Enzalutamide for Treatment of Patients with Metastatic Castration-Resistant Prostate Cancer Who Have Previously Received Docetaxel: U.S. Food and Drug Administration Drug Approval Summary

Docetaxel in combination with prednisone was the first chemotherapy agent approved by the U.S. Food and Drug Administration (FDA) that improves survival in patients with metastatic castration-resistant prostate cancer (mCRPC). It received full FDA approval in 2004 based on a 2.4-month improvement in median overall survival (OS) for docetaxel compared with mitoxantrone [HR = 0.76; 95% confidence interval (CI), 0.62–0.94; P < 0.009; ref. 1, 2]. Since then, docetaxel has been commonly used for patients with mCRPC, particularly for those with symptomatic or visceral disease.

There was no effective therapy for patients with mCRPC and prior treatment with docetaxel until the approval of cabazitaxel in 2010. This approval was based on a 2.4-month improvement in median OS for cabazitaxel in combination with prednisone compared with mitoxantrone in combination with prednisone (HR = 0.70; 95% CI, 0.59–0.83; P < 0.0001) in patients with mCRPC who were previously treated with docetaxel (3). The overall risk–benefit assessment of cabazitaxel in the study patient population was generally favorable, but there were significant toxicities associated with cabazitaxel (4).

In April 2011, abiraterone acetate received FDA approval for the treatment of patients with mCRPC who have received docetaxel (5). Unlike cabazitaxel, abiraterone acetate acts as an androgen biosynthesis inhibitor by targeting CYP17 and inhibiting extragonadal androgen synthesis in patients with castrate levels of testosterone (6). In patients with mCRPC who had received prior docetaxel, treatment with abiraterone acetate led to a statistically significant and clinically important improvement in OS when compared with placebo (HR = 0.646; 95% CI, 0.543–0.768; P < 0.0001; ref. 7). The median OS was 14.8 months versus 10.9 months in the abiraterone acetate and placebo arms, respectively.

Moreover, the demonstrated effectiveness of abiraterone acetate in patients with mCRPC provides clinical evidence that impeding the androgen signaling pathway represents an important therapeutic approach to development of new products to treat mCRPC. Indeed, multiple lines of evidence have shown that CRPC continues to utilize active androgen signaling in its progression despite maintenance of castrate levels of serum testosterone (8).

Enzalutamide is an androgen receptor inhibitor. Its clinical development was initiated by Medivation Inc. in 2007. A phase I–II study of enzalutamide (formerly named MDV3100) at oral doses ranging from 30 to 600 mg daily demonstrated promising antitumor activity in 133 patients with mCRPC who were either chemotherapy naïve or previously treated with docetaxel (9, 10). Although this study determined that the maximum tolerated dose of enzalutamide was 240 mg once daily, an additional evaluation of the dose-related activity and safety data, particularly of the 3 cases of seizure occurring at the doses greater than 240 mg, led to the choice of using enzalutamide, 160 mg once daily, for further clinical studies. To evaluate whether the antitumor activity of enzalutamide could be translated into a tangible clinical benefit, the applicant conducted a randomized, placebo-controlled trial (CRPC2) in patients with mCRPC previously treated with docetaxel (11, 12). Patients with conditions that could predispose them to seizure were excluded from this randomized trial.

The new drug application (NDA) for enzalutamide was submitted and received by the FDA on May 22, 2012. This NDA was designated for a 6-month priority review and was approved on August 31, 2012, 3 months after submission. This article summarizes key findings from the FDA's multidisciplinary review teams, with a focus on the clinical review findings that support the approved indication. For more details, see the reviews of enzalutamide at Drugs@FDA (13).

Enzalutamide has a chemical designation as 4-{3-[4-cyano-3-(trifluoromethyl)phenyl]-5,5-dimethyl-4-oxo-2-sulfanylideneimidazolidin-1-yl}-2-fluoro-N-methylbenzamide. Its molecular formula is C₂₁H₁₆F₄N₄O₂S, with a molecular weight of 464.44. Enzalutamide is a white crystalline nonhygroscopic solid that is practically insoluble in water.

The inactive ingredients of XTANDI include caprylocaproyl polyoxylglycerides, butylated hydroxyanisole, butylated hydroxytoluene, gelatin, sorbitol sorbitan solution, glycerin, purified water, titanium dioxide, and black iron oxide.

XTANDI is provided as liquid-filled soft gelatin capsules. Each capsule contains 40 mg of enzalutamide as a solution in caprylocaproyl polyoxylglycerides.

In vitro, enzalutamide inhibited androgen binding to androgen receptors, androgen-dependent androgen receptor nuclear translocation, androgen-dependent androgen receptor association with DNA, and decreased proliferation and induced cell death of prostate cancer cells. In vivo, enzalutamide decreased tumor volume in a mouse xenograft model of human prostate cancer.

Major target organ systems of toxicity that were identified in repeat-dose toxicity studies with enzalutamide in rats and dogs were the reproductive organs and central nervous system. Consistent with the pharmacologic activity of enzalutamide, major toxicity findings were noted in male reproductive organs. In a 26-week study in rats, decreased organ weights were correlated with atrophy of the prostate and seminal vesicles, which were observed at systemic exposures similar to the human exposure based on AUC. In 4- and 13-week studies in dogs, decreased organ weights were correlated with hypospermatogenesis and atrophy of the prostate and epididymides, which were observed at 0.3 times the human AUC. Convulsions were noted in repeat-dose studies in mice and dogs. A dose-dependent increase in convulsions was observed in mice at 0.6 times the human AUC, and a convulsion was observed in one dog at 3.3 times the human AUC. Other nonclinical findings of minimal severity and without significant clinical correlations were noted in the liver (hepatocellular hypertrophy), pituitary (hypertrophy and hyperplasia), and kidney (chronic progressive nephropathy) following repeat-dose administration of enzalutamide to rats.

Enzalutamide did not induce mutations in the bacterial reverse mutation (Ames) assay and was not genotoxic in either the in vitro mouse lymphoma tk gene mutation assay or the in vivo mouse bone marrow micronucleus assay. Carcinogenicity studies with enzalutamide were not conducted or required to support approval for use in the indicated patient population.

Enzalutamide is not indicated for use in female patients. Reproductive and developmental toxicology studies with enzalutamide were not required to support approval for use in the indicated patient population. However, based on its mechanism of action and findings from repeat-dose toxicity studies in rats and dogs, enzalutamide may impair male fertility. In addition, enzalutamide can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Enzalutamide was assigned pregnancy category X and is contraindicated for use in pregnant women.

Following oral administration of enzalutamide, the median time to reach maximum plasma enzalutamide concentrations is 1 hour (range, 0.5–3 hours). The mean terminal half-life for enzalutamide is 5.8 days. Enzalutamide steady state is achieved by day 28, and the accumulation ratio is 8.3 fold. At steady state, enzalutamide showed approximately dose proportional pharmacokinetics over the daily dose range of 30 to 360 mg. Enzalutamide is primarily eliminated by hepatic metabolism. Following oral administration of ¹⁴C-enzalutamide, 71% and 14% of radioactivity were recovered in urine and feces, respectively. The major metabolite of enzalutamide, N-desmethyl enzalutamide, has similar in vitro activity to that of enzalutamide. The mean terminal half-life for N-desmethyl enzalutamide is 7.8 days.

Food does not alter the systemic exposure of enzalutamide or N-desmethyl enzalutamide, and enzalutamide can be administered with or without food.

Comedications can significantly affect the exposure to enzalutamide. Coadministration of gemfibrozil (a strong CYP2C8 inhibitor) increased the composite exposure of enzalutamide plus N-desmethyl enzalutamide by 2.2 fold. The concomitant use of strong CYP2C8 inhibitors should be avoided if possible. If patients must be coadministered a strong CYP2C8 inhibitor, the enzalutamide dose should be reduced to 80 mg once daily. The effects of CYP2C8 inducers on the pharmacokinetics of enzalutamide have not been evaluated, and coadministration of enzalutamide with strong and moderate CYP2C8 inducers should be avoided if possible. Coadministration of itraconazole (a strong CYP3A4 inhibitor) increased the composite exposure of enzalutamide plus N-desmethyl enzalutamide by 1.3 fold. The effects of CYP3A4 inducers on the pharmacokinetics of enzalutamide have not been evaluated, and co-administration of enzalutamide with strong or moderate CYP3A4 inducers should be avoided if possible.

Enzalutamide can significantly affect the exposure to other comedications. In vivo, enzalutamide is a strong CYP3A4 inducer and a moderate CYP2C9 and CYP2C19 inducer. At steady state, enzalutamide reduced the plasma exposure to midazolam (a CYP3A4 substrate), warfarin (a CYP2C9 substrate), and omeprazole (a CYP2C19 substrate) by 86%, 56%, and 70%, respectively. Therefore, concomitant use of enzalutamide with narrow therapeutic index drugs that are metabolized by CYP3A4, CYP2C9, or CYP2C19 should be avoided if possible. If coadministration with warfarin (a CYP2C9 substrate) is unavoidable, conduct additional INR monitoring should be done.

No exposure-response relationship for overall survival (OS) could be identified for enzalutamide within a single fixed dose of 160 mg/day in the phase III CRPC2 trial. An exposure-response analysis for seizure was not possible due to its low incidence in the trial; however, 4 patients who were reported to have a seizure and who had available pharmacokinetic data belonged to the higher exposure quartiles (Q3/Q4) rather than the lower exposure quartiles (Q1/Q2). The recommendation for dose adjustment when coadministered with strong CYP2C8 inhibitors is intended to keep the enzalutamide exposures within the concentration range that has been studied.

No starting dose adjustment is needed for patients with creatinine clearance (CrCL) greater than 30 mL/min. Clinical and pharmacokinetic data are insufficient to assess the potential effect of severe renal impairment (CrCL < 30 mL/min) on enzalutamide pharmacokinetics.

The composite exposure of enzalutamide and N-desmethyl enzalutamide following a single dose of enzalutamide was similar in subjects with baseline mild or moderate hepatic impairment (Child–Pugh Class A and B, respectively) versus those with normal hepatic function, and no starting dose adjustment is needed. Enzalutamide has not been studied in subjects with baseline severe hepatic impairment (Child–Pugh class C).

This NDA was primarily based on results from the CRPC2 trial and was supported by data from two open-label, single-arm phase I–II studies in the same or similar patient populations. The clinical review revealed that the two open-label studies showed similar prostate-specific antigen (PSA) response rates (approximately 50%) and safety signals.

The CRPC2 trial was a randomized, double-blind, placebo-controlled, multicenter phase III trial comparing the efficacy and safety of once daily dosing of enzalutamide with that of placebo in patients with mCRPC who had previously received docetaxel. The primary endpoint was OS. Key secondary endpoints included radiographic progression-free survival, time to PSA progression, and the percentage of confirmed PSA declines of ≥50%.

Patients had to have documented evidence of disease progression by PSA and/or radiographic scans while maintaining castrate levels of testosterone. Patients with the following conditions were excluded: prostate cancer with evidence of neuroendocrine differentiation or small cell features, or with evidence of metastases in the brain or active epidural disease; a history of seizure, including any febrile seizure, loss of consciousness, or transient ischemia attack within 12 months of enrollment, or any condition that might predispose them to seizure (e.g., prior stroke, brain arteriovenous malformation or head trauma with loss of consciousness requiring hospitalization); or taking medicines known to decrease the seizure threshold.

Patients were randomly allocated 2:1 to receive either enzalutamide orally at a dose of 160 mg once daily or placebo orally once daily. All patients continued androgen deprivation therapy during the trial. Patients were allowed, but not required to continue or initiate systemic use of glucocorticoids. Study treatment continued until patients experienced disease progression (evidence of radiographic progression, a skeletal-related event, or clinical progression), initiation of new treatment for the disease, unacceptable toxicity, or withdrawal.

All randomized patients constituted the intent-to-treat (ITT) population, regardless of whether the actual allocated study treatment was administered or not. Primary efficacy analyses were conducted in the ITT population. In contrast, the safety population consisted of all patients who received at least one dose of study treatment.

This trial enrolled 1,199 patients from 156 study centers in 15 countries, with 800 patients allocated to the enzalutamide arm and 399 to the placebo arm. Twenty-four percent of the patients were recruited from the United States. Baseline demographics were balanced between the two arms. The median age was 69 years (range, 41–92) and the distribution by race was 93% white, 4% black, 1% Asian, and 2% other.

Key disease characteristics, as summarized in Table 1, were generally balanced between the two arms at study entry. Of note, 91% of patients had metastases in bone and 23% had visceral involvement in the lung and/or liver. The percentage of patients with visceral involvement was 4% more in the enzalutamide arm than that in the placebo arm, which may favor the placebo arm in terms of prognosis.

All patients had received prior docetaxel-based chemotherapy, and 24% of the patients had received two cytotoxic chemotherapy regimens. The prior docetaxel usage, including the cumulative dosage (Table 1) and the time intervals of docetaxel use relative to the initiation of study treatment, appears to have been balanced between the arms (13).

Prior use of the marketed androgen receptor antagonists was examined and found to be balanced between the two arms. Across the arms, 85% of patients used bicalutamide, 14% used flutamide, and 10% used nilutamide.

Analysis of the primary endpoint OS was conducted according to the prespecified interim analysis plan with a total of 520 events (80% of the events required for the planned final analysis). The analysis demonstrated a statistically significant improvement in OS in patients on the enzalutamide arm compared with patients on the placebo arm (stratified HR 0.63; 95% CI, 0.53–0.75; P < 0.0001, log-rank test). The median survival time was 18.4 (95% CI, 17.3, NR) and 13.6 (95% CI, 11.3–15.8) months in the enzalutamide and placebo arms, respectively. Figure 1 shows the Kaplan–Meier OS curves of the analysis.

The above findings were sustained in an updated survival analysis (with 93% of the required events for the final analysis) and were also preserved in a number of sensitivity analyses conducted during the review (13). Likewise, subgroup analyses showed that the enzalutamide survival advantage was consistent for all subsets of patients grouped by key baseline characteristics, including age (<65, ≥65, and ≥75 years), ECOG performance score (0–1, 2), disease progression type (radiologic or PSA progression), metastasis site, and prior use of other androgen receptor antagonists such as bicalutamide.

Analyses of key secondary endpoints revealed that, compared with placebo, enzalutamide significantly prolonged radiographic progression-free survival and time to PSA progression (13). In addition, 54% of patients on the enzalutamide arm had confirmed PSA declines of ≥50% from baseline as compared with 2% of patients on the placebo arm. The enzalutamide-induced PSA response rate from this large randomized trial is consistent with that observed from the two small single-arm Phase I–II studies. All of these findings demonstrated antitumor activity for enzalutamide and provided important supportive evidence for the observed survival advantage of enzalutamide in the study population.

Analyses of the safety data were primarily based on the CRPC2 trial. Patients on the enzalutamide arm had a median treatment duration of 8.3 months compared with a median duration of 3.0 months for patients on the placebo arm.

Table 2 summarizes the adverse reactions occurring at a ≥ 2% absolute increase in frequency in the enzalutamide arm compared with the placebo arm. The most common adverse reactions with an incidence frequency of ≥10% included asthenia or fatigue, back pain, diarrhea, arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, and upper respiratory infection. Other common adverse reactions (≥5% but <10%) were muscular weakness, dizziness, insomnia, lower respiratory infection, spinal cord compression and cauda equina syndrome, hematuria, paresthesia, anxiety, and hypertension. Grade 3–4 adverse reactions were more common in patients receiving placebo (53%) than in patients receiving enzalutamide (47%). Grade 3–4 adverse reactions occurring at a ≥ 2% absolute increase in frequency in the enzalutamide arm compared with the placebo arm were spinal cord compression and cauda equina syndrome.

A unique safety signal with enzalutamide is the increased risk of seizure. Seizures occurred in 0.9% of patients on enzalutamide and represented the most common adverse reaction leading to study treatment discontinuation. In contrast, no patients on the placebo arm experienced seizures.

Common laboratory abnormities were grade 1–4 neutropenia in 15% of patients on enzalutamide (1% with grade 3–4) and in 6% of patients on placebo (0% with grade 3–4).

The FDA's review and analyses of the enzalutamide NDA found substantial evidence of the safety and efficacy of enzalutamide in patients with mCRPC who had previously received docetaxel. This finding was primarily based on the nonactive but placebo-controlled CRPC2 trial. The observed improvement in OS with enzalutamide, a 4.8 month difference in median OS as compared with placebo, represents a clinically important benefit. In addition, the safety profile of enzalutamide, including a 0.9% risk of seizure, is acceptable in the study population. Given the public health benefit, this NDA was granted full approval approximately 3 months after submission of the application, highlighting the FDA's continued efforts to expedite patient access to important new medications.

This review also confirmed the increased risk of developing seizures with enzalutamide treatment. This risk is highlighted as a Warning and Precaution in the package insert. Because patients at risk for seizure were excluded from the randomized trial, it is important to assess whether patients with predisposing risk factors for seizure can safely tolerate this medication. The need for a trial to assess this risk was identified during the review. The trial will be conducted by the applicant as a postmarketing requirement.

On the basis of similar PSA response rates with enzalutamide in patients who were chemotherapy-naïve and in patients who received prior docetaxel (10), a randomized, placebo-controlled phase III trial is ongoing to investigate the effectiveness and safety of enzalutamide in chemotherapy-naïve patients with mCRPC (14). Results from this trial may help provide additional information about how to best use enzalutamide in the treatment of patients with mCRPC.

The FDA's approval of enzalutamide provides a new treatment option for patients with mCRPC who have received prior docetaxel. Enzalutamide is the third product approved for use in patients with mCRPC in the last 2 years (4, 5, 13). These three products, cabazitaxel, abiraterone acetate, and enzalutamide, differ in their mechanism of action and benefit–risk profile and will provide more options in the treatment of patients with mCRPC. Nevertheless, choice of a treatment from the three products will require best assessments of patient's overall disease condition relative to the known benefit–risk profile. Comparative effectiveness studies may help define what sequence or combination of the products is more beneficial to patients.

No potential conflicts of interest were disclosed.

Conception and design: Y.M. Ning, W. Pierce, R. Pazdur

Development of methodology: Y.M. Ning, W. Pierce, V.E. Maher, R. Pazdur

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): Y.M. Ning, W. Pierce, R. Pazdur

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Y.M. Ning, W. Pierce, V.E. Maher, S. Karuri, S. Tang, H.-J. Chiu, T. Palmby, J.F. Zirkelbach, D. Marathe, N. Mehrotra, Q. Liu, J. Leighton, R. Sridhara, R. Pazdur

Writing, review, and/or revision of the manuscript: Y.M. Ning, W. Pierce, V.E. Maher, S. Karuri, S. Tang, H.-J. Chiu, T. Palmby, J.F. Zirkelbach, D. Marathe, N. Mehrotra, Q. Liu, D. Ghosh, J. Leighton, R. Sridhara, R. Justice, R. Pazdur

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Y.M. Ning, C.L. Cottrell, J. Leighton, R. Pazdur

Other: Supervision of the review of the enzalutamide NDA: A. Ibrahim

Study supervision: R. Pazdur