CHICAGO – Adding the androgen-binding inhibitor apalutamide to androgen deprivation therapy (ADT) significantly increased radiographic progression-free survival and overall survival in men with metastatic castration-sensitive prostate cancer (mCSPC) compared with ADT alone in the phase 3 TITAN trial.
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Dr. Kim Chi
Among 1052 patients randomized to apalutamide (Erleada) plus either ADT or placebo, the overall survival rate at 24 months was 82.4% in the apalutamide group, compared with 73.5% in the placebo group, translating into a hazard ratio for death with apalutamide of 0.67 (P = .005), reported Kim N. Chi, MD, from the BC Cancer and Vancouver Prostate Centre in Vancouver, British Columbia, Canada.
“The TITAN study met its dual primary end points, demonstrating significant benefits with apalutamide plus ADT in an all-comer mCSPC population. There were significant improvements in overall survival with a 33% reduction in the risk of death. There was also a significant improvement in radiographic progression-free survival with a 52% reduction in the risk of progression or death,” he said at the American Society of Clinical Oncology annual meeting.
The study was also published online in the New England Journal of Medicine to coincide with Dr. Chi’s presentation.
The TITAN (Targeted Investigational Treatment Analysis of Novel Anti-androgen) study was designed to evaluate apalutamide vs. placebo in a broad population of patients with mCSPC treated with continuous ADT.
“The rationale behind the TITAN study was that direct inhibition of the androgen receptor by apalutamide will provide a more complete reduction of androgen signaling than ADT alone, leading to improved clinical outcomes,” Dr. Chi said.
The investigators enrolled a total of 1052 men with castration-sensitive prostate cancer, distant metastatic disease manifested as one or more lesions on bone scans, and Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
All patients were on continuous ADT. Prior therapies allowed under the protocol included docetaxel for a maximum of 6 cycles with no evidence of progression during treatment or before randomization, ADT for not more than 6 months for mCSPC or not more than 3 years for localized prostate cancer, one course of radiation of surgery for symptoms associated with metastatic disease, or other localized treatments completed at least 1 year before randomization.
The median patient age was 68 years. In all 62.7% of patients had high-volume disease, and the remainder had low-volume disease.
In this, the first interim analysis conducted at a median follow-up of 22.7 months, the 68.2% of patients in the apalutamide group had radiographic PFS, compared with 47.5% in the placebo group. The hazard ratio for progression or death with apalutamide was 0.48 (P less than .001).
As noted before, 24-month overall survival rates were 82.4% vs. 73.5%, respectively.
The secondary endpoint of median time to cytotoxic chemotherapy also significantly favored apalutamide, with a hazard ratio of 0.39 (P less than .0001). Other secondary endpoints, including median time to pain progression, median time to chronic opioid use, and median time to skeletal-related events trended in favor of apalutamide but were not statistically significant.
Grade 3 or 4 adverse events occurred in 42.2% of patients in the apalutamide arm and 40.8% in the placebo arm. The incidence of any serious adverse event was 19.8% with apalutamide and 20.3% with placebo. Adverse events leading to discontinuation occurred in 8% and 5.3%, respectively, and adverse events leading to death occurred in 1.9% vs. 3.0%.
Apalutamide was associated with higher incidences of rash, fatigue, hypothyroidism, and fracture.
The study results show that “androgen deprivation therapy and apalutamide for metastatic hormone-sensitive prostate cancer improves survival, and thus reinforces the current practice of ADT plus a single agent, whether it be docetaxel, abiraterone, enzalutamide, and now apalutamide,” commented Michael A. Carducci, MD, from the Johns Hopkins Sidney Kimmel Cancer Center in Baltimore, the invited discussant.
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Dr. Michael A. Carducci
Metastatic castration-sensitive prostate cancer is a broadly heterogeneous disease state, and the treatment benefits offered with various drugs is not consistent in subsets of patients. Investigators need to develop better molecularly based methods, combined with cliniopathologic factors, to better determine which subgroups of patients can benefit from specific drugs, he said.
The TITAN trial was supported by Aragon Pharmaceuticals. Dr. Chi disclosed grants and personal fees from multiple companies, not including Aragon. Dr. Carducci disclosed consulting or advisory roles and institutional research funding from multiple companies, not including Aragon.
SOURCE: Chi KN, ASCO 2019 Abstract 5006. N Engl J Med doi: 10.1056/NEJMoa1903307 .