Clinical trialPhase 3Prostate cancer

Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer

N Engl J Med · 20191052 patients (525 in the apalutamide group and 527 in the placebo group)

Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. N Engl J Med. 2019. 381:13-24

Study type: Clinical trial
Study name: TITAN
Phase: Phase 3
Design: Randomised, double-blind, placebo-controlled trial
Sample size: 1052 patients (525 in the apalutamide group and 527 in the placebo group)
Source: N Engl J Med · 2019
Trial registration: NCT02489318

In plain words

This research showed that in men with prostate cancer that has spread to other parts of the body but still responds to hormone therapy, adding the drug apalutamide to standard hormone therapy lengthened the time without the disease growing and helped men live longer. Serious side effects were about the same in the two groups, but skin rash was more common with apalutamide. Decisions about this treatment should be made with your treating doctor.

Key results

68.2% vs 47.5%

Radiographic progression-free survival at 24 months

HR for radiographic progression or death 0.48 (95% CI 0.39 to 0.60); P<0.001

82.4% vs 73.5%

Overall survival at 24 months

HR for death 0.67 (95% CI 0.51 to 0.89); P = 0.005

42.2% vs 40.8%

Grade 3 or 4 adverse events

Apalutamide vs placebo; rash was more common in the apalutamide group

Dose and schedule cards

ADT + apalutamide (TITAN)

mHSPC with at least one bone metastasis, high or low volume; ECOG 0 to 1Cycle length: ContinuousOn the page “Prostate cancer” · Metastatic hormone-sensitive disease (mHSPC)

mHSPC with at least one bone metastasis, high or low volume; ECOG 0 to 1

Drug	Dose	Route	Schedule
Apalutamide	240 mg once daily	Oral, with or without food; swallow the tablets whole	Daily
ADT (GnRH agonist or antagonist, or prior orchiectomy)	Per formulation	—	Continuous

Cycle length: Continuous
Duration: Until progression or unacceptable toxicity

Dose per the FDA label and the trial. For grade 3–4 adverse reactions, withhold, then resume at the same dose or at 180 or 120 mg; severe hepatic impairment (Child-Pugh C): 120 mg. Warnings: cardiac and cerebrovascular ischemic events, fractures and falls, seizures (0.4%; discontinue permanently), severe cutaneous reactions (SJS/TEN and DRESS) and pneumonitis.

On the page “Prostate cancer” · Metastatic hormone-sensitive disease (mHSPC)

Doses follow the trial protocol, guideline or official drug label (source given in the notes of each regimen). Before prescribing, check blood counts, renal and hepatic function, drug interactions and the patient’s condition, and adjust the dose according to the drug label.

Treatment arms and regimens

1Apalutamide plus ADT

Apalutamide 240 mg (4 × 60 mg tablets) orally once daily in 28-day cycles, with continued ADT (GnRH analogue or surgical castration) (525 patients).

2Placebo plus ADT

Placebo orally once daily with ADT (527 patients).

Source of the regimen details: ClinicalTrials.gov NCT02489318 and the FDA label for ERLEADA (DailyMed)

Doses are given for the information of specialists, as in this study’s protocol, and are not a prescription. Every drug must be prescribed by the treating physician for the individual patient.

Study population

1052 men with metastatic castration-sensitive prostate cancer with at least one bone lesion on bone scan (lymph node-only or visceral-only disease was not eligible), ECOG performance status 0 or 1; both high-‎ and low-volume disease. Allowed: up to 6 months of prior ADT, up to 6 cycles of docetaxel for mHSPC (last dose no more than 2 months earlier and without progression), and prior treatment of localised disease (completed at least one year earlier). Median age 68 years; 16.4% prior prostatectomy or radiotherapy; 10.7% prior docetaxel; 62.7% high volume.

Endpoints

Primary endpoints: radiographic progression-free survival and overall survival.

Safety and side effects

Grade 3 or 4 adverse events: 42.2% with apalutamide versus 40.8% with placebo; rash was more common with apalutamide. According to the FDA label, apalutamide was discontinued for adverse events in 8% of patients (most common cause rash, 2.3%), and ischaemic cardiovascular events occurred in 4.4% versus 1.5%.

Clinical significance and place in guidelines

This trial showed that adding apalutamide to ADT in metastatic castration-sensitive prostate cancer improves radiographic progression-free survival and overall survival, without a major difference in the adverse event profile. Regulatory approval status and guideline recommendations should be checked separately, as they are not mentioned in the abstract.

Limitations

The results in the abstract are from the first interim analysis at a median follow-up of 22.7 months. Other limitations are not stated in the abstract and should be checked in the full text.

Original article (DOI)PubMed ClinicalTrials.gov

This summary was prepared by the editorial team from the published paper; the original paper is the final reference. Read the original abstract on PubMed.