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Earlier this year, apalutamide (Erleada) was approved for the treatment of nonmetastatic castration-resistant prostate cancer.1,2
Supporting Efficacy Data
Approval was based on the findings of the double-blind phase III SPARTAN trial3 in which 1,207 patients were randomized 2:1 to receive oral apalutamide at 240 mg once daily in combination with androgen-deprivation therapy (ADT; n = 806) or placebo once daily with ADT (n = 401). Patients had to have a prostate-specific antigen doubling time of 10 months or less. All patients in the trial received a concomitant gonadotropin-releasing hormone (GnRH) analog or had bilateral orchiectomy. The major efficacy endpoint was metastasis-free survival, defined as time from randomization to first evidence of distant metastasis (new bone or soft-tissue lesions or enlarged lymph nodes outside the pelvis) or death due to any cause.
The labeling for apalutamide has warnings or precautions for falls, fractures, and seizure. Patients should be evaluated for fall and fracture risk and treated with bone-targeted agents according to established guidelines.
The median age of patients was 74 years (26% ≥ 80 years); 66% were white, 12% were Asian, and 6% were black; 77% had prior surgery or radiotherapy to the prostate; 78% had a Gleason score ≥ 7; 15% had pelvic lymph nodes < 2 cm; and 73% had received prior treatment with an antiandrogen.
On blinded independent central review, median metastasis-free survival was 40.5 months in the apalutamide group vs 16.2 months in the placebo group (hazard ratio [HR] = 0.28, P < .0001). The median time to metastasis was 40.5 months vs 16.6 months (HR = 0.27, P < .0001). The median progression-free survival was 40.5 months vs 14.7 months (HR = 0.29, P < .0001). Overall survival data were not mature at the time of analysis.
How It Works
Apalutamide is an androgen receptor inhibitor that binds directly to the ligand-binding domain of the androgen receptor. Apalutamide inhibits androgen receptor nuclear translocation, inhibits DNA binding, and impedes androgen receptor–mediated transcription. A major metabolite, N-desmethyl apalutamide, is a less potent inhibitor of androgen receptor, exhibiting one-third the activity of apalutamide in an in vitro transcriptional reporter assay. Apalutamide administration produced decreased tumor cell proliferation and increased apoptosis, leading to decreased tumor volume, in mouse xenograft models of prostate cancer.
How It Is Used
The recommended dose of apalutamide is 240 mg once daily with or without food. Patients should receive a GnRH analog concurrently or should have had a bilateral orchiectomy.
For adverse events of grade ≥ 3 or intolerable adverse events, dosing should be held until symptoms improve to ≤ grade 1 or original grade and can then be resumed at the same dose or a reduced dose (180 mg or 120 mg) if warranted.
Concomitant use of apalutamide with medications that are sensitive substrates of CYP3A4, CYP2C19, CYP2C9, UDP-glucuronosyl transferase, P-glycoprotein, breast cancer resistance protein, and organic anion transporting polypeptide 1B1 can result in lower exposure to and loss of activity of these medications.
In the SPARTAN trial, the most common adverse events of any grade occurring in at least 10% of the apalutamide group with a ≥ 2% greater incidence vs the placebo group were fatigue (39% vs 28%), hypertension (25% vs 20%), rash (24% vs 6%), diarrhea (20% vs 15%), nausea (18% vs 16%), weight decrease (16% vs 6%), arthralgia (16% vs 8%), falls (16% vs 9%), hot flush (14% vs 9%), decreased appetite (12% vs 9%), fracture (12% vs 7%), and peripheral edema (11% vs 9%). The most common grade 3 or 4 adverse events in the apalutamide group included hypertension (14% vs 12%) and rash (5% vs < 1%). The most common grade 3 or 4 laboratory abnormalities in the apalutamide group were lymphopenia, hyperglycemia, hypertriglyceridemia, and hyperkalemia (2% each).
Serious adverse events occurred in 25% of the apalutamide group vs 23% of the placebo group, with the most common event in the apalutamide group being fracture (3%). In patients treated with apalutamide, adverse events led to dose interruption or reduction in 33% (with the most common reasons [> 1%] being rash, diarrhea, fatigue, nausea, vomiting, hypertension, and hematuria) and to treatment discontinuation in 11% (with the most common reason being rash [3%]). Adverse events led to death in eight patients treated with apalutamide (1%), including death due to infection in four, myocardial infarction in three, and cerebral hemorrhage in one. One patient in the placebo group (0.3%) died of an adverse reaction of cardiopulmonary arrest.
The labeling for apalutamide has warnings/precautions for falls, fractures, and seizure. Patients should be evaluated for fall and fracture risk and treated with bone-targeted agents according to established guidelines. Seizure occurred in 0.2% of patients receiving apalutamide. Treatment should be permanently discontinued in patients experiencing seizure. Apalutamide is contraindicated in pregnancy; males with female partners of reproductive potential must be advised to use effective contraception while being treated with apalutamide. ■
1. U.S. Food and Drug Administration: FDA approves apalutamide for non-metastatic castration-resistant prostate cancer. Available at https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm596796.htm. Accessed June 21, 2018.
2. Erleada (apalutamide) tablets prescribing information, Janssen Pharmaceutical Companies, February 2018. Available at https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210951s000lbl.pdf. Accessed June 21, 2018.
3. Smith MR, Saad F, Chowdhury S, et al: Apalutamide treatment and metastasis-free survival in prostate cancer. N Engl J Med 378:1408-1418, 2018.
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).