Chicago, IL—Enzalutamide (Xtandi) and apalutamide (Erleada) had strong showings in 2 separate, randomized phase 3 clinical trials demonstrating that these drugs delay disease progression when added to background androgen-deprivation therapy (ADT) in patients with metastatic, hormone-sensitive prostate cancer. Both studies were presented at ASCO 2019 and were recently published in the New England Journal of Medicine.1,2
The field is moving toward the earlier use of agents such as enzalutamide and apalutamide in addition to abiraterone (Zytiga), docetaxel (Taxotere), and possibly darolutamide, in the treatment of prostate cancer before it becomes castration-resistant.
Significant Survival Benefit with Enzalutamide
In the ENZAMET phase 3 clinical trial presented at ASCO 2019, enzalutamide plus ADT extended survival in patients with metastatic, hormone-sensitive prostate cancer versus other nonsteroidal antiandrogens (NSAAs), including bicalutamide, nilutamide, or flutamide.
At 3 years, 80% of men with metastatic hormone-sensitive prostate cancer were alive in the enzalutamide-ADT arm compared with 72% of men who received other NSAAs along with ADT.
“Physicians and patients with prostate cancer now have a new treatment option with enzalutamide, and this is especially relevant for men who cannot tolerate chemotherapy and have a lower burden of disease on scans,” said the study’s co-chair Christopher Sweeney, MBBS, Medical Oncologist, Lank Center for Genitourinary Oncology, Dana-Farber Cancer Institute, Boston, MA.
“ENZAMET is the first study in metastatic hormone-sensitive prostate cancer to report survival data of enzalutamide and testosterone suppression, and outcomes if patients also received concurrent docetaxel,” Dr Sweeney emphasized.
ENZAMET randomized 1125 men with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to enzalutamide or to bicalutamide, nilutamide, or flutamide, with or without docetaxel. All patients were receiving background ADT. Randomization was stratified by disease volume (high or low), planned early docetaxel, planned antiresorptive therapy, comorbidity score, and study site.
The median follow-up for the first interim analysis was 33 months. At 3 years, 64% of the patients in the enzalutamide arm still received it versus 36% of those in the NSAA arm who still received the assigned treatment.
In addition, at 3 years, 80% of the men who received enzalutamide, with or without docetaxel, were alive versus 72% of men who received an NSAA (P = .002). Overall, enzalutamide treatment reduced mortality risk by 33% compared with the NSAA group.
Subgroup analyses showed that among the 596 men with high disease burden, 71% of the enzalutamide arm versus 64% of the NSAA group were alive at 3 years. Similarly, of 529 men with low disease burden, 90% of the enzalutamide group versus 82% of the comparator group were alive at 3 years. Survival was numerically higher with enzalutamide in men who did not receive early docetaxel therapy. Among this group, the 3-year survival rate was 83% versus 70% in the comparator group.
Enzalutamide significantly delayed the time to prostate-specific antigen progression rise, clinical progression, or death compared with the comparator group (P <.001). In patients who received concurrent docetaxel, enzalutamide delayed clinical progression-free survival (PFS) compared with NSAAs but did not significantly improve overall survival (OS). However, in patients who did not receive docetaxel, enzalutamide reduced the risk for clinical progression by 66% and improved OS by 47% compared with the other treatment arm. In the group receiving docetaxel, 71% of the men had high-volume disease compared with 37% in the group not receiving docetaxel.
“Most of the men on docetaxel were high-volume disease. We have to think about what to give patients if they get docetaxel. There is no benefit of early docetaxel in patients with low-volume disease and good prognosis,” Dr Sweeney noted.
The use of docetaxel concurrent with enzalutamide is controversial. ASCO Expert Neeraj Agarwal, MD, Director, Genitourinary Oncology Program, Huntsman Cancer Institute, University of Utah, Salt Lake City, said, “There is no role or survival benefit for adding docetaxel to enzalutamide. We should avoid chemotherapy in patients on enzalutamide. Based on current data, there is no role for combination therapy with enzalutamide. The answer is simple: use one of them.”
Serious adverse event rates were similar in both arms. Side effects higher with enzalutamide included grade 2 or 3 hypertension (20% vs 9%), fatigue (31% vs 15%), grade 2 or 3 falls (6% vs 1%), syncope (4% vs 1%), and grade 1 or 2 concentration impairment (4% vs 1%).
Improved Survival with Apalutamide
The addition of apalutamide to ADT significantly improved survival in men with metastatic hormone-sensitive prostate cancer in TITAN, a phase 3 clinical trial.
For the co-primary end point, apalutamide significantly reduced the risk for radiographic progression or death by 52% versus placebo.
TITAN joins ENZAMET in support of earlier, more aggressive treatment with apalutamide or enzalutamide, respectively, when prostate cancer is still hormone-sensitive.
“These results support the addition of apalutamide to ADT for a broad range of patients with metastatic, hormone-sensitive prostate cancer, such as those in the TITAN study, which included patients with high-volume and low-volume disease, with prior docetaxel treatment, those who had metastatic disease at diagnosis or relapsed metastatic disease, and those who had received prior treatment for localized disease,” said lead investigator Kim N. Chi, MD, FRCPC, Chair, Genitourinary Cancer, BC Cancer, Vancouver, Canada.
Dr Chi presented the final analysis of radiographic PFS (rPFS) and the first planned interim analysis of OS. Once the findings were released, the independent review committee recommended allowing patients in the placebo group to cross over to the apalutamide cohort.
TITAN evaluated the addition of apalutamide versus placebo in a broad population of men with metastatic, hormone-sensitive prostate cancer, regardless of disease burden; all men received treatment with background ADT.
A total of 1052 patients (median age, 68 years) were randomized in a 1:1 ratio to apalutamide or to matched placebo in 28-day cycles. The patients were stratified by Gleason score, geographic region, and previous treatment with docetaxel.
A total of 16.4% of patients had prostatectomy or radiation therapy for localized disease, 10.7% received previous docetaxel, 62.7% had high-volume disease, and 37.3% had low-volume disease.
At a median follow-up of 22 months, apalutamide reduced the risk for rPFS by 52% versus placebo. At 2 years, rPFS was 68% in the apalutamide arm versus 48% with placebo (P <.0001). Apalutamide reduced mortality risk by 33% versus placebo. The 2-year OS rate was 82% with apalutamide versus 74% with placebo (P = .005). Apalutamide was superior to placebo across all subgroups for rPFS and OS.
For the exploratory end point of PFS with second-line treatment (ie, PFS2; time to disease progression with second-line treatment), apalutamide reduced the risk by 34% compared with placebo (P = .0026). The 2-year PFS2 was 75% with apalutamide and 36% with placebo.
Adverse events were not significantly different between the 2 arms. Grade 3 or 4 adverse events were 42.2% with apalutamide and 40.8% with placebo. Rash was 27% with apalutamide versus 8.5% with placebo. Discontinuation rates were 8% with apalutamide versus 5.3% with placebo.
“This further supports the earlier use of apalutamide,” Dr Chi said. “Health-related quality of life according to FACT-P was preserved in both arms.”
- Davis ID, Martin AJ, Stockler MR, et al; for the ENZAMET trial investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381:121-131.
- Chi KN, Agarwal N, Bjartell A, et al; for the TITAN investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13-24.