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Addition of apalutamide to ADT extends survival in metastatic castration-sensitive prostate cancer
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CHICAGO — The addition of apalutamide to androgen deprivation therapy significantly improved radiographic PFS and OS among men with metastatic castration-sensitive prostate cancer, according to final results of the randomized phase 3 TITAN study presented at ASCO Annual Meeting.
Researchers observed the benefit among patients with high-volume and low-volume disease, as well as those who had received prior docetaxel.
“These results support the addition of apalutamide to ADT for a broad range of patients with metastatic castration-sensitive prostate cancer,” Kim N. Chi, MD, senior scientist at BC Cancer Agency, said during his presentation.
Apalutamide (Erleada, Janssen), a selective next-generation androgen receptor inhibitor, is approved in the United States and European Union for treatment of men with nonmetastatic castration-resistant prostate cancer.
Chi and colleagues conducted the double-blind TITAN study to determine whether the agent improved outcomes compared with placebo among men with metastatic castration-sensitive prostate cancer undergoing ADT.
“The rationale behind the TITAN study was that direct inhibition of the androgen receptor with apalutamide may provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes,” Chi said.
The study enrolled 1,052 men (median age, 68 years) with castration-sensitive disease, distant metastatic disease as evidenced by at least one lesion on bone scan, and ECOG performance status of 0 or 1.
Ten percent of patients had received prior docetaxel for castration-sensitive disease.
Study criteria permitted prior ADT for up to 6 months for metastatic castration-sensitive prostate cancer or up to 3 years for prior treatment of local disease. Local treatment had to be completed within 1 year prior to study entry.
Eighty percent had metastatic disease at diagnosis, and 63% had high-volume disease.
Researchers randomly assigned 525 men to apalutamide 240 mg daily plus continuous ADT in 28-day cycles. The other 527 men received placebo plus continuous ADT.
Baseline characteristics were balanced between treatment groups.
Radiographic PFS and OS served as dual primary endpoints. Secondary endpoints included time to initiation of cytotoxic chemotherapy, time to pain progression, time to chronic opioid use and time to skeletal-related events.
Exploratory endpoints included time to PSA progression, second PFS — defined as time to progression on next subsequent treatment — and time to symptomatic progression.
Chi and colleagues performed their first planned OS interim analysis after approximately 50% of expected events occurred.
After median follow-up of 22.6 months, 66% of men assigned apalutamide and 46% of those assigned placebo remained on therapy.
Results showed apalutamide conferred a 52% reduction in risk for death or radiographic progression (HR = 0.48; 95% CI, 0.39-0.6).
Median radiographic PFS had not been reached in the apalutamide group and was 22.1 months in the placebo group.
At 2 years, results showed an absolute 20 percentage point difference in the rate of radiographic PFS in favor of apalutamide (68% vs. 48%).
Researchers observed the benefit across all analyzed patient subgroups, including those stratified by extent of disease at baseline, disease volume or receipt of prior docetaxel.
Apalutamide also appeared associated with a significant improvement in OS (HR = 0.67; 95% CI, 0.51-0.89). Median OS had not been reached in either treatment group. At 2 years, OS rates were 82% in the apalutamide group and 74% in the placebo group.
The OS benefit observed with apalutamide also was consistent across subgroups, Chi said.
Men assigned apalutamide also achieved significantly longer time to initiation of cytotoxic chemotherapy (HR = 0.39; 95% CI, 0.27-0.56).
The difference in time to pain progression between treatment groups favored apalutamide but did not reach statistical significance, so formal statistical testing for other secondary endpoints was stopped.
Exploratory endpoint analysis also favored apalutamide, including time to PSA progression (median, not reached vs. 12.91 months; HR = 0.26; 95% CI, 0.21-0.32; 24-month event-free rate, 75% vs. 36%; P < .0001) and second PFS (median not reached in either arm; HR = 0.66; 95% CI, 0.5-0.87; 24-month event-free rate, 81% vs. 72%; P = .0026).
In January, an independent data monitoring committee recommended study unblinding to allow men assigned placebo to cross over to apalutamide.
Researchers reported no significant difference between the apalutamide and placebo groups with regard to any adverse events (96.8% vs. 96.6%), grade 3 or grade 4 adverse events (42.2% vs. 40.8%), any serious adverse event (19.8% vs. 20.3%), adverse events leading to treatment discontinuation (8% vs. 5.3%), or adverse events leading to death (1.9% vs. 3%).
A higher percentage of patients assigned apalutamide experienced rash (any grade, 27.1% vs. 8.5%; grade 3 or grade 4, 6.3% vs. 0.6%) and hypothyroidism (any grade, 6.5% vs. 1.1%). However, rash largely was asymptomatic and hypothyroidism was largely grade 1 and did not require intervention. Rates of fatigue, falls, fracture and seizure were similar between treatment groups.
“In line with the adverse event profile, health-related quality of life as measured by the FACT-P questionnaire was preserved, with no change from baseline in the apalutamide arm. This was not different from placebo,” Chi said. – by Mark Leiser
Reference:
Chi KN, et al. Abstract 5006. Presented at: ASCO Annual Meeting; May 31-June 4, 2019; Chicago.
Disclosures: Chi reports honoraria from, consultant/advisory roles with, or research funding to his institution from Amgen, Astellas, Bayer, Bristol-Myers Squibb, Eli Lilly/ImClone, ESSA Pharma, Janssen, Merck, Roche, Sanofi and Tokai Pharmaceuticals. Please see the abstract for all other authors’ relevant financial disclosures.
Perspective
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Michael A. Carducci, MD, FASCO
This study showed ADT and apalutamide for metastatic hormone-sensitive prostate cancer improves survival. These results reinforce the current standard of ADT plus a single agent, whether it be docetaxel, abiraterone (Zytiga, Janssen), enzalutamide (Xtandi; Astellas, Pfizer) or apalutamide.
The OS benefit was not statistically significant for a few subgroups, including those with visceral disease, those who received prior docetaxel, the elderly — specifically those aged 75 years or older — and those with low disease volume.
Metastatic hormone-sensitive prostate cancer is broadly heterogeneous, and the treatment benefit we offer with these drugs is not consistent in all of these subsets. We are still not sure which drug to use when. New methodology based on specific molecular taxonomy in addition to conventional clinical/pathological factors may provide better risk classification and predict response to treatment.
We have more biomarkers that are coming forward, including markers for androgen sensitivity.
To further define treatment benefits in the various risk groups, clinical studies need to prospectively test treatment effects in the various predefined subsets.
Practically speaking, combination ADT and chemotherapy or androgen-targeted agents is the standard for metastatic hormone-sensitive prostate cancer. Apalutamide clearly fits in this space.
And yet when we’re talking about this patient population, we have different patients who get there. I have patients who have deferred hormonal therapy because they don’t want to have hormonal effects for many years, but now they have new metastases. How do I make the argument that I want to up the ante and give them more therapy when I have been telling them they didn’t need therapy to begin with.
The oligometastatic disease state is certainly out there, and you have people with very low volume disease or “not high volume” disease. We have a number of patients who are elderly who care about some of these side effects and don’t want to feel old or frail. And finally, our underinsured patients have the struggle of covering the costs of these medications, as well as the duration of therapy.
There are a number of studies from which we are still awaiting results. Several are focused on treatment intensification. Even more studies are focused on de novo metastatic disease and management of the local tumor with radiation, surgery and directed therapy to metastatic disease. There’s also the question about what we do after these patients progress.
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