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Erleada (Apalutamide) First Drug Approved by the FDA for Nonmetastatic Castration-Resistant Prostate Cancer

March 2019, Vol 12, Tenth Annual Payers' Guide - Select Drug Profiles, Payers' Guide
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Prostate cancer, the second most common type of cancer in men, is expected to affect 11.6% of all men during their lifetime.1 In fact, more than 3 million men in the United States are living with prostate cancer. It is estimated that in 2017, 161,360 men were newly diagnosed with prostate cancer, and 26,730 men died from the disease.1

Approximately 10% to 20% of patients with prostate cancer have castration-resistant disease, an aggressive form that often continues to progress despite hormone therapy, and approximately 16% of these patients have nonmetastatic prostate cancer at the time of their diagnosis.2,3 Among patients diagnosed with nonmetastatic castration-resistant prostate cancer (CRPC), approximately 33% will have progressive disease that will become metastatic cancer within 2 years.3

Prostate cancer most often metastasizes to the bones, lymph nodes, adrenal gland, lung, and liver.4 Metastatic prostate cancer is associated with an increased rate of complications, pain, morbidity, and mortality.5,6

Until recently, the treatment for nonmetastatic prostate cancer consisted mainly of bilateral orchiectomy, luteinizing hormone-releasing hormone (LHRH) agonists, LHRH antagonists, and antiandrogens.7 There remains a marked need for treatment strategies to prevent or delay the progression to metastatic prostate cancer and improve duration of metastasis-free survival.5,6

Erleada First Treatment for Nonmetastatic Prostate Cancer

On February 14, 2018, apalutamide (Erleada; Janssen) was approved by the US Food and Drug Administration (FDA) for the treatment of patients with nonmetastatic CRPC that is progressing despite treatment with appropriate hormone therapy.2

Apalutamide, a new-generation oral androgen receptor inhibitor, is the first nonhormone therapy drug to receive FDA approval for the treatment of nonmetastatic CRPC.2 The FDA approval of apalutamide is the first time the FDA used the clinical end point of metastasis­free survival as the basis for a drug approval. Apalu­tamide was granted a priority review by the FDA.

“This approval is the first to use the endpoint of metastasis-free survival, measuring the length of time that tumors did not spread to other parts of the body or that death occurred after starting treatment,” said Richard Pazdur, MD, Director of the FDA’s Oncology Center of Excellence. “In the trial supporting approval, Erleada had a robust effect on this endpoint.”2

The practice guidelines from the National Comprehensive Cancer Network (NCCN) recently added apalutamide as part of the systemic therapy regimen for the treatment of patients with nonmetastatic CRPC.7 The NCCN guidelines recommend that the risks and benefits of apalutamide treatment should be discussed with patients, and that supportive care for bone health should be used.7

Mechanism of Action

Androgens, including testosterone, can stimulate tumor growth in prostate cancer. Apalutamide is an androgen receptor inhibitor that blocks the effect of androgens on the tumor.2,8 Specifically, apalutamide binds to the ligand-binding domain of the androgen receptor, blocks androgen-receptor nuclear translocation, inhibits DNA binding, and obstructs androgen receptor–mediated transcription.8

Dosing and Administration

The recommended dosing of apalutamide is 240 mg (four 60-mg tablets) taken orally once daily. Apalu­tamide is available as a 60-mg tablet.8 The apalutamide tablet should be swallowed whole. Apalutamide can be taken with or without food.8

Patients receiving apalutamide should also be treated concurrently with a gonadotropin-releasing hormone (GnRH) analog, or should have had a bilateral orchiectomy.8

The SPARTAN Clinical Trial

The efficacy and safety of apalutamide were evaluated in the SPARTAN trial, a double-blind, randomized, placebo-controlled, phase 3 clinical trial that included 1207 patients with nonmetastatic CRPC.5 Eligible patients (median age, 74 years; range, 48-97 years) were randomized to apalutamide 240 mg once daily (N = 806) or to placebo once daily (N = 401). Patients also received a concomitant GnRH analog or had a bilateral orchiectomy.5 The primary efficacy end point in the SPARTAN study was metastasis-free survival.5

Based on results from the planned primary analysis conducted after 378 metastasis or death events were reported, the median metastasis-free survival was 40.5 months in the apalutamide group versus 16.2 months in the placebo group (hazard ratio [HR] for metastasis or death, 0.28; 95% confidence interval [CI], 0.23-0.35; P <.001), a significant 24.31 months longer duration of metastasis-free survival. The time to symptomatic disease progression was also significantly longer with apalutamide versus placebo (HR, 0.45; 95% CI, 0.32-0.63; P <.001).5

The efficacy results, assessed by a blind independent review committee, are shown in the Table.5,8 These results were further supported by improvements in time to metastasis and progression-free survival achieved with apalutamide treatment versus placebo.5


Overall survival results were not mature at the time of the metastasis-free survival analysis.5

Adverse Events

The most common (incidence ≥10%) adverse reactions associated with apalutamide are fatigue (39%), hypertension (25%), rash (24%), diarrhea (20%), nausea (18%), weight decrease (16%), arthralgia (16%), fall (16%), hot flush (14%), decreased appetite (12%), fracture (12%), and peripheral edema (11%).8

Overall, 8 (1%) patients who received apalutamide died from adverse reactions, including infection (N = 4), myocardial infarction (N = 3), and cerebral hemorrhage (N = 1). In the placebo group, 1 (0.3%) patient died from cardiopulmonary arrest. In addition, apalutamide was discontinued because of adverse events in 11% of patients, most often because of a rash (3%). Grade 3 or 4 adverse reactions (>2%) were hypertension (14%), fractures (3%), and falls (2%).8


Apalutamide can cause harm to the fetus. The drug is not indicated for women, and is contraindicated in pregnant women.8

Drug Interactions

Coadministration of strong cytochrome (CY) P2C8 inhibitors (ie, gemfibrozil) with apalutamide is predicted to increase the exposure of apalutamide. The exposure of apalutamide is not expected to be affected by mild or moderate CYP32C8 inhibitors or CYP3A4 inhibitors.8

Concomitant use of drugs that are metabolized primarily by CYP3A4, CYP2C19, or CYP2C9 can result in a reduced exposure to these drugs. It is recommended that these medications are substituted, if possible, and that patients are monitored for reduced activity of these drugs. Concomitant use of apalutamide with UDP-glucuronosyltransferase (UGT) can result in a lower exposure of the UGT substrate. If apalutamide is coadministered with a UGT substrate, patients should be monitored for the loss of activity of the UGT substrate.8

Concomitant use of apalutamide with medications that are substrates of P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), or organic anion transporting polypeptide 1B1 (OATP1B1) can lead to the reduced exposure of these drugs. When substrates of P-gp, BCRP, or OATP1B1 are coadministered with apalutamide, patients should be monitored for loss of activity of these substrates.8

Use in Specific Populations

Men of reproductive potential should use effective contraception during apalutamide treatment and for 3 months after the last dose of apalutamide. The drug can cause harm to a fetus or loss of pregnancy. Men with a female partner with reproductive potential should use contraception. Apalutamide may increase the risk for impaired fertility in men of reproductive potential.8

No overall differences in the effectiveness of apalu­tamide were reported in patients aged ≥65 years compared with younger patients.8

Warnings and Precautions

Apalutamide is contraindicated in pregnant women, because it can cause harm to the fetus and loss of pregnancy.8

Because apalutamide increases the risk for falls and fractures, patients should be evaluated for falls and fractures risk and receive bone-targeted agents.8

Seizure was reported in 0.2% of patients who received apalutamide. If a patient has a seizure during apalutamide treatment, apalutamide should be discontinued permanently.8


The FDA approval of apalutamide marks the availability of the first FDA-approved treatment for nonmetastatic CRPC. The SPARTAN study, which led to the FDA approval, used a novel clinical end point of metastasis-free survival. Apalutamide increased metastasis-free survival by more than 2 years versus placebo. Moreover, patients who received apalutamide showed a significantly longer time to metastasis, progression-free survival, and time to symptomatic disease progression than patients receiving placebo. Apalutamide, an androgen receptor inhibitor, is a new, once-daily oral treatment option that may improve outcomes for patients with CRPC.


  1. National Cancer Institute. SEER cancer stat facts: prostate cancer. Accessed February 27, 2018.
  2. US Food and Drug Administration. FDA approves new treatment for a certain type of prostate cancer using novel clinical trial endpoint. February 14, 2018. Accessed February 27, 2018.
  3. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180-1192.
  4. National Cancer Institute. Metastatic cancer. Updated February 6, 2017. Accessed March 6, 2018.
  5. Smith MR, Saad F, Chowdhury S, et al; for the SPARTAN investigators. Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med. 2018 Feb 8. Epub ahead of print.
  6. Scher HI, Solo K, Valant J, et al. Prevalence of prostate cancer clinical states and mortality in the United States: estimates using a dynamic progression model. PLoS One. 2015;10:e0139440.
  7. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): Prostate Cancer. Version 2.2018. March 8, 2018. Accessed March 16, 2018.
  8. Erleada (apalutamide) tablets [prescribing information]. Horsham, PA: Janssen; February 2018.
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Last modified: August 30, 2021