Andrew Krivoshik

Neoadjuvant Enzalutamide Prior to Prostatectomy

Purpose: Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride (dut) and leuprolide (enza/dut/luteinizing hormone-releasing hormone analogues [LHRHa]). Experimental Design: Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enzalutamide or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of PSA and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa. Results: In the enzalutamide arm, none of the 25 patients achieved pCR or MRD. In the enza/dut/LHRHa arm, one of 23 patients (4.3%) achieved pCR and 3 of 23 (13.0%) achieved MRD. Median RCB was higher in the enzalutamide arm than in the enza/dut/LHRHa arm (0.41 cm3 vs. 0.06 cm3, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported. Conclusions: Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable with historical controls. Evidence of continued AR activity in residual tumor suggests that AR signaling may contribute to survival. Strategies to more effectively ablate AR activity are warranted to determine whether more substantial antitumor effects are observed. Clin Cancer Res; 23(9); 2169–76. ©2016 AACR.

Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer

BACKGROUND Men with nonmetastatic, castration‐resistant prostate cancer and a rapidly rising prostate‐specific antigen (PSA) level are at high risk for metastasis. We hypothesized that enzalutamide, which prolongs overall survival among patients with metastatic, castration‐resistant prostate cancer, would delay metastasis in men with nonmetastatic, castration‐resistant prostate cancer and a rapidly rising PSA level. METHODS In this double‐blind, phase 3 trial, we randomly assigned, in a 2:1 ratio, men with nonmetastatic, castration‐resistant prostate cancer and a PSA doubling time of 10 months or less who were continuing androgen‐deprivation therapy to receive enzalutamide (at a dose of 160 mg) or placebo once daily. The primary end point was metastasis‐free survival (defined as the time from randomization to radiographic progression or as the time to death without radiographic progression). RESULTS A total of 1401 patients (median PSA doubling time, 3.7 months) underwent randomization. As of June 28, 2017, a total of 219 of 933 patients (23%) in the enzalutamide group had metastasis or had died, as compared with 228 of 468 (49%) in the placebo group. The median metastasis‐free survival was 36.6 months in the enzalutamide group versus 14.7 months in the placebo group (hazard ratio for metastasis or death, 0.29; 95% confidence interval, 0.24 to 0.35; P<0.001). The time to the first use of a subsequent antineoplastic therapy was longer with enzalutamide treatment than with placebo (in 142 vs. 226 patients; hazard ratio, 0.21; P<0.001) as was the time to PSA progression (in 208 vs. 324 patients; hazard ratio, 0.07; P<0.001). At the first interim analysis of overall survival, 103 patients (11%) receiving enzalutamide and 62 (13%) receiving placebo had died. Adverse events of grade 3 or higher occurred in 31% of the patients receiving enzalutamide, as compared with 23% of those receiving placebo. CONCLUSIONS Among men with nonmetastatic, castration‐resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.)

Radiographic progression with nonrising PSA in metastatic castration-resistant prostate cancer: post hoc analysis of PREVAIL

Background:Advanced prostate cancer is a phenotypically diverse disease that evolves through multiple clinical courses. PSA level is the most widely used parameter for disease monitoring, but it has well-recognized limitations. Unlike in clinical trials, in practice, clinicians may rely on PSA monitoring alone to determine disease status on therapy. This approach has not been adequately tested.Methods:Chemotherapy-naive asymptomatic or mildly symptomatic men (n=872) with metastatic castration-resistant prostate cancer (mCRPC) who were treated with the androgen receptor inhibitor enzalutamide in the PREVAIL study were analyzed post hoc for rising versus nonrising PSA (empirically defined as >1.05 vs ⩽1.05 times the PSA level from 3 months earlier) at the time of radiographic progression. Clinical characteristics and disease outcomes were compared between the rising and nonrising PSA groups.Results:Of 265 PREVAIL patients with radiographic progression and evaluable PSA levels on the enzalutamide arm, nearly one-quarter had a nonrising PSA. Median progression-free survival in this cohort was 8.3 months versus 11.1 months in the rising PSA cohort (hazard ratio 1.68; 95% confidence interval 1.26–2.23); overall survival was similar between the two groups, although less than half of patients in either group were still at risk at 24 months. Baseline clinical characteristics of the two groups were similar.Conclusions:Non-rising PSA at radiographic progression is a common phenomenon in mCRPC patients treated with enzalutamide. As restaging in advanced prostate cancer patients is often guided by increases in PSA levels, our results demonstrate that disease progression on enzalutamide can occur without rising PSA levels. Therefore, a disease monitoring strategy that includes imaging not entirely reliant on serial serum PSA measurement may more accurately identify disease progression.

Long-Term Antitumor Activity and Safety of Enzalutamide Monotherapy in Hormone Naïve Prostate Cancer: 3-Year Open Label Followup Results

Purpose: A phase 2 study of enzalutamide monotherapy in patients with hormone naïve prostate cancer demonstrated high prostate specific antigen response rates at 25 weeks, 1 year and 2 years with minimal effects on total body bone mineral density and favorable safety. In this followup analysis we evaluated enzalutamide antitumor activity and safety at 3 years. Materials and Methods: In a single arm analysis 67 patients with hormone naïve prostate cancer and noncastrate testosterone (230 ng/dl or greater) received enzalutamide 160 mg per day orally until disease progression or unacceptable toxicity. The primary end point was the prostate specific antigen response (80% or greater decline from baseline). Results: No patients discontinued treatment during year 3. Of 42 patients with prostate specific antigen assessments at 3 years 38 (90.5%, 95% CI 77.4–97.3) maintained a prostate specific antigen response. Of 26 patients with metastases at baseline 17 (65.4%) had a complete or partial response as the best overall response during 3 years. In patients who completed the 3‐year visit minimal mean changes from baseline were observed in total body bone mineral density or bone mineral density of the femoral neck, trochanter, spine L1–L4 or forearm (range –2.7% to –0.1%). At 3 years total body fat had increased a mean of 16.5%, total lean body mass had decreased a mean of –6.5% and global health status had minimally decreased from baseline. Common adverse events were gynecomastia, fatigue, hot flush and nipple pain. Conclusions: Enzalutamide antitumor activity was maintained in patients with hormone naïve prostate cancer at 3 years. Overall bone mineral density, global health status and safety results were similar to those at 2 years.

Seizure Rates in Enzalutamide-Treated Men With Metastatic Castration-Resistant Prostate Cancer and Risk of Seizure: The UPWARD Study

Importance The androgen receptor inhibitor enzalutamide prolongs survival in men with metastatic castration-resistant prostate cancer (mCRPC). In controlled clinical studies, 0.5% (10 of 2051) of patients experienced seizure, but patients with a history of or risk factors for seizure were excluded. Men with mCRPC and seizure risk factors have an estimated seizure rate of 2.8 per 100 patient-years without enzalutamide exposure. Objective To assess seizure incidence in patients with seizure risk factors who were receiving enzalutamide for mCRPC. Design, Setting, and Participants The UPWARD study (A Study to Evaluate the Potential Increased Risk of Seizures Among Metastatic Castration-Resistant Prostate Cancer Patients Treated With Enzalutamide) is an international, multicenter (73 sites in 20 countries), single-arm, open-label safety study in institutional practice. Data were collected from September 25, 2013, to February 1, 2016. Patients had at least 1 risk factor for seizure at baseline, including medications that lower seizure threshold, history of stroke, or history of seizure. Exclusion criteria included seizure (assessed by neurologic examination and history) requiring antiseizure medication within the past 12 months. Intervention Treatment with oral enzalutamide, 160 mg/d. Main Outcomes and Measures The primary end point was the proportion of evaluable patients with 1 or more independently confirmed seizures during the 4-month study period; evaluable patients were defined as those who had 3 months or more of treatment or 1 or more confirmed seizures during this treatment period. Results Of 423 patients with mCRPC receiving enzalutamide, 366 were evaluated. At baseline, risk factors for seizure included medications that lowered seizure threshold (242 of 423 patients [57.2%]), history of brain injury (112 [26.5%]), and history of cerebrovascular accident or transient ischemic attack (94 [22.2%]). Four of the 366 evaluable patients (1.1%) had at least 1 confirmed seizure within 4 months of enzalutamide initiation, and 3 (0.8%) additional patients experienced a seizure within 4 months following the 4-month study period. The incidence of confirmed seizure was 2.6 per 100 patient-years (7 seizures). Of the 423 patients receiving enzalutamide, 357 (84.4%) experienced at least 1 treatment-emergent adverse event (an adverse event temporally related to the study treatment); 141 (33.3%) had at least 1 serious treatment-emergent adverse event, and 29 (6.9%) had at least 1 drug-related serious adverse event. Thirty-eight deaths (9.0%) were reported during treatment or within 30 days of drug discontinuation; 4 were considered possibly drug related. Conclusions and Relevance Incidence of seizure is similar in patients with mCRPC and similar seizure risk factors with or without enzalutamide exposure. The risk profile presented, along with the previously established efficacy of enzalutamide, suggests that enzalutamide can benefit patients with a history of seizures or other predisposing factors, but each patient should be closely monitored for the duration of treatment.

Radiographic Progression-Free Survival as a Clinically Meaningful End Point in Metastatic Castration-Resistant Prostate Cancer: The PREVAIL Randomized Clinical Trial

Importance Drug development for metastatic castration-resistant prostate cancer has been limited by a lack of clinically relevant trial end points short of overall survival (OS). Radiographic progression-free survival (rPFS) as defined by the Prostate Cancer Clinical Trials Working Group 2 (PCWG2) is a candidate end point that represents a clinically meaningful benefit to patients. Objective To demonstrate the robustness of the PCWG2 definition and to examine the relationship between rPFS and OS. Design, Setting, and Participants PREVAIL was a phase 3, randomized, double-blind, placebo-controlled multinational study that enrolled 1717 chemotherapy-naive men with metastatic castration-resistant prostate cancer from September 2010 through September 2012. The data were analyzed in November 2016. Interventions Patients were randomized 1:1 to enzalutamide 160 mg or placebo until confirmed radiographic disease progression or a skeletal-related event and initiation of either cytotoxic chemotherapy or an investigational agent for prostate cancer treatment. Main Outcomes and Measures Sensitivity analyses (SAs) of investigator-assessed rPFS were performed using the final rPFS data cutoff (May 6, 2012; 439 events; SA1) and the interim OS data cutoff (September 16, 2013; 540 events; SA2). Additional SAs using investigator-assessed rPFS from the final rPFS data cutoff assessed the impact of skeletal-related events (SA3), clinical progression (SA4), a confirmatory scan for soft-tissue disease progression (SA5), and all deaths regardless of time after study drug discontinuation (SA6). Correlations between investigator-assessed rPFS (SA2) and OS were calculated using Spearman &rgr; and Kendall &tgr; via Clayton copula. Results In the 1717 men (mean age, 72.0 [range, 43.0-93.0] years in enzalutamide arm and 71.0 [range, 42.0-93.0] years in placebo arm), enzalutamide significantly reduced risk of radiographic progression or death in all SAs, with hazard ratios of 0.22 (SA1; 95% CI, 0.18-0.27), 0.31 (SA2; 95% CI, 0.27-0.35), 0.21 (SA3; 95% CI, 0.18-0.26), 0.21 (SA4; 95% CI, 0.17-0.26), 0.23 (SA5; 95% CI, 0.19-0.30), and 0.23 (SA6; 95% CI, 0.19-0.30) (P < .001 for all). Correlations of rPFS and OS in enzalutamide-treated patients were 0.89 (95% CI, 0.86-0.92) by Spearman &rgr; and 0.72 (95% CI, 0.68-0.77) by Kendall &tgr;. Conclusions and Relevance Sensitivity analyses in PREVAIL demonstrated the robustness of the PCWG2 rPFS definition using additional measures of progression. There was concordance between central and investigator review and a positive correlation between rPFS and OS among enzalutamide-treated patients. Trial Registration clinicaltrials.gov Identifier: NCT01212991

Development and validation of a prognostic model for overall survival in chemotherapy-naïve men with metastatic castration-resistant prostate cancer

Background Prognostic models are needed that reflect contemporary practice for men with metastatic castration-resistant prostate cancer (mCRPC). We sought to identify predictive and prognostic variables for overall survival (OS) in chemotherapy-naïve men with mCRPC treated with enzalutamide. Patients and methods Patients from the PREVAIL trial database (enzalutamide versus placebo) were randomly split 2 : 1 into training (n = 1159) and testing (n = 550) sets. Using the training set, 23 predefined variables were analyzed and a multivariable model predicting OS was developed and validated in an independent testing set. Results Patient characteristics and outcomes were well balanced between training and testing sets; median OS was 32.7 months in each. The final validated multivariable model included 11 independent prognostic variables. Median OS for low-, intermediate-, and high-risk groups (testing set) defined by prognostic risk tertiles were not yet reached (NYR) (95% CI NYR-NYR), 34.2 months (31.5-NYR), and 21.1 months (17.5-25.0), respectively. Hazard ratios (95% CI) for OS in the low- and intermediate-risk groups versus high-risk group were 0.20 (0.14-0.29) and 0.40 (0.30-0.53), respectively. Secondary outcomes of response and progression differed widely in model-defined risk groups. Enzalutamide improved outcomes in all prognostic risk groups. Conclusions Our validated prognostic model incorporates variables routinely collected in chemotherapy-naïve men with mCRPC treated with enzalutamide, identifying subsets of patients with widely differing survival outcomes that provide useful information for external validation, patient care, and clinical trial design. Trial registration ClinicalTrials.gov: NCT01212991.

Abstract A24: Neuropilin 1 (NRP1) as a potential biomarker for tivozanib + mFOLFOX6 versus bevacizumab + mFOLFOX6 in metastatic colorectal cancer (mCRC): Post-hoc biomarker analysis of BATON-CRC phase 2 trial

Purpose: Tivozanib (T), is a potent oral selective inhibitor of VEGF receptors 1, 2, and 3. Bevacizumab (B) is an antibody targeting VEGF A mediated signaling. The randomized, open label phase 2 BATON-CRC (Biomarker Assessment of Tivozanib in ONcology), trial compared the progression free survival (PFS) and safety of T + mFOLFOX6 vs. B + mFOLFOX6 in mCRC patients. Data from the pre-specified interim analysis demonstrated futility for superiority; however the addition of T to mFOLFOX6 resulted in comparable PFS (9.4 vs 10.7 months, p=0.706), overall response rate (45.2% vs 43.2%, p=0.718), and safety to B + mFOLFOX6 and resulted in discontinuation of the study. At the time of the interim analysis (September, 2013) 62 patients out of 163 progressed to generate a PFS event and none of the pre-specified biomarkers demonstrated statistically significant association with PFS (ESMO 2014). At the close of the study (February, 2014), there were 91 PFS events out of 164 patients with baseline serum samples. The final analysis included the updated events which led to the observation that serum NRP1 may be a predictive biomarker for T. Serum NRP1, a pre-specified biomarker in BATON CRC, is associated with improved PFS and overall survival (OS) in multiple T studies in renal cell carcinoma (RCC). This strong association and clinical benefit in RCC prompted a post-hoc analysis of the final BATON-CRC PFS data to examine the differential association between base line serum NRP1 levels and outcomes in the two arms. Methods: Similar to the RCC trials, baseline serum from patients in BATON-CRC had NRP1 quantified using the Myriad RBM ELISA assay. The median NRP1 level from this dataset was used to define the cut off for NRP1 high and NRP1 low. A Cox proportional hazard model was used to assess the association between serum NRP1 levels and PFS. Results: In BATON-CRC, 265 patients were enrolled and randomized 2:1 to T + mFOLFOX6 (n = 177) or B + mFOLFOX6 (n = 88). A total of 164 baseline serum samples (T, n = 109 and B, n = 55) were available for NRP1 analysis. In both the T and B arms, patients with NRP1 low showed an improved PFS vs patients with NRP1 high; for T HR (95% CI): 0.224 [0.120, 0.42], p=3.56e-7 and for B HR [95% CI]: 0.487 [0.237, 1.00], p=0.046) supporting the value of NRP1 as a potential prognostic marker for angiogenesis inhibitors. T treated NRP1 low patients demonstrated a statistically significantly improvement in PFS vs B, PFS =17.9 vs 11.2 mos (multivariate analysis stratified for cancer origin, metastatic sites, LDH levels HR [95% CI]: 0.325 [0.147, 0.717], p=0.005). In NRP1 high patients, there was no difference in PFS between the two arms (HR (95% CI): 0.889 [0.639, 1.980], p=0.683). The interaction p-value is 0.027. Conclusions: The data suggest that NRP1 might be a predictive biomarker of T PFS benefit over B in combination with mFOLFOX 6 in advanced CRC. This finding needs to be further validated in another prospective trial. The differential activity observed with T vs B, in NRP1 low patients is potentially due to the broader VEGF pathway inhibitory activity of T. Citation Format: Al Benson, III, Andrew K. Krivoshik, Chip Van Sant, Jeno Gyuris, Bin Feng. Neuropilin 1 (NRP1) as a potential biomarker for tivozanib + mFOLFOX6 versus bevacizumab + mFOLFOX6 in metastatic colorectal cancer (mCRC): Post-hoc biomarker analysis of BATON-CRC phase 2 trial. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Angiogenesis and Vascular Normalization: Bench to Bedside to Biomarkers; Mar 5-8, 2015; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl):Abstract nr A24.

Abstract A47: Clinical profile of ASP8273, a mutant-selective EGFR inhibitor, in subjects with EGFR-mutation positive non-small cell lung cancer: interim results from an ongoing, phase 1, open-label, dose-escalation study

Introduction: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have demonstrated antitumor effects in patients with EGFR-mutant lung cancers; however, within a year, patients typically become resistant to TKI treatment. ASP8273 is a third-generation, once daily, orally administered, irreversible EGFR TKI that selectively inhibits EGFR mutations (e.g., exon 19 deletions, L858R, exon 20 insertion) as well as a secondary mutation associated with TKI resistance (T790M). Methods: ASP8273 is under evaluation in an ongoing, Phase 1 dose-escalation study conducted in the United States. Subjects diagnosed with EGFR mutation-positive non-small cell lung cancer (NSCLC) previously treated with an EGFR TKI were enrolled into the dose escalation cohort (25-500 mg) and response expansion (100-400 mg) cohorts. Response expansion cohorts enrolled subjects with EGFR T790M mutation and required submission of tissue samples for central confirmatory testing. Primary endpoint was tolerability assessed via adverse events (AEs) monitoring; secondary endpoints were pharmacokinetic (PK) parameters and antitumor activity based on RECIST 1.1 criteria. Results: As of June 18, 2015, 69 subjects (19 M/50 F) with a median age of 64 years (range: 38-85 years) had been enrolled into the dose escalation (n = 34) and response expansion (n = 35) cohorts. All patients had EGFR mutation(s); exon 19 deletions, L858R, and exon 20 insertions were identified in 54%, 17%, and 3% of subjects, respectively. EGFR T790M mutation was confirmed in 51% of subjects. Diarrhea, nausea, and fatigue (all Grades) were the most common treatment-emergent and treatment-related AEs. Hyponatremia (n = 8), anemia (n = 2), diarrhea (n = 2), nausea (n = 2), and progressive disease (n = 2) were the only Grade ≥3 treatment-emergent AEs reported in ≥2 subjects; serious AEs reported in ≥2 subjects were hyponatremia (n = 2), nausea (n = 2), and progressive disease (n = 2). ASP8273 exposure appeared dose proportional with peak concentration occurring approximately 1-4 h after administration with a half-life of 6-14 h. Of the 45 subjects treated with ASP8273 100-500 mg with evaluable data, partial response (PR) has been achieved by 42% (19/45) subjects. PR was reached by 12 of the 25 (48%) T790M-positive subjects, 3 of the 6 (50%) T790M-negative subjects, 4 of the 14 (29%) of subjects with unknown T790M status, and 1 of the 2 (50%) subjects with a confirmed exon 20 insertion. Conclusions: ASP8273, at doses Citation Format: Helena Yu, Geoffrey R. Oxnard, Alexander Spira, Leora Horn, Jared Weiss, Yan Feng, Howard West, Giuseppe Giaccone, Tracey Evans, Ronan Kelly, Tanya Fleege, Srinivasu Poondru, Fei Jie, Kouji Aoyama, Debbie Whitcomb, Anne Keating, Andrew Krivoshik. Clinical profile of ASP8273, a mutant-selective EGFR inhibitor, in subjects with EGFR-mutation positive non-small cell lung cancer: interim results from an ongoing, phase 1, open-label, dose-escalation study. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A47.