Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer
Open accessAbstract
BACKGROUND: Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS: We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS: A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28; 95% confidence interval [CI], 0.23 to 0.35; P<0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45; 95% CI, 0.32 to 0.63; P<0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS: Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development; SPARTAN ClinicalTrials.gov number, NCT01946204 .).
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Multiple phase 3 clinical trials have demonstrated the benefit of AR-targeted therapies on patient survival.
“Multiple phase 3 clinical trials have demonstrated the benefit of AR-targeted therapies on patient survival9–18.”
From Genome-scale CRISPR screens identify PTGES3 as a direct modulator of androgen receptor function in advanced prostate cancer (2025) · cites this paper as [9]
The Primary End Point section reports significantly longer metastasis-free survival with apalutamide than with placebo. But the Discussion's secondary-endpoint table reports that the overall-survival result did not meet the efficacy threshold (hazard ratio 0.70, P=0.07). This trial therefore supports a survival-related benefit, but not a demonstrated overall-survival benefit; it also cannot by itself establish the claim about multiple trials. Page numbers were not available in our copy. (LLM, conf=0.88)
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- Authors
- Smith, M. R., Saad, F., Chowdhury, S., Oudard, S., Hadaschik, B. A., Graff, J. N., Olmos, D., Mainwaring, P. N., Lee, J. Y., Uemura, H., Lopez-Gitlitz, A., Trudel, G. C., Espina, B. M., Shu, Y., Park, Y. C., Rackoff, W. R., Yu, M. K., & Small, E. J.
- Affiliations
- Harvard University (US)
- From the Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston (M.R.S.); Centre Hospitalier de l’Université de Montréal, Université de Montréal, Montreal (F.S.); Guy’s, King’s and St. Thomas’ Hospitals, Great Maze Pond, London (S.C.); Georges Pompidou Hospital, Paris (S.O.); University of Duisburg–Essen and German Cancer Consortium (DKTK)–University Hospital Essen, Essen, and Ruprecht-Karls-University Heidelberg, Heidelberg — both in Germany (B.A.H.); Veterans Affairs...
- ORCID
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2018-04-12
- Volume
- 378
- Issue
- 15
- Pages
- 1408-1418
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2792086148
- Cited by
- 1,344
- References
- 13
- Citations by year
- 2026: 75 · 2025: 117 · 2024: 145 · 2023: 138 · 2022: 179 · 2021: 205 · 2020: 196 · 2019: 180 · 2018: 99 · 2017: 2 · 2014: 1
- FWCI
- 128.84
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (publishedVersion, other-oa)
- Research at the University of Copenhagen (University of Copenhagen) (publishedVersion)
- IRIS Research product catalog (Sapienza University of Rome) (submittedVersion, other-oa)
- Institutional Research Information System University of Turin (University of Turin) (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion, other-oa)
- Tampere University Institutional Repository (Tampere University) (submittedVersion)
- Universitätsbibliographie, Universität Duisburg-Essen (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion, other-oa)
- RISalud Institutional Health Repository of Andalucía (submittedVersion, other-oa)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- Janssen Research and Development
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Treatment and Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Prostate Cancer Diagnosis and Treatment
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Advanced Breast Cancer Therapies
- Keywords
- apalutamide, castration-resistant prostate cancer, androgen receptor antagonists, metastasis-free survival, androgen deprivation therapy, PSA doubling time, adverse events, hypothyroidism, fracture, rash
- MeSH terms
- Adenocarcinoma, Aged, Aged, 80 and over, Androgen Antagonists, Double-Blind Method, Exanthema, Humans, Male, Middle Aged, Neoplasm Metastasis, Thiohydantoins, Proportional Hazards Models, Prostate-Specific Antigen, Disease Progression, Disease-Free Survival, Prostatic Neoplasms, Castration-Resistant
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