Upfront Apalutamide Delays Time to Second Progression in Metastatic Castration-Sensitive Prostate Cancer

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The addition of apalutamide to androgen-deprivation therapy (ADT) reduced the risk of second disease progression or death (PFS2) by 34% vs ADT alone in patients with metastatic castration-sensitive prostate cancer, in a post hoc analysis of the phase III TITAN trial presented at the 2020 Genitourinary Cancers Symposium.1 The risk reduction was observed regardless of the first subsequent therapy patients received—ie, hormonal therapy or a taxane.

“Whichever subsequent therapy patients were on, those treated early with apalutamide in the TITAN trial did much better. Early intensive treatment with apalutamide in men with [metastatic castration-sensitive prostate cancer] improved outcomes. In the totality of the treatment trajectory, it matters if patients got apalutamide first,” said lead author Neeraj ­Agarwal, MD, of Huntsman Cancer Center, University of Utah, Salt Lake City.

Neeraj ­Agarwal, MD

Neeraj ­Agarwal, MD

“Apalutamide upfront helps patients live longer with subsequent therapy,” he emphasized. In an interview with The ASCO Post, Dr. Agarwal explained that the PFS2 endpoint was defined as the time from initiating first therapy with apalutamide to the time to disease progression or death on first subsequent therapy. Results of the study he presented indicate the benefit of early intensification of treatment with apalutamide.

Primary results from the TITAN trial demonstrated a reduction in the risk of death by 33% with the addition of apalutamide to ADT.2 At a median follow-up of 22.7 months, the 2-year overall survival rate was 82.4% in the apalutamide arm vs 73.5% in patients receiving ADT alone, a significant 33% improvement (P = .005). Median overall survival was not reached in either arm. The addition of apalutamide also significantly reduced the risk of radiographic disease progression or death by 52%.

Based on these primary data, the U.S. Food and Drug Administration expanded the approval of apalutamide in September 2019 to include metastatic castration-sensitive prostate cancer. (It was previously approved for nonmetastatic castration-resistant prostate cancer alone.)

TITAN Details

The international, double-blind TITAN study enrolled 1,052 patients with metastatic castration-sensitive prostate cancer, regardless of prior docetaxel treatment or extent of disease. Patients were randomly assigned to treatment with oral apalutamide at 240 mg once daily plus ADT or placebo combined with ADT until disease progression, unacceptable toxicity, or the end of treatment.

A total of 277 patients received subsequent systemic therapy for prostate cancer, of which 87 were in the apalutamide-plus-ADT arm and 190 were in the placebo-plus-ADT arm. Novel hormonal therapy was the first subsequent therapy for 24 patients in the apalutamide arm and for 62 in the control arm. Taxane therapy was the first subsequent therapy in 30 patients in the apalutamide arm and 69 in the control arm. Other systemic therapies were given to 33 patients in the apalutamide arm and 59 in the control arm.


  • In a post hoc analysis of the phase III TITAN trial, apalutamide plus androgen-deprivation therapy delayed the time to second disease progression or death, regardless of subsequent therapy.
  • Results suggest that upfront use of apalutamide helps patients live longer.
  • Longer follow-up is needed to confirm these results.

Baseline demographics and disease characteristics were similar between the hormonal and taxane groups, including Eastern Cooperative Oncology Group performance score, Gleason score at initial diagnosis, metastasis stage at diagnosis, and median prostate-specific antigen level at baseline. Patients who received prior docetaxel in the castration-sensitive setting before enrollment in TITAN were more likely to have received a novel hormonal therapy vs taxane therapy as a first subsequent therapy (20.9% vs 8.1%).

First subsequent therapy was physician’s choice based on patient and disease characteristics. “It is not possible from this trial to determine the best subsequent therapy,” Dr. Agarwal said, due to the fact that first subsequent therapy was not randomized.

A significant advantage was observed in second disease progression or death for apalutamide—a 34% reduction (P = .0026), which was consistent across patients treated with hormonal therapy (P = .0326) or taxane (P = .0062) as first subsequent treatment. Median PFS2 was not reached for either apalutamide or placebo in each of the subsequent treatment arms. 

DISCLOSURE: Dr. Agarwal has served in a consulting or advisory role for Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb, Exelixis, Foundation One Inc, Foundation Medicine, Janssen Oncology, Lilly, Medivation/Astellas, Merck, Nektar, Novartis, Pfizer, and Pharmacyclics and has received institutional research funding from Active Biotech, Amgen, AstraZeneca, Bavarian Nordic, Bayer, BN ImmunoTherapeutics, Bristol-Myers Squibb, Calithera Biosciences, Celldex, Eisai, Exelixis, Genentech, GlaxoSmithKline, Immunomedics, Janssen, Merck, NewLink Genetics, Novartis, Pfizer, Prometheus, Rexahn Pharmaceuticals, Sanofi, Takeda, and TRACON Pharma.


1. Agarwal N, Chowdhury S, Bjartell A, et al: Time to second progression in patients from TITAN with metastatic castration-sensitive prostate cancer by first subsequent therapy (hormonal vs taxane). 2020 Genitourinary Cancers Symposium. Abstract 82. Presented February 13, 2020.

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


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