Updated ENZAMET Data Highlight Long-Term OS Benefit with Enzalutamide in mHSPC

The addition of enzalutamide over a conventional nonsteroidal antiandrogen agent to testosterone suppression continued to provide clinically meaningful improvements in overall survival in patients with hormone-dependent metastatic prostate cancer. sensitive.

The addition of enzalutamide (Xtandi) to testosterone suppression (TS) over a conventional nonsteroidal antiandrogen agent (NSAA) continued to provide clinically meaningful improvements in overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to updated data from the Phase 3 ENZAMET trial (NCT02446405) presented at the 2022 ASCO Annual Meeting.1

Data from the international phase 3 collaborative study, which compared enzalutamide to standard treatment as first-line treatment in mHSPC, showed that the median OS in the combined cohort was not yet reached (NR) with enzalutamide vs 73.2 months (95% CI, 64.7-NR) in control group (HR, 0.70; 95% CI, 0.58-0.84; P

Notably, patients with low-volume disease and high-volume disease M1 were found to derive a more pronounced benefit from enzalutamide than the other subgroups analyzed in the study.

“ENZAMET adds to the body of knowledge from several other pivotal trials and now informs best practice for mHSPC,” Ian D. Davis, MBBS, PhD, FRACP, FAChPM, from Eastern Health Clinical School at Monash University in Box Hill, Australia, said in a presentation on the data.

Previously, patients with low-volume mHSPC did better than those with high-volume disease when TS alone was used, and the same was true for patients with metachronous metastatic disease compared with metastatic disease. synchronous. However, combination treatments have been shown to be more beneficial than TS alone in various prognostic groups.

Patients in the ENZAMET trial (n=1125) were randomized 1:1 to the control arm consisting of TS plus a standard NSAA in the form of bicalutamide, nilutamide, or flutamide (arm A), or enzalutamide at 160 mg per day plus TS (arm B). Both arms were assessed every 12 weeks until progression. Stratifying factors included high or low volume of metastases and early planned use of docetaxel.

At the time of the trial’s interim analysis, the primary OS endpoint was achieved in the overall combined cohort (HR, 0.67; 95% CI, 0.52-0.86; P = .002).2 There was an improvement in favor of the enzalutamide, TS, and docetaxel triplet for prostate-specific antigen (PSA) progression-free survival (PFS) and clinical PFS, which were secondary endpoints. The clinical benefit outweighed the additional toxicity seen with the addition of enzalutamide, based on patient-reported outcomes.

“It was clear that longer follow-up would be needed, including, if possible, investigation of differential effects in various prognostic subgroups,” Davis said.

After a median follow-up of 68 months, with a data collection cut-off date of January 19, 2022, the preplanned analysis point of 470 events was reached (n=476).1 Investigators assessed the effect of enzalutamide based on prognostic moiety and docetaxel use. The presence or absence of M1 disease at initial diagnosis and whether patients had high-volume disease at study entry were the 2 binary prognostic factors for the updated data.

“OS is, of course, influenced by subsequent treatment access and use, as well as the study intervention,” Davis explained. “The main 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 of 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, compared to 22.6 months in the NSAA arm. About 48% of patients remained on enzalutamide in the experimental arm at 5 years versus 23% in the control arm.

When reviewing these data, other key considerations included that this trial was representative of multiple patient subgroups, including synchronous and metachronous disease, high and low volume disease, and those with whether or not they received docetaxel. The use of docetaxel for study patients depended on the discretion of the investigator and the assessment of “chemo-suitability” or expected benefit. Concomitant docetaxel was planned for up to 6 cycles in 45% of patients, and 108 patients received 1 cycle of docetaxel and 62 received 2 cycles before randomization.

OS results by subgroup and other secondary endpoints were evaluated as an exploratory analysis and not as formal comparisons due to the limited number 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 across baseline characteristics,” Davis said.

Adding enzalutamide improved OS for those who received docetaxel, although those who received docetaxel early did not have as much benefit. Additionally, those with low-volume mHSPC may have had a greater relative advantage than those with high-volume disease, even though both groups benefited. Of note, 71% of patients with high volume disease also received docetaxel compared to 37% of those with low volume disease.

There were no significant differences in the percentage of patients alive at 5 years for those receiving enzalutamide when examining baseline characteristics of disease volume, M1 time, and docetaxel use. Patients who received docetaxel concurrently and had a high volume of disease had a 5-year OS rate of 54% with enzalutamide and 51% with NAA, and those with low volume had a 5-year OS rates of 78% and 67%, respectively. The 5-year OS rates were 81% and 66% for people with low-volume mHSPC who did not receive docetaxel with enzalutamide and NSAA therapy, respectively, and 57% and 47% for those at high volume.

The 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 concomitant treatment with docetaxel most likely had a poorer prognosis according to Davis.

Many patients did not have PSA progression and continued in the experimental arm beyond the initial scan. Enzalutamide added benefit for PSA PFS in all subgroups assessed.

“This planned analysis after 476 events with a median follow-up of 68 months confirms the benefits of enzalutamide when added to best practice care,” Davis said. The strengths of the ENZAMET study were the active control arm, the concomitant use of docetaxel, the combination of prognostic groups and the primary OS endpoint. Limitations included that the use of docetaxel was not randomized and the trial was not powered for formal subgroup analysis.

Long-term follow-up confirms the OS benefit of enzalutamide in patients with mHSPC, particularly for those with low-volume disease. In the subgroups, no significant difference was observed with enzalutamide; however, exploratory analyzes suggested an additional benefit with the triplet.

“Exploratory analyzes raised the hypothesis that the greatest benefit of this triple therapy with TS plus enzalutamide plus docetaxel might be limited to people with the poorest prognostic 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 inappropriate or unlikely to be of benefit,” Davis concluded.

References

  1. Davis ID, Martin AJ, Zielinski RR, et al; ENZAMET investigators. Updated overall survival results in ENZAMET (ANZUP 1304), an international collaborative group trial of enzalutamide in metastatic hormone-responsive prostate cancer (mHSPC). J Clin Oncol. 2022;40(supplement 17):LBA5004. doi:10.1200/JCO.2022.40.17_suppl.LBA5004
  2. Davis ID, Martin AJ, Stockler MR, et al; Investigators of the ENZAMET trial and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide as standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835

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