Updated data from the phase 3 ENZAMET trial shared during the 2022 ASCO Annual Meeting showed that with over 5 years’ of follow-up enzalutamide (Xtandi) sustained its overall survival (OS) benefit in patients with metastatic hormone-sensitive prostate cancer (mHSPC).1
The ENZAMET trial (NCT02446405) is an international, cooperative group study comparing enzalutamide with the standard of care as first-line therapy in mHSPC. In the 3-year update of the study, patients with low-volume disease and M1 high-volume disease had more benefit than other groups on the study in addition to the benefit seen in the overall cohort.
“ENZAMET adds to the body of knowledge from several other pivotal trials and now informs best practices for mHSPC,” Ian D. Davis, MBBS, PhD, FRACP, FAChPM, of the Eastern Health Clinical School at Monash University in Box Hill, Australia, said in his presentation.
Previously, patients with low-volume mHSPC did better than those with high-volume disease when testosterone suppression (TS) alone was used, and the same was true in patients with metachronous metastatic disease over synchronous disease. However, combination treatments have shown to be more beneficial than TS alone in varying prognostic groups.
Patients in the ENZAMET trial (n = 1125) were randomized 1:1 to arm A, the control arm consisting of TS plus a standard non-steroidal antiandrogen ([NSAA] bicalutamide, nilutamide, or flutamide), or enzalutamide at 160 mg per day plus TS in arm B. Both arms were evaluated every 12 weeks until progression. Stratification factors included high versus low volume of metastases and use of planned early docetaxel.
At the time of ENZAMET’s interim analysis, the primary end point of OS was met in the combined overall cohort (HR, 0.67; 95% CI, 0.52-0.86; P = .002).2 There was improvement favoring the triplet of enzalutamide, TS, and docetaxel for prostate-specific antigen (PSA) progression-free survival (PFS) and clinical PFS, which were secondary end points. The clinical benefit outweighed the additional toxicity seen with the addition of enzalutamide, according to patient-reported outcomes. “It was clear that longer follow-up would be required, including, where possible, investigation of differential effects in various prognostic subgroups,” Davis said.
After a median follow-up of 68 months, with a data cutoff date of January 19, 2022, the preplanned analysis point of 470 events was met (n = 476).1 Investigators assessed the effect of enzalutamide based on prognostic grouping and the use of docetaxel. The presence or absence of M1 disease at initial diagnosis and whether or not patients had high-volume disease upon study entry were the 2 binary factors for prognosis for the updated data.
The median OS in the combined cohort was not reached (NR) with enzalutamide versus 73.2 months (95% CI, 64.7-NR) in the control arm (HR, 0.70; 95% CI, 0.58-0.84; P < .0001). The 5-year survival rate was 67% compared with 57% in arm B and arm A, respectively.
“OS is, of course, influenced by access to and use of subsequent therapy, as well as the study intervention,” Davis explained. “The major difference between the treatment groups for subsequent therapies was the much higher use of enzalutamide or abiraterone [Zytiga] beyond progression in the control group. At the time of the analysis, 76% of those who progressed in the control group were treated with enzalutamide or abiraterone after progression compared to 26% in the enzalutamide group. The survival benefits for enzalutamide were not due to lack of access to effective therapies in the control group.”
In the enzalutamide arm, there was a median of 57.8 months of treatment, for those who remained on treatment, versus 22.6 months on the NSAA arm. Approximately 48% of patients remained on enzalutamide in the experimental arm at 5 years versus 23% of the control arm.
When reviewing these data, other key considerations included that this trial was representative of multiple subgroups of patients, including synchronous and metachronous disease, high- and low-volume disease, and those who did and did not receive docetaxel. The use of docetaxel for study patients was dependent on investigator discretion and assessment of “chemofitness” or predicted benefit. Concurrent docetaxel was planned for up to 6 cycles in 45% of patients, and 108 patients were given 1 cycle of docetaxel and 62 received 2 cycles before randomization.
The OS outcomes by subgroup and other secondary end points were evaluated as exploratory analysis and not formal comparisons due to limited numbers and potential confounders, according to Davis. There were 503 patients who received docetaxel, 602 with high-volume disease, and 683 with synchronous M1 disease. “The message is that no major differences in the effect of enzalutamide were detectable according to baseline characteristics,” Davis stated.
The addition of enzalutamide improved OS for those who received docetaxel, though those who were given early docetaxel did not have as much benefit. Additionally, those who had low-volume mHSPC may have had greater relative benefit over those with high-volume disease, even though both groups benefited. Of note, 71% of patients with high-volume disease also received docetaxel compared with 37% in those with low-volume disease.
There were no significant differences in the percent of patients alive at 5 years for those receiving enzalutamide when looking at baseline characteristics of volume of disease, M1 timing, and docetaxel use. Patients who received concurrent docetaxel who had high volume of disease had a 54% 5-year OS rate with enzalutamide and 51% with NSAA, and those with low volume had a 78% and 67% 5-year OS rate, respectively. The 5-year OS rates were 81% and 66% for those with low-volume mHSPC who did not receive docetaxel with enzalutamide and NSAA treatment, respectively, and 57% and 47% for those with high volume.
NSAA alone had the worst outcomes in the synchronous and metachronous subgroups, regardless of high- or low-volume disease. Enzalutamide and enzalutamide plus docetaxel had similar results, although treatment with concurrent docetaxel most likely has poorer prognosis according to Davis.
Many patients have not had PSA progression and continued on the experimental arm beyond the initial analysis. Enzalutamide added benefit for PSA PFS in all subgroups evaluated.
“This planned analysis after 476 events with a median follow-up of 68 months confirms the benefits of enzalutamide when added to best-practice standard of care,” Davis said. The ENZAMET study strengths were the active control arm, concurrent use of docetaxel, the mix of prognostic groups, and the primary end point of OS. Limitations included that the use of docetaxel was not randomized, and the trial was not powered for formal analysis of the subgroups.
The long-term follow-up confirms the OS benefit of enzalutamide in patients with mHSPC, especially for those with low-volume disease. Across the subgroups, there were no significant differences found with enzalutamide; however, the exploratory analyses suggested additional benefit with the triplet.
“The exploratory analyses raised the hypothesis that the greatest benefit of this triplet therapy with TS plus enzalutamide plus docetaxel may be limited to those with the poorest prognosis disease, particularly synchronous and high-volume metastatic disease. Enzalutamide should be considered in all patients with metastatic disease and especially in those for whom docetaxel is considered unsuitable or unlikely to be beneficial,” Davis concluded.
1. Davis ID, Martin AJ, Zielinski RR, et al; ENZAMET investigators. Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2022;40(suppl 17):LBA5004. doi:10.1200/JCO.2022.40.17_suppl.LBA5004
2. Davis ID, Martin AJ, Stockler MR, et al; 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(2):121-131. doi:10.1056/NEJMoa1903835