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Hussain M, et al. "Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer". The New England Journal of Medicine. 2018. 378(26):2465-2474.
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Clinical Question

In men with non-metastatic castrate resistant prostate cancer, does enzalutamide improve metastatic free survival compared with placebo?

Bottom Line

For those that completed the trial there is a clinically significant and meaningful reduction in risk of metastasis or death (71%) comparing treatment with enzalutamide and placebo. With additional benefits to delaying anti-neoplastic chemotherapy and PSA progression. This is compared with other trial medications like denosumab, atrasentan, zibotentan.

Larger number of Enzalutamide patients 634/933 compared to placebo patients 176/468 had yet to reach a primary end point Total deaths: enzalutamide 103/933(11%) v placebo 62/468(13%).

Whilst there was a greater risk of adverse effects with enzalutamide, it was reported to be well within the expected safety profile of enzalutamide. It is unknown if the adverse effects were statistically significant but was reported to not affect quality of life.

Major Points

  • The patient group was closely selected, including for previous cardiac events, which were a common adverse event.
  • This patient group has limited treatment options according to current guidelines.
  • The benefit in terms of metastatic free survival is promising, though the final overall survival analysis is still outstanding.
  • The adverse event profile is not insignificant.

Guidelines

European Urology Association - The EUA guidelines state: "currently there is insufficient evidence to allow a recommendation to be provided"

The National Comprehensive Cancer Network (NCCN)

    • Maintain castrate resistant levels of testosterone
    • Clinical trial is the preferred option
    • Observation for those with PSADT >=10 months
    • Anti-androgen/anti-androgen withdrawal
    • Second generation anti-androgen, corticosteroids

Design

  • Trial type: double blind, randomised, placebo-controlled, phase III trial.
  • N=number of patients randomized, N = 1401
    • Experimental arm (enzalutamide) n = 933
    • Standard (placebo) n = 468
  • Setting: where the study took place: > 300 sites in 32 countries
  • Enrollment: November 2013 to June 2017
  • Mean follow-up: median follow-up for primary end point 18.5 months (enzalutamide group), 15.1 months (placebo)
  • Analysis: main analysis type:intention-to-treat
  • Primary outcome: metastasis-free survival

Population

Inclusion Criteria

  • Age 18 years or older and willing and able to provide informed consent.
  • Histologically or cytologically confirmed adenocarcinoma of the prostate without neuroendocrine differentiation, signet cell, or small cell features.
  • Ongoing androgen deprivation therapy with a GnRH agonist/antagonist or prior bilateral orchiectomy (medical or surgical castration).
  • Testosterone ≤ 50 ng/dL (≤ 1.73 nmol/L) at screening.
  • For patients receiving bisphosphonates or denosumab, dose must be stable for at least 4 weeks before randomization.
  • Progressive disease on androgen deprivation therapy at enrollment defined as a minimum of 3 rising PSA values (PSA1 < PSA2 < PSA3) assessed by a local laboratory (local PSA) with an interval of ≥ 1 week between each determination.
  • The most recent local PSA and the screening PSA assessed by the central laboratory (central PSA) should be ≥ 2 μg/L (2 ng/mL). In the event of prior androgen receptor inhibitor use, the most recent local PSA and the central PSA assessed at screening must be obtained at least 4 weeks after the last dose of the androgen receptor inhibitor.
  • PSA doubling time ≤ 10 months calculated by the sponsor using the method of Pound et al, 1999.
  • No prior or present evidence of metastatic disease as assessed by CT/MRI for soft tissue disease and whole-body radionuclide bone scan for bone disease. If the screening bone scan shows a lesion suggestive of metastatic disease, the patient will be eligible only if a second imaging modality (plain film, CT, or MRI) does not show bone metastasis. If the imaging results are equivocal or consistent with metastasis, the patient is not eligible for enrollment. Patients with soft tissue pelvic disease may be eligible if lesions do not qualify as target lesions (eg, lymph nodes below aortic bifurcation are permissible if the short axis of the largest lymph node is < 15 mm).
  • Asymptomatic prostate cancer.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • Estimated life expectancy ≥ 12 months.
  • Able to swallow the study drug and comply with study requirements.
  • Male patient and his female partner who is of childbearing potential must use 2 acceptable methods of birth control (1 of which must include a condom as a barrier method of contraception) starting at screening and continuing throughout the study period and for 3 months after final study drug administration. Two acceptable methods of birth control thus include the following:
    • Condom (barrier method of contraception), AND One of the following is required:
    • Established use of oral, or injected or implanted hormonal method of contraception by the female partner
    • Placement of an intrauterine device (IUD) or intrauterine system (IUS) by the female partner
    • Additional barrier method: Occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository in the female partner
    • Tubal ligation in the female partner
    • Vasectomy or other procedure resulting in infertility (eg, bilateral orchiectomy),for more than 6 months
  • Male patient must use a condom if having sex with a pregnant woman.

Exclusion Criteria

  • Prior cytotoxic chemotherapy, aminoglutethimide, ketoconazole, abiraterone acetate, or enzalutamide for the treatment of prostate cancer or participation in a clinical trial of an investigational agent that inhibits the androgen receptor or androgen synthesis (unless treatment was placebo).
  • Treatment with hormonal therapy (eg, androgen receptor inhibitors, estrogens, 5-alpha reductase inhibitors) or biologic therapy for prostate cancer (other than approved bone-targeting agents and GnRH agonist/antagonist therapy) within 4 weeks of randomization.
  • Use of an investigational agent within 4 weeks of randomization.
  • Known or suspected brain metastasis or active leptomeningeal disease.
  • History of another invasive cancer within 3 years of randomization, with the exception of fully treated cancers with a remote probability of recurrence in the opinion of both the medical monitor and investigator.
  • Absolute neutrophil count < 1000/μL, platelet count < 100,000/μL, or hemoglobin < 10 g/dL (6.2 mmol/L) at screening. NOTE: may not have received growth factors or blood transfusions within 7 days before obtaining the hematology values at screening.
  • Total bilirubin ≥ 1.5 times the upper limit of normal (ULN) (except patients with a diagnosis of Gilbert’s disease); alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 2.5 times ULN at screening.
  • Creatinine > 2 mg/dL (177 μmol/L) at screening.
  • Albumin < 3.0 g/dL (30 g/L) at screening.
  • History of seizure or any condition that may predispose to seizure (eg, prior cortical stroke or significant brain trauma). History of loss of consciousness or transient ischemic attack within 12 months of randomization.
  • Clinically significant cardiovascular disease including the following:
    • Myocardial infarction within 6 months before screening
    • Uncontrolled angina within 3 months before screening
    • Congestive heart failure New York Heart Association class 3 or 4, or a history of congestive heart failure New York Heart Association class 3 or 4, unless a screening echocardiogram or multigated acquisition scan performed within 3 months before randomization demonstrates a left ventricular ejection fraction ≥ 50%
    • History of clinically significant ventricular arrhythmias (eg, sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)
    • History of Mobitz II second-degree or third-degree heart block without a permanent pacemaker in place
    • Hypotension as indicated by systolic blood pressure < 86 millimeters of mercury (mm Hg) at screening
    • Bradycardia as indicated by a heart rate of < 45 beats per minute on the screening electrocardiogram (ECG) and on physical examination
    • Uncontrolled hypertension as indicated by systolic blood pressure > 170 mm Hg or diastolic blood pressure > 105 mm Hg at screening
  • Gastrointestinal disorder affecting absorption (eg, gastrectomy, active peptic ulcer disease within 3 months before randomization).
  • Major surgery within 4 weeks of randomization.
  • Hypersensitivity reaction to the active pharmaceutical ingredient or any of the capsule components, including Labrasol, butylated hydroxyanisole, and butylated hydroxytoluene.
  • Any concurrent disease, infection, or comorbid condition that interferes with the ability of the patient to participate in the trial, which places the patient at undue risk, or complicates the interpretation of data, in the opinion of the investigator or medical monitor.

Baseline Characteristics

No significant differences at baseline reported.

For the Enzalutamide group –

  • Age: median – 74 years, range 50-95
  • ECOG: 0 (80%), 1(20%)
  • PSA median: 11.1; range 0.8- 1071
  • PSA doubling time: median 3.8 months, range 0.4-37.4
  • PSA doubling time distribution (randomisation strata): < 6 months – 77%; >=6 months – 23%
  • Use of bone targeting agent (randomisation strata): no-89%, yes 11%

Interventions

  • ADT + enzalutamide (160mg) (Enzalutamide Group)

vs

  • ADT + placebo (Placebo Group)

Outcomes

Comparisons are intensive therapy vs. standard therapy.

Primary Outcomes

Metastatic free survival
HR 0.29 (95% CI 0.24-0.35) p<0.001

Secondary Outcomes

Time to PSA progression
HR 0.07, 95% CI 0.05-0.08 p<0.001
Time to first use of subsequent antineoplastic therapy
HR 0.21, 95% CI 0.17-0.26 p<0.001
Overall survival
HR 0.80 (95% CI 0.06-1.09), p=0.15 (median not reached for either group).
Quality of life

No statistics or data presented in the paper of supplementary data. A comment is made that “the median time to degradation in the Functional Assessment of Cancer Therapy- Prostate score, indicating a clinically meaningful decrease in health related quality of life, was the same for the two groups”

Safety

No formal statistics reported comparing the two groups. The overall level of adverse events appears to be significantly higher in the treatment arm (87% vs 23%)

Subgroup Analysis

19 subgroup analyses are described in the supplementary material. All analyses appear to support a similar outcome for the primary outcome. Groups include strata for: PSA doubling time, geographic region, age, ECOG, Gleason score, baseline PSA, LDH, haemoglobin, use of bone targeting agents.

Adverse Events

Adverse events were seen in 87% of the treatment arm and 77% of the placebo arm. Serious adverse events were seen in 24% in the treatment arm and 18% in the placebo arm. The most common adverse events in the treatment arm included: fatigue (33% vs 14%); hot flush (13% vs 8%); nausea (11% vs 9%).

Criticisms

  • In the same setting, Apalutamide has also been approved recently, and there is some evidence that this may be more effective (although there is yet to be a head to head comparison). Apalutamide appears to have a simar adverse event profile, and similarly shows no benefit in terms of overall survival.
  • PSA enrolment criteria don’t appear to have been met - the range reported at baseline includes values outside the inclusion criteria (both baseline value and doubling time)
  • Quality of life data does not seem to match adverse event profile
  • Overall survival is no different between the two groups, though the final analysis of this endpoint has not been conducted.
  • Possible bias from sponsor in regards to the level of involvement in analysis and reporting.

Funding

Medivation (Pfizer) and Astellas. The sponsors conducted all analyses and paid a medical writer to draft the manuscript.

Further Reading

  • Apalutamide trial [1]
  • Rationale behind the selection of the primary outcome [2]