694 (parent compound) from the prior monotherapy trial (23) and in combination with enzalutamide (enza) on day 1 and day 15 of cycle 1. D, Steady-state serum concentration of enzalutamide and desmethyl enzalutamide following 14 day lead-in of enzalutamide (day −14 to day −1), by ZEN-3694 dose level. QD, every day.

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Pharmacodynamics analyses

Pre- and up to 24-hour postdose whole-blood RNA analyses were available from 69 patients enrolled on study. There was a dose-dependent two- to fourfold decrease in the whole-blood mRNA levels of the BETi target genes MYC, IL8, CCR1, GPR183, and IL1RN (Fig. 2A) upon treatment with ZEN-3694, which was sustained for at least 8 hours. Decrease in expression of BETi target genes appeared to plateau at ZEN-3694 dose levels ≥96 mg. There was a direct correlation between cumulative exposure to ZEN-3694 + ZEN-3791 (AUC0–2 for MYC and GPR183, and AUC0–4 for CCR1, IL1RN, and IL8) with downregulation of whole-blood mRNA levels of the BETi target genes (R2 ranging from 0.20 to 0.51; P ≤ 0.0001; Fig. 2B).

Figure 2.

Pharmacodynamics assessments. A, Fold-change from baseline in whole-blood RNA expression of BETi target genes CCR1, IL1RN, IL8, MYC, and GPR183 by ZEN-3694 dose level. B, Correlation between fold change from baseline in whole-blood RNA expression of BETi target genes and AUC0–24 of ZEN-3694 + ZEN-3791 indicates strong pharmacokinetics–pharmacodynamics relationship. C, GSEA of change from baseline in gene expression by RNA-seq in paired metastatic tumor biopsies. Downregulation of MYC signaling pathway was observed in on-treatment versus baseline tumor biopsy.

Figure 2.

Pharmacodynamics assessments. A, Fold-change from baseline in whole-blood RNA expression of BETi target genes CCR1, IL1RN, IL8, MYC, and GPR183 by ZEN-3694 dose level. B, Correlation between fold change from baseline in whole-blood RNA expression of BETi target genes and AUC0–24 of ZEN-3694 + ZEN-3791 indicates strong pharmacokinetics–pharmacodynamics relationship. C, GSEA of change from baseline in gene expression by RNA-seq in paired metastatic tumor biopsies. Downregulation of MYC signaling pathway was observed in on-treatment versus baseline tumor biopsy.

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Four patients had evaluable paired metastatic tumor biopsies obtained at baseline and on-treatment (median duration of treatment 8 weeks prior to on-treatment biopsy). Time after the last ZEN-3694 + enzalutamide dosing prior to the biopsy ranged from 3.5 to 24 hours. The limited sample size precluded ability to perform statistical analyses of change in expression by dose level. However, on GSEAs, looking at changes between on-treatment versus pretreatment samples, there were strong indications of downregulation of expression of MYC and AR signaling on-treatment compared with baseline biopsies, as well as downregulation of BET-dependent genes previously identified in LnCaP cells treated with the I-BET762 BETi (Fig. 2C; ref. 23).

Efficacy analyses

The median rPFS in the overall cohort was 9.0 months [95% confidence interval (CI), 4.6–12.9], with 7.8 months for patients that had progressed on abiraterone (95% CI, 4.9–10.6) and 10.1 months for patients that had progressed on enzalutamide (95% CI, 4.4–12.9; Fig. 3A). Composite median radiographic or clinical PFS was 5.5 months (95% CI, 4.0–7.8) in the overall cohort, and 5.5 months (95% CI, 4.4–7.8) and 5.1 months (95% CI, 3.2–10.1) in those with prior progression on abiraterone and enzalutamide, respectively (Fig. 3B). Thirteen (17%) and four (5%) patients remained on treatment for greater than 12 and 24 months without progression, respectively (Fig. 3C). In patients with radiographic progression at the time of study entry, the median rPFS was 7.8 months (95% CI, 4.4–10.6; Fig. 3D) and composite PFS was 4.8 months (95% CI, 3.5–7.7). An analysis of the subset of patients with primary resistance to prior first-line AR-targeted therapy (N = 12), defined by progression within 6 months of treatment initiation, demonstrated an on-treatment median rPFS of 10.6 months (95% CI, 7.5–not reached; Fig. 3E). Using a more stringent cutoff of primary resistance of progression within 16 weeks of prior first-line AR-targeted therapy (N = 5), likewise demonstrated prolonged median rPFS (median rPFS, 22.4 months; 95% CI, 7.8–not reached) and composite PFS (median PFS, 10.6 months; 95% CI, 4.0, not reached) in this subset of patients (Supplementary Fig. S1A and S1B).

Figure 3.

rPFS and duration of treatment. A, Kaplan–Meier curve demonstrating rPFS by PCWG2 criteria in all evaluable study participants (black curve), patients with prior enzalutamide (enza) progression (blue curve), or prior abiraterone (abi) progression (green curve). B, Kaplan–Meier curve demonstrating composite PFS (time to first clinical or radiographic progression). C, Swimmer plot showing duration of treatment, with color labels by ZEN-3694 dose level (hashed line, treatment ongoing). D and E, Kaplan–Meier curves showing rPFS in subsets of patients with radiographic progression or primary resistance to prior ASI, respectively.

Figure 3.

rPFS and duration of treatment. A, Kaplan–Meier curve demonstrating rPFS by PCWG2 criteria in all evaluable study participants (black curve), patients with prior enzalutamide (enza) progression (blue curve), or prior abiraterone (abi) progression (green curve). B, Kaplan–Meier curve demonstrating composite PFS (time to first clinical or radiographic progression). C, Swimmer plot showing duration of treatment, with color labels by ZEN-3694 dose level (hashed line, treatment ongoing). D and E, Kaplan–Meier curves showing rPFS in subsets of patients with radiographic progression or primary resistance to prior ASI, respectively.

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Of the four exceptional responders who remained on treatment for greater than 24 months duration, three had radiographic progression at study entry, two had progressed on prior enzalutamide, and one of the four patients experienced an objective radiographic response on enzalutamide + ZEN-3694 (Supplementary Table S2).

Six patients (8%) experienced a greater than 50% decline from baseline in serum PSA by PCWG2 criteria (PSA50 response), including two patients with prior progression on enzalutamide monotherapy. All PSA responses were confirmed on repeat measurement. Four patients (5.3%) experienced a greater than 90% decline in serum PSA from baseline on study treatment. PSA50 responses were sustained in the majority of cases with median duration of PSA50 response of 21.1 months (95% CI, 19.0–23.2). The median PSA PFS was 3.2 months (95% CI, 3.2–5.1) in the overall study cohort and 3.2 months (95% CI, 2.8–6.4) in those with PSA-only progression at study entry. There were no substantial differences with respect to rPFS, composite PFS, or PSA PFS noted between 48- and 96-mg dose-expansion cohorts.

In addition, in a subset of patients (n = 21), there was a transient increase of >2 ng/mL and 25% above baseline in serum PSA within the first 12 weeks of treatment with subsequent plateau in serum PSA level (Supplementary Fig. S2A). Patients with transient PSA increase as defined above appeared to derive sustained clinical benefit with median rPFS of 10.1 months (95% CI, 5.6–11.7). In contrast, patients whose serum PSA consistently rose beyond the 12-week timepoint (n = 21) experienced a median rPFS of 7.2 months (95% CI, 3.9–9.0; Supplementary Fig. S2B).

Predictors of prolonged clinical benefit with ZEN-3694 + enzalutamide

Exploratory analyses were performed with available genomic and transcriptional data from baseline tumor biopsies to evaluate association with subsequent time to progression (TTP) on treatment. Interestingly, patients whose baseline metastatic tumor biopsies (N = 13) harbored lower canonical AR transcriptional activity, as assessed by 5-gene score (25) as well as the HALLMARK_ANDROGEN_RESPONSE signature, experienced a longer median TTP (median TTP 19 vs. 45 weeks; Fig. 4A and B). In support of the notion that tumors with lower canonical AR activity might be more responsive to BET inhibition, we observed a trend toward prolonged TTP among patients meeting clinical criteria for aggressive variant prostate cancer [e.g., low serum PSA <10 ng/mL with concomitant high disease burden (visceral metastases and/or >10 bone metastases); ref. 26]. The median TTP in patients with aggressive variant disease was 11.6 months (95% CI, 7.2–12.8) versus 5.5 months (95% CI, 2.3–10.6, P = 0.24) in those without aggressive variant clinical features at baseline (Fig. 4C).

Figure 4.

AR signaling score and clinical outcomes. A, Lower AR activity level in baseline tumor biopsies is correlated with longer time on study (R2 = 0.38) using either the 5-gene AR score (left) or the HALLMARK_ANDROGEN_RESPONSE (right) signatures. For the hallmark signature, baseline gene expression of biopsies from patients with radiographic progression prior to 24 weeks versus greater than 24 weeks were compared (FDR = 0.04). B, Kaplan–Meier curve showing significant increase in time to median rPFS in patients with lower AR signaling compared with patients with higher AR signaling score (median rPFS 10.4 months in tumors with low AR score versus 4.3 months in tumors with high AR activity). C, Patients with high tumor burden and lower baseline PSA levels (<10 ng/mL; blue curve) demonstrate longer PFS than patients with higher baseline PSA (>10 ng/mL) levels.

Figure 4.

AR signaling score and clinical outcomes. A, Lower AR activity level in baseline tumor biopsies is correlated with longer time on study (R2 = 0.38) using either the 5-gene AR score (left) or the HALLMARK_ANDROGEN_RESPONSE (right) signatures. For the hallmark signature, baseline gene expression of biopsies from patients with radiographic progression prior to 24 weeks versus greater than 24 weeks were compared (FDR = 0.04). B, Kaplan–Meier curve showing significant increase in time to median rPFS in patients with lower AR signaling compared with patients with higher AR signaling score (median rPFS 10.4 months in tumors with low AR score versus 4.3 months in tumors with high AR activity). C, Patients with high tumor burden and lower baseline PSA levels (<10 ng/mL; blue curve) demonstrate longer PFS than patients with higher baseline PSA (>10 ng/mL) levels.

Close modal

Our results demonstrate that the pan-BETi, ZEN-3694, has acceptable tolerability and encouraging preliminary efficacy data in combination with enzalutamide in patients with mCRPC. The median rPFS in the overall cohort was 9 months, and more than 10 months in those with prior progression on enzalutamide monotherapy. ZEN-3694 + enzalutamide treatment led to a two- to fourfold reduction in the expression of BET target genes including MYC, which was sustained throughout the 24-hour dosing interval. On the basis of the aggregate of the safety, efficacy, and evidence of robust downregulation of expression of BET-dependent target genes, ZEN-3694 at 96 mg daily has been selected as the recommended phase II dose to move forward in further clinical development in combination with enzalutamide. The clinical and pharmacodynamics data provide clinical evidence that BET inhibition may be able to abrogate resistance mechanisms and resensitize patients to ASIs.

The prolonged PFS observed in this study in relevant subsets, including those with radiographic progression at study entry, primary resistance to prior AR-targeted therapy, as well as those with prior progression on enzalutamide monotherapy, is consistent with an additive or potentially synergistic interaction between enzalutamide and ZEN-3694. The baseline characteristics of the study cohort are representative of other studies in the post-ASI mCRPC setting, including nearly one-third of patients with intermediate- or high-risk disease by Halabi prognostic model (27), and a quarter of whom required opioid analgesics at study entry. These features argue against the possibility of enrichment of better than average-risk group contributing significantly to the prolonged PFS observed on treatment. Taken together, the data support a randomized study to evaluate for the magnitude of benefit of ZEN-3694 in combination with enzalutamide.

With the caveat of cross-trial comparisons, the median PFS observed with ZEN-3694 + enzalutamide in this study compares favorably with outcomes observed with sequential AR targeting in mCRPC with abiraterone followed by enzalutamide, or vice versa, in prior studies. In the prospective SWITCH phase II cross-over study, the median PFSs of second-line enzalutamide and abiraterone were 3.5 and 1.7 months, respectively (6). Similarly, median PFSs with second-line AR-targeting therapy have been less than 8 months in most retrospective series (9). Caution should be applied to overinterpretation of these cross-trial comparisons, and a randomized trial will be necessary to assess the individual contribution of ZEN-3694 added to enzalutamide in mCRPC.

The PSA50 response rate with the combination of ZEN-3694 plus enzalutamide was less than 10% in the study, and median PSA PFS was less than 4 months. Although this may reflect lack of additive benefit of ZEN-3694 in combination with enzalutamide, decline in serum PSA and PSA PFS may not be the best metrics to gauge efficacy of BETis including ZEN-3694. In fact, a subset of patients experienced transient early rises in serum PSA levels by week 8 of treatment, which were associated with longer TTP. In addition, tumors harboring lower AR activity at baseline appeared to derive more clinical benefit from treatment. Finally, those with low serum PSA in relation to metastatic disease burden, a clinical profile consistent with small-cell/neuroendocrine prostate cancer, may also have longer rPFS compared with those with higher baseline serum PSA levels. Although these observations are hypothesis generating and require prospective validation, it raises the intriguing possibility that BETis may restore dependency on AR signaling in tumors that are less reliant on AR prior to BETi or that BETi is blocking important AR-independent survival mechanisms, such as MYC, which have been shown to be critical for BETi effects in CRPC (13, 28, 29). AR-independent mCRPC is becoming more prevalent with the earlier application of ASIs, and is associated with shortened survival and unmet need to develop novel therapeutic approaches (14).

The acceptable toxicity profile of ZEN-3694 in combination with enzalutamide stands in contrast to the results observed with several other recent BETis reported in the literature, which have been limited by thrombocytopenia and GI toxicities (30, 31). In this study, there was substantially less thrombocytopenia observed. GI toxicities were not as prevalent or severe as prior studies and were manageable with early institution of antiemetics and dose reductions, if necessary. The reasons underlying the potentially more favorable toxicity profile observed in this study, as compared with other BETis, may relate to patient factors such as excluding prior chemotherapy for mCRPC. Furthermore, it is possible that a pharmacokinetics interaction between ZEN-3694 and enzalutamide may have accelerated production of the first-generation active metabolite, ZEN-3791, which may have a more favorable toxicity profile. The differential toxicity compared with other BETis does not appear to relate to differences in potency, given the robust downregulation of BETi target genes observed in this study.

There were several limitations of the study, including the limited number of baseline and on-treatment paired biopsies, precluding the ability to identify a consistent predictive biomarker with a high degree of statistical confidence. The nonrandomized nature of the dose expansion portion of the study also limits our ability to draw definitive conclusions regarding the potential additive benefit of ZEN-3694, although evidence of contribution is provided by favorable comparison with contemporary controls from other studies as outlined above. AR-V7 splice variant status in circulating tumor cells, a validated resistance mechanism to AR-targeted therapy that may be downregulated with BETi treatment, was not reliably captured in this study in a sufficient number of patients to permit evaluation. Finally, there did not appear to be a relationship between dose level and efficacy outcomes, potentially related to fairly broad interpatient variability in ZEN-3694 exposure, limited sample size, and limited single-agent activity of ZEN-3694.

With the shift in application of potent AR-targeted therapy in earlier castration-sensitive settings, there is an increasing medical need to develop therapies that reverse therapeutic resistance and restore dependency on AR signaling. The preliminary data provided by the phase Ib/II study of ZEN-3694 plus enzalutamide provides strong justification to further investigate it in a prospective, randomized study.

R. Aggarwal reports grants from Zenith Epigenetics during the conduct of the study, grants and personal fees from Janssen, Merck, and AstraZeneca, and personal fees from Dendreon and Clovis Oncology outside the submitted work. M.T. Schweizer reports grants from Zenith Epigenetics (research funds to institution) during the conduct of the study, as well as other from Janssen (research funds to institution), AstraZeneca (research funds to institution), Madison Vaccines (research funds to institution), Pfizer (research funds to institution), and Hoffmann-La Roche (research funds to institution), and personal fees from Resverlogix (consulting fee) outside the submitted work. D.M. Nanus reports personal fees from Genentech Roche (DSMB) outside the submitted work. A. Pantuck reports grants from UCLA (clinical trial contract/grant) during the conduct of the study. E. Campeau reports personal fees and other from Zenith Epigenetics Ltd. (salary paid by Zenith Epigenetics Ltd.) during the conduct of the study and outside the submitted work, and has a patent for Combination Therapy for the Treatment of Prostate Cancer pending (all patent rights were transferred to Zenith Epigenetics Ltd.). M. Snyder reports personal fees and other from Zenith Epigenetics (employment) during the conduct of the study and outside the submitted work, and reports employment with Zenith Epigenetics. S. Lakhotia reports personal fees and other from Zenith Epigenetics (paid salaried employee of Zenith, lead clinical development for Zenith) during the conduct of the study and outside the submitted work, and has a patent on the combination of ZEN-3694 + enzalutamide for the treatment of prostate cancer, owned by Zenith Epigenetics. F.Y. Feng reports personal fees from Janssen Oncology (advisory board), Sanofi (advisory board), and Bayer (consultant), grants and other from Zenith Epigenetics (research funding from Zenith Epigenetics), other from PFS Genomics (founding member, ownership interests), and personal fees from Celgene (advisory board), Blue Earth Diagnostics (advisory board), Genentech (consultant), Myovant Sciences (consultant), Roivant Sciences (consultant), and Astellas Pharma (consultant) outside the submitted work. E.J. Small reports personal fees and other from Fortis Therapeutics (consulting and stock) and personal fees from Harpoon Therapeutics (consulting), Janssen (consulting), BeiGene (consulting), Tolero (consulting), and Teon Therapeutics (consulting) outside the submitted work. W. Abida reports grants from Zenith Epigenetics (research funding to institution) during the conduct of the study, as well as grants from Clovis Oncology (research funding to institution) and GlaxoSmithKline (research funding to institution), personal fees from Clovis Oncology, Janssen Biotech, MORE Health, ORIC pharmaceuticals, and Daiichi Sankyo, and grants from AstraZeneca (research funding to institution) outside the submitted work. J. Alumkal reports grants from Zenith Epigenetics (research support to institution) and NCI (research support to institution) during the conduct of the study, and grants from Aragon Pharmaceuticals (research support to institution) and Gilead Sciences (research support to institution), and grants and personal fees from Astellas (consulting fees and research support to institution) and Janssen Biotech (consulting fees and research support to institution) outside the submitted work. No potential conflicts of interest were disclosed by the other authors.

R. Aggarwal: Conceptualization, formal analysis, supervision, validation, investigation, visualization, methodology, writing-original draft, writing-review and editing. M.T. Schweizer: Conceptualization, formal analysis, supervision, validation, investigation, visualization, methodology, writing-original draft, writing-review and editing. D.M. Nanus: Formal analysis, supervision, validation, investigation, visualization, methodology, writing-original draft, writing-review and editing. A. Pantuck: Conceptualization, formal analysis, supervision, validation, investigation, visualization, methodology, writing-original draft, writing-review and editing. E. Heath: Conceptualization, data curation, software, supervision, validation, investigation, visualization, methodology, writing-original draft, writing-review and editing. E. Campeau: Data curation, software, formal analysis, visualization, writing-original draft, writing-review and editing. S. Attwell: Conceptualization, data curation, software, formal analysis, supervision, investigation, methodology, writing-original draft, project administration, writing-review and editing. K. Norek: Conceptualization, software, supervision, validation, investigation, visualization, methodology. M. Snyder: Conceptualization, resources, data curation, software, formal analysis, validation, visualization, methodology, writing-original draft, project administration, writing-review and editing. L. Bauman: Conceptualization, resources, data curation, software, formal analysis, supervision, validation, visualization, methodology, writing-original draft, writing-review and editing. S. Lakhotia: Conceptualization, resources, supervision, funding acquisition, writing-review and editing. F.Y. Feng: Conceptualization, data curation, software, supervision, validation, investigation, visualization, methodology, writing-original draft, writing-review and editing. E.J. Small: Conceptualization, software, formal analysis, funding acquisition, validation, investigation, visualization, methodology, writing-original draft, writing-review and editing. W. Abida: Conceptualization, data curation, software, formal analysis, supervision, validation, investigation, visualization, methodology, writing-original draft, writing-review and editing. J. Alumkal: Conceptualization, data curation, software, formal analysis, supervision, funding acquisition, validation, investigation, visualization, methodology, writing-original draft, writing-review and editing.

The financial support and study drug supply was provided by Zenith Epigenetics. R. Aggarwal received funding from the Prostate Cancer Foundation and the Department of Defense Prostate Cancer Research Program grant W81XWH1820039. W. Abida was funded by NIH NCI Cancer Center Support grant (P30CA008748) and Prostate Cancer SPORE (P50CA092629), the Department of Defense Physician Research Award W81XWH-17-1-0124, and the Prostate Cancer Foundation. J. Alumkal received funding from NCI R01 CA251245, the Pacific Northwest Prostate Cancer SPORE (NCI P50 CA097186), and the Michigan Prostate SPORE (NCI P50 CA186786). J. Alumkal is currently employed by the University of Michigan. F.Y. Feng received funding from the Prostate Cancer Foundation.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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