The addition of enzalutamide to a conventional NSAID for testosterone suppression continued to result in clinically meaningful improvements in overall survival in patients with metastatic hormone-sensitive prostate cancer.
The addition of enzalutamide (Xtandi) to testosterone suppression (TS) versus a conventional nonsteroidal antiandrogen (NSAA) drug continued to result in clinically meaningful improvements in overall survival (OS) in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to the updated study. Data from the Phase 3 ENZAMET study (NCT02446405) presented at the 2022 ASCO Annual Meeting.1
Data from the phase 3 study of the international, collaborative group comparing enzalutamide to standard of care as first-line therapy in mHSPC showed that the median OS in the combined cohort with enzalutamide had not yet been reached (NR) versus 73.2 months ( 95% CI, 64.7-NR) in the control arm (HR, 0.70; 95% CI, 0.58-0.84; P < 0.0001). The 5-year survival rate was 67% compared to 57% in the study and control arms.
Notably, patients with low-volume disease and M1 high-volume disease were found to benefit more from enzalutamide than other subgroups analyzed in the study.
“ENZAMET expands knowledge from several other pivotal studies and now shares best practice for mHSPC,” said Ian D Davis, MBBS, PhD, FRACP, FAChPM, of the Eastern Health Clinical School at Monash University in Box Hill, Australia in a presentation about the data.
Previously, patients with low-volume mHSPC performed better than patients with high-volume disease when TS was used alone, and the same was true for patients with metachronous metastatic disease versus synchronous disease. However, combination treatments have been shown to be more beneficial than TS alone in different prognostic groups.
Patients in the ENZAMET study (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 160 mg daily plus TS (Arm B ). Both arms were evaluated every 12 weeks until progression. Stratification factors included high versus low metastatic volume and use of planned early docetaxel.
At the time of the interim analysis of the study, the primary endpoint of OS was met in the combined overall cohort (HR, 0.67; 95% CI, 0.52-0.86; P = 0.002).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 observed with the addition of enzalutamide, based on patient-reported results.
“It was clear that longer follow-up would be needed, including, where possible, examining differential effects in different prognostic subgroups,” Davis said.
After a median follow-up of 68 months with a cut-off date of January 19, 2022, the preplanned analysis time point of 470 events was reached (n=476).1 Investigators assessed the effect of enzalutamide based on prognostic grouping and use of docetaxel. The presence or absence of M1 disease at initial diagnosis and whether patients had high disease volume at study entry were the two binary factors in predicting the updated data.
“Obviously, OS is affected by access to and use of follow-up therapy, as well as study intervention,” Davis explained. “The main difference between the treatment groups for subsequent therapies was the significantly higher use of enzalutamide or abiraterone [Zytiga] beyond the progression in the control group. At the time of analysis, 76% of patients in the control group who had disease progression 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, the median duration of treatment was 57.8 months for those who continued treatment versus 22.6 months in the NSAA arm. Approximately 48% of patients in the experimental arm remained on enzalutamide at 5 years versus 23% in the control arm.
One of the considerations in reviewing these data was that this study was representative of several subgroups of patients, including synchronous and metachronous disease, high and low volume disease, and those receiving and not receiving docetaxel. Use of docetaxel in study patients was dependent on investigator discretion and assessment of “chemofitness” or predicted benefit. Concomitant treatment with 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 prior to randomization.
OS results by subgroup and other secondary endpoints were evaluated as an exploratory analysis rather than formal comparisons due to limited numbers and potential confounders, Davis said. There were 503 patients receiving docetaxel, 602 with high volume disease and 683 with synchronous M1 disease. “The message is that there weren’t any major differences in the effect of enzalutamide from baseline characteristics,” Davis said.
The addition of enzalutamide improved OS for those who received docetaxel, although those who received docetaxel early did not have as much benefit. In addition, those who had low volume mHSPC may have had a greater relative benefit over those with high disease volume, although both groups benefited. Notably, 71% of patients with high morbidity also received docetaxel, compared to 37% of patients with low morbidity.
There were no significant differences in the percentage of patients alive at 5 years from those receiving enzalutamide when considering baseline characteristics of disease volume, M1 timing, and docetaxel use. Patients receiving docetaxel concomitantly and with high disease volume had a 5-year OS rate of 54% with enzalutamide and 51% with NSAA, and low-volume patients had a 5-year OS rate of 78% and 50%, respectively .67%. The 5-year OS rates were 81% and 66% for patients with low-volume mHSPC not receiving docetaxel with enzalutamide and NSAA treatment, respectively, and 57% and 47% for high-volume patients, respectively.
NSAA alone had the worst results in the synchronous and metachronous subgroups, regardless of high or low volume disease. Enzalutamide and enzalutamide plus docetaxel had similar results, although treatment with concomitant docetaxel most likely has a worse prognosis, Davis said.
Many patients had no PSA progression and continued on the experimental arm beyond the initial analysis. Added benefit of enzalutamide for PSA PFS in all subgroups examined.
“This planned analysis after 476 events with a median follow-up of 68 months validates the benefits of enzalutamide when added to the best practice standard of care,” Davis said. The strengths of the ENZAMET study were the active control arm, co-administration of docetaxel, the mix of prognostic groups and the primary endpoint OS. Limitations included that docetaxel use was not randomized and the study was not designed for formal subgroup analysis.
Long-term follow-up confirms the OS benefit of enzalutamide in patients with mHSPC, particularly those with low-volume disease. No significant differences to enzalutamide were observed between the subgroups; However, the exploratory analyzes indicated an additional benefit with the triplet.
“The exploratory analyzes have raised the hypothesis that the greatest benefit of this triplet regimen of TS plus enzalutamide plus docetaxel may be limited to those with the disease with the poorest prognosis, particularly synchronous and high-volume metastatic disease. Enzalutamide should be considered in all patients with metastatic disease, particularly in patients for whom docetaxel is considered unsuitable or unlikely,” Davis concluded.
- Davis ID, Martin AJ, Zielinski RR, et al.; ENZAMET investigators. Updated overall survival results from ENZAMET (ANZUP 1304), an international collaborative group study of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). J Clin Oncol. 2022;40(Supplement 17):LBA5004. doi:10.1200/JCO.2022.40.17_suppl.LBA5004
- Davis ID, Martin AJ, Stockler MR, et al.; Investigators of the ENZAMET Study and the Australian and New Zealand Urogenital and Prostate Cancer Study Groups. Enzalutamide with standard first-line therapy for metastatic prostate cancer. N Engl. J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835