A study published in the New England Journal of Medicine found that metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide vs placebo in men with nonmetastatic castration-resistant prostate cancer (CRPC).
Androgen deprivation therapy—the current standard of care for treating metastatic prostate cancer—is initially effective, but almost all men develop castration-resistant disease.
An international, randomized, placebo-controlled trial was conducted to evaluate the effect of apalutamide on metastasis-free survival in men with nonmetastatic CRPC and a prostate-specific antigen (PSA) doubling time of ten months or less.
The study, dubbed the SPARTAN trial (Selective Prostate Androgen Receptor Targeting with ARN-509), was led by Matthew R. Smith, MD, Massachusetts General Hospital Cancer Center and Harvard Medical School, Boston, MA.
Participants were men over 18 years of age who had histologically or cytologically confirmed castration-resistant adenocarcinoma of the prostate and who were at high risk for metastasis, defined as a PSA doubling time of ten months or less during continuous androgen deprivation therapy.
At screening, all the patients underwent a bone scan and computed tomography (CT) of the pelvis, abdomen, chest, and head, and had no local or regional nodal disease (N0 on the tumor-node-metastasis staging system) or had malignant pelvic lymph nodes that measured less than 2 cm in the short axis (classified as N1).
Androgen deprivation therapy was continued throughout the trial.
Disease assessments, including bone scans and CT scans, were performed every 16 weeks, and if distant metastasis was suspected.
Patients were stratified according to PSA doubling time (>6 months vs ≤6 months), use of bone-sparing agents, and classification of local or regional nodal disease (N0 vs N1) at the time of trial entry.
Patients were randomly assigned in a 2:1 ratio to receive apalutamide 240 mg orally daily or placebo until protocol-defined progression, adverse events, or withdrawal of consent occurred.
The primary endpoint was metastasis-free survival, defined as the time from randomization to detection of distant metastasis on imaging or death from any cause.
Secondary endpoints were time to metastasis, progression-free survival, time to symptomatic progression, overall survival, and time to the initiation of cytotoxic chemotherapy.
Exploratory endpoints included time to PSA progression, PSA response rate, patient-reported outcomes, and second progression-free survival (PFS), defined as the time from randomization to investigator-assessed disease progression during the first subsequent treatment for metastatic castration-resistant disease or death from any cause.
Patient-reported outcomes were assessed with two questionnaires: the Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire and the three-level version of the European Quality of Life-5 Dimensions (EQ-5D-3L) questionnaire.
In all, 1,207 patients from 332 sites in 26 countries in North America, Europe, and the Asia-Pacific region underwent randomization: 806 were assigned to the apalutamide group and 401 to the placebo group.
The final analysis for metastasis-free survival was performed after distant metastasis or death had been observed in 378 patients: 184 (22.8%) in the apalutamide group and 194 (48.4%) in the placebo group. The median metastasis-free survival was 40.5 and 16.2 months in the apalutamide group and placebo group, respectively (hazard ratio [HR] for metastasis or death: 0.28; P < 0.001).
The treatment effect of apalutamide was consistently favorable across pre-specified subgroups, therefore the independent data and safety monitoring committee unanimously recommended that the trial be unblinded and that patients in the placebo group be given the option to receive apalutamide.
Furthermore, apalutamide was associated with better results than placebo for all secondary endpoints. Time to metastasis, PFS, and time to symptomatic progression were significantly longer with apalutamide than with placebo (P < 0.001 for all comparisons).
The median time to PSA progression was not reached in the apalutamide group, compared with 3.7 months in the placebo group (HR: 0.06).
At 12 weeks after randomization, the median PSA level had decreased by 89.7% in the apalutamide group and had increased by 40.2% in the placebo group.
Patient-reported outcomes using the FACT-P and EQ-5D-3L indicated that patients who received apalutamide in addition to androgen deprivation therapy maintained stable overall health-related quality of life over time, as did patients in the placebo group.
Of the patients who discontinued the trial regimen, 52.5% in the apalutamide group and 77.8% in the placebo group received subsequent approved treatment for metastatic CRPC.
Second PFS was significantly longer in the apalutamide group than in the placebo group (HR for progression or death: 0.49).
The trial regimen was discontinued due to progressive disease in 155 patients (19.3%) in the apalutamide group and in 210 (52.8%) in the placebo group.
Adverse events led to discontinuation of the trial regimen in 85 patients (10.6%) in the apalutamide group and in 28 (7.0%) in the placebo group. Apalutamide was associated with higher rates of rash, fatigue, arthralgia, weight loss, falls, and fracture than placebo. The majority of adverse events were grade 1 or 2.
The investigators point out that newer and more sensitive imaging studies, such as prostate-specific membrane antigen positron-emission tomography, might have identified metastases at baseline in some patients with no evidence of metastases on conventional imaging. However, the consistent increase in metastasis-free survival associated with apalutamide across all patient subgroups (including those with a high PSA level, a short PSA doubling time, or local or regional nodal disease at trial entry) suggests that the clinical benefits of apalutamide extend to patients with a high disease burden.
“Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival was significantly longer with apalutamide than with placebo,” concluded the authors. In addition, other clinical outcomes were also consistently improved.
To read more about this study, click here.