Regulatory Decision Summary for Xtandi

This Priority Review, Supplemental to a New Drug Submission (SNDS) was filed by Astellas Pharma Canada Inc. to obtain market authorization for the following indication: “Xtandi (enzalutamide capsules) is indicated for the treatment of patients with non-metastatic castration sensitive prostate cancer (nmCSPC) with high-risk biochemical recurrence (BCR).”

Upon review, the indication was modified as follows: “Xtandi (enzalutamide capsules) is indicated for the treatment of patients with non‑metastatic castration‑sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk of metastasis (high-risk BCR).”

This submission was reviewed in collaboration with foreign jurisdictions as a Type A Orbis.

The benefit of Xtandi was evaluated in the Phase 3 EMBARK trial, a randomized, double-blind, placebo-controlled, multicentre study. The study enrolled adult non-metastatic castration sensitive prostate cancer (nm-CSPC) subjects with biochemical recurrence at high risk for metastasis (high-risk BCR), defined as PSA doubling time (PSA-DT) ≤9 months and screening PSA levels. Subjects received prior definitive therapy with curative intent and were not candidates for salvage radiotherapy at screening. The primary efficacy endpoint was metastasis-free survival (MFS) as per blinded independent central review (BICR) in the enzalutamide plus leuprolide arm versus leuprolide plus placebo arm. Key alpha-protected secondary endpoints were Overall Survival (OS) and MFS between enzalutamide monotherapy compared to leuprolide plus placebo arm.

The ITT analysis set consisted of 1,061 subjects randomized 1:1:1 to blinded enzalutamide plus leuprolide (referred to as enzalutamide combination therapy), blinded placebo plus leuprolide (referred to as leuprolide monotherapy), or open-label enzalutamide monotherapy. Enzalutamide was administered as 160 mg orally, once daily, and leuprolide was administered by injection once every 3 months, on an intermittent schedule. Treatment was suspended at week 37 if PSA levels were undetectable. Treatment was re-initiated when PSA rose to a pre-specified threshold and continued until radiographic progression or unacceptable toxicity.

At a median duration of follow-up of 5 years, and an event rate of 13% and 26% in the enzalutamide combination arm and leuprolide monotherapy arm respectively, the stratified hazard ratio (HR) was 0.42 (95% CI: (0.30, 0.61), p<0.0001. The results demonstrate a statistically and clinically significant 58% reduction in the risk of MFS, as assessed by BICR, for the enzalutamide combination therapy arm compared to leuprolide monotherapy arm. Treatment with enzalutamide monotherapy was associated with a statistically significant 37% reduction in the risk of MFS, as assessed by BICR, compared to leuprolide monotherapy (HR = 0.63 [95% CI: 0.46, 0.87]; p = 0.0049). Enzalutamide combination therapy reduced the risk of both soft tissue and bone metastatic progression compared to leuprolide monotherapy. Enzalutamide monotherapy reduced the risk of soft tissue, but not bone metastatic progression, compared to leuprolide monotherapy. The sensitivity analyses support the robustness of the enzalutamide combination and monotherapy MFS results. Pre-specified exploratory analyses demonstrated a consistent MFS benefit for most subgroups in the enzalutamide combination arm.

The OS data were immature at the interim analysis. There was a positive trend in favor of enzalutamide combination therapy compared with leuprolide monotherapy (9% deaths in enzalutamide combination arm vs. 15% deaths in leuprolide monotherapy arm vs. 12% in enzalutamide monotherapy arm). Mature OS results were requested as a post-market commitment to further assess the enzalutamide monotherapy clinical benefit.

The majority of adverse reactions associated with enzalutamide were mild to moderate in severity and consistent with the known safety profile. A new safety signal for hemorrhages associated with enzalutamide treatment was identified.

During the duration receiving drug treatment, common adverse reactions (≥20%) more frequently observed with enzalutamide combination therapy arm compared to leuprolide monotherapy were hot flush, fatigue and hypertension. Grade ≥3 adverse events were reported in 38%, 43% and 37% of subjects in the enzalutamide combination arm, enzalutamide monotherapy arm and leuprolide monotherapy arms respectively. Grade ≥3 adverse reactions reported with enzalutamide combination therapy compared to leuprolide monotherapy (≥2% difference) were hypertension (6%) and fatigue (4%). The safety profile of enzalutamide monotherapy was similar to combination therapy, except for a higher incidence of breast-related toxicities and ischemic heart disease, and a lower incidence of hot flush.

Serious AE’s were reported in 32% of participants in the enzalutamide monotherapy group, 27% in the enzalutamide combination arm and 28% in the leuprolide monotherapy arm. The most common serious adverse reaction was ischemic heart disease (5% of participants in enzalutamide monotherapy arm, 3% in enzalutamide combination therapy arm, and 3% in leuprolide monotherapy arm). There were no deaths assessed as treatment-related by the investigator in all arms. Adverse events of special interest ≥2% more frequently reported with either of the enzalutamide arms compared to leuprolide monotherapy were fatigue, falls, fractures, cognitive and memory impairment, hypertension and ischemic heart disease.

Adverse reactions leading to permanent discontinuation were reported in 21%, 18% and 10% of participants in the enzalutamide combination arm, enzalutamide monotherapy arm leuprolide monotherapy arm respectively. The most common adverse reactions leading to drug discontinuation in either of the enzalutamide arms were fatigue, hot flush, cognitive disorders and nausea. Adverse events leading to dose reductions were reported in 7%, 16% and 5% of participants in the enzalutamide combination arm, enzalutamide monotherapy arm leuprolide monotherapy arm respectively. The most common adverse reactions leading to dose reduction in either of the enzalutamide arms were fatigue, cognitive disorder, hypertension, dizziness and gynecomastia.

GnRH analogues have different testosterone recovery patterns. There is a potential risk that rapid testosterone recovery (with a different GnRH analogue compared to leuprolide) following treatment suspension could lead to a shorter treatment suspension period. Risk mitigation measures included a cautionary statement on potential risks and uncertainties with switching to a different GnRH analogue compared to leuprolide.

Uncertainties in the MFS benefit for several subgroups in the enzalutamide monotherapy arm were labelled in the PM.

The RMP was acceptable upon review. Standard monitoring was recommended.

The magnitude of clinical benefit is greatest when enzalutamide is administered in combination with a GnRH analogue as a treatment for nm-CSPC with high-risk BCR. Enzalutamide as a monotherapy is a treatment option for patients who are not amenable to treatment with androgen deprivation therapy. The benefit-harm-uncertainties profile for Xtandi, with or without a GnRH analogue, as a treatment for nm-CSPC with high-risk BCR is positive. A Notice of Compliance is recommended.

For further details about Xtandi, please refer to the Product Monograph, approved by Health Canada and available through the Drug Product Database.