On September 17, 2019, apalutamide was approved for the treatment of patients with metastatic castration-sensitive prostate cancer.^1,2

Supporting Efficacy Data

The approval is based on overall survival and radiographic progression-free survival findings in the phase III double-blind TITAN trial.^2,3 In the trial, 1,052 patients were randomly assigned to receive apalutamide at 240 mg daily (n = 525) or placebo (n = 527). All patients received androgen-deprivation therapy, consisting of either concomitant gonadotropin-releasing hormone (GnRH) analog treatment or prior bilateral orchiectomy. Enrolled patients could have high-volume or low-volume disease.

Patients had a median age of 68 years (23% ≥ 75 years); 68% were white and 22%, Asian; 63% had high-volume and 37%, low-volume disease; 16% had prior surgery, radiotherapy of the prostate, or both; 67% had a Gleason score ≥ 8; 68% had prior treatment with an antiandrogen (bicalutamide, flutamide, or nilutamide); and all but one patient had an Eastern Cooperative Oncology Group performance status of 0 or 1.

At a prespecified interim analysis, the hazard ratio (HR) for overall survival was 0.67 (P = .0053) in favor of apalutamide. Median overall survival was not reached in either group, but death had occurred in 16% of the apalutamide group vs 22% of the placebo group at the time of analysis.

Median radiographic progression-free survival was not reached in the apalutamide group vs 22.1 months in the placebo group (HR = 0.48, P < .0001). The benefits of apalutamide were consistent across patient subgroups according to Gleason score ≤ 7 vs > 7, disease volume, and prior/no prior docetaxel use for radiographic progression-free survival, and according to disease volume and Gleason score for overall survival. Apalutamide was associated with significantly delayed initiation of cytotoxic chemotherapy (HR = 0.39, P < .0001).

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 the 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. 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 the 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.

Safety Profile

The most common adverse events of any grade (≥ 10%) observed with apalutamide in clinical trials have been fatigue, arthralgia, rash, decreased appetite, fall, decreased weight, hypertension, hot flush, diarrhea, and fracture.

In the TITAN trial, the median duration of study drug exposure was 20 months in patients who received apalutamide and 18 months in those who received placebo. Adverse events of any grade that occurred in ≥ 10% of the apalutamide group and with a higher incidence vs the placebo group were rash (28% vs 9%), fatigue (26% vs 25%), hot flush (23% vs 16%), hypertension (18% vs 16%), arthralgia (17% vs 15%), and pruritus (11% vs 5%). The most common grade 3 or 4 adverse events included hypertension (8% vs 9%) and rash (6% vs < 1%). Ischemic cardiovascular events occurred in 4% of patients in the apalutamide group vs 2% of the placebo group. The most common grade 3 or 4 laboratory abnormality in the apalutamide group was hypertriglyceridemia (3.0%).

Adverse events led to the discontinuation of apalutamide in 8% of patients, with the most common cause being rash (2%), and to dose interruption or reduction in 23% of patients, with the most common causes (> 1%) being rash, fatigue, and hypertension. Serious adverse events occurred in 20% of the apalutamide group and 20% of the placebo group. Adverse events led to death in 10 patients (2%) in the apalutamide group, with the causes consisting of ischemic cardiovascular events in three patients, acute kidney injury in two, cardiorespiratory arrest in one, sudden cardiac death in one, respiratory failure in one, cerebrovascular accident in one, and large intestinal ulcer perforation in one.

Apalutamide carries warnings/precautions for ischemic cardiovascular events, fractures, falls (with increased incidence in elderly patients), seizure, and embryofetal toxicity. Patients should be monitored for signs and symptoms of ischemic heart disease, and management of cardiovascular risk factors should be optimized. Patients should be evaluated for fracture risk and treated with bone-targeted agents according to established guidelines. Apalutamide should be permanently discontinued in patients experiencing seizure. Patients with female partners of reproductive potential should be advised to use effective contraception. 

REFERENCES

1. U.S. Food and Drug Administration: FDA approves apalutamide for metastatic castration-sensitive prostate cancer. Available at www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-apalutamide-metastatic-castration-sensitive-prostate-cancer. Accessed November 11, 2019.

2. Erleada (apalutamide) tablets prescribing information, Janssen Pharmaceutical Companies, September 2019. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2019/210951s001lbl.pdf. Accessed November 11, 2019.

3. Chi KN, Agarwal N, Bjartell A, et al: Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 381:13-24, 2019.