Enzalutamide plus ADT found beneficial regardless of chemo status

Adding enzalutamide (XTANDI) to androgen deprivation therapy (ADT) significantly improves outcomes for men with metastatic hormone-sensitive prostate cancer (mHSPC) regardless of whether they received prior chemotherapy.

That new finding is from the phase III ARCHES (Androgen Receptor Inhibition with CHemohormonal Therapy in Men with Metastatic Hormone-Sensitive Prostate Cancer) study, which was presented at the American Society of Clinical Oncology annual meeting in Chicago.

The research showed that men randomized to enzalutamide had a statistically significant improvement in radiographic progression-free survival (rPFS) compared with the placebo-treated control group whether or not they received prior docetaxel (Taxotere). Statistically significant between-group differences favoring the enzalutamide group versus placebo were also seen in the subgroups of patients with and without prior docetaxel in key secondary endpoint analyses, and the benefits of treatment with the androgen receptor-targeted therapy were achieved without any compromise in quality of life.

“The inclusion of men with prior docetaxel therapy in ARCHES is important considering that current NCCN guidelines recommend the use of docetaxel for men with high-volume mHSPC. The results from ARCHES provide the first evidence of efficacy of enzalutamide in this important high-volume/risk patient subgroup and also provide further support for considering enzalutamide plus ADT as a treatment option in men with lower volume/risk mHSPC,” said lead author Andrew J. Armstrong, MD, professor of medicine and associate professor of pharmacology and cancer biology at Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC.

“Overall survival data from ARCHES remain immature. So, now we are waiting for longer follow-up to determine whether triple therapy also leads to better survival versus double therapy with docetaxel and ADT. However, recently published data from the phase III ENZAMET trial (N Engl J Med June 2, 2019 [Epub ahead of print]) suggest that these improvements in these early endpoints will lead to an improvement in overall survival with further follow-up.”

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Men were eligible for enrollment in the ARCHES study if they had mHSPC with metastasis confirmed by bone scan, computed tomography scan, or magnetic resonance imaging, and an ECOG performance status of 0 or 1. Enrolled patients were stratified prior to randomization based on disease volume (low or high) and history of prior docetaxel therapy (none, 1-5 cycles, or 6 cycles). Existing ADT had to have been started no more than 3 months earlier in patients who had not received docetaxel or no longer than 6 months earlier in men who had been on chemotherapy.

“In contrast to the ENZAMET trial conducted largely in Australia and New Zealand that investigated enzalutamide given concurrently with or without docetaxel as first-line therapy in metastatic prostate cancer, ARCHES is investigating enzalutamide as ‘maintenance therapy’ to prevent the development of castrate-resistant disease. ENZAMET established a survival advantage with the early use of enzalutamide, predominantly in men with metastatic disease who did not receive docetaxel,” Dr. Armstrong told Urology Times.

“Additional studies, longer follow-up of existing studies like ARCHES, ENZAMET, and TITAN, and new studies like PEACE are needed to understand whether combination or sequential approaches with androgen receptor-targeted therapies are preferred,” Dr. Armstrong added.

In ARCHES, a total of 1,150 patients were randomized 1:1 to enzalutamide 160 mg/day plus ADT or placebo plus ADT. The two study groups were well balanced at randomization. Median patient age was 70 years, approximately three-fourths of men had ECOG performance status 0, just over one-third of men had low-volume disease, 82% had not received prior docetaxel, and 91% of men were on ADT or had undergone orchiectomy.

Median follow-up at the time of the analysis was 14.4 months. At the cut-off, 76% of men randomized to enzalutamide and 58% of control group patients were still on treatment.

Next: Progression risk reduced by 61% vs. placeboProgression risk reduced by 61% vs. placebo

The primary endpoint analysis for the overall study population showed that the addition of enzalutamide to ADT reduced the risk of radiographic progression or death by 61% compared with placebo (p<.0001). The addition of enzalutamide to ADT in men with a history of prior docetaxel reduced the risk of radiographic progression or death by 47% (p=.0077), and it had an even greater benefit among men who had no prior docetaxel in whom there was a 64% delay in progression or death (p<.0001).

“The men who had not been given chemotherapy typically had low-volume disease, and perhaps their prostate cancer is more androgen receptor dependent,” Dr. Armstrong said.

Similarly, adding enzalutamide to ADT had a statistically significant benefit for improving rPFS regardless of previous use of ADT or orchiectomy.

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The secondary endpoint analyses showed that in the overall population, treatment with enzalutamide had statistically significant benefits for delaying time to PSA progression (p<.0001), time to initiation of new antineoplastic therapy (p<.0001), time to first symptomatic skeletal event (p=.0026), and time to castration resistance (p<.0001).

In addition, a significantly greater proportion of men treated with enzalutamide compared with placebo achieved undetectable PSA (45.3% vs 17.6%) and an objective response (83.1% vs. 63.7%) (p<.0001 for both comparisons). Analyses in the subgroups of patients with and without a history of docetaxel use showed that enzalutamide maintained its statistically significant benefit in all of the outcomes in both subgroups, with one exception. Although time to first symptomatic skeletal event was delayed in the enzalutamide-treated patients with prior docetaxel treatment, the effect was not statistically significant.

Baseline QoL maintained over time

Quality of life was evaluated using the FACT-P questionnaire. Median total score at baseline was approximately 115 and it remained stable among men treated with enzalutamide in analyses of the overall population and regardless of prior docetaxel.

“The baseline quality of life of men enrolled in this study was high, and it was maintained over time in both treatment groups,” said Dr. Armstrong. “In addition, data collected with the Brief Pain Inventory-Short Form showed that low levels of pain were maintained throughout the study in both the overall population and prior docetaxel subgroups.”

The safety review showed that the incidence of grade 3-4 adverse events was nearly the same in the enzalutamide and placebo groups (24% and 25%, respectively). Known side effects of enzalutamide include fatigue, hot flushes, fracture risk, hypertension, and falls and were increased in the ARCHES trial.

Dr. Armstrong receives honoraria from, is a consultant/adviser to, and/or receives travel expenses from Astellas, Pfizer, Janssen, and Bayer, and is on the speakers’ bureau for Dendreon, Bayer, and Sanofi. For full study disclosures, see bit.ly/ARCHESdisclosures19