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The addition of enzalutamide (Xtandi) to androgen deprivation therapy significantly prolonged radiographic progression-free survival compared with ADT alone in men with metastatic hormone-sensitive prostate cancer.
Andrew J. Armstrong, MD
The addition of enzalutamide (Xtandi) to androgen deprivation therapy (ADT) significantly prolonged radiographic progression-free survival (rPFS) compared with ADT alone in men with metastatic hormone-sensitive prostate cancer (mHSPC), according to findings from the phase III ARCHES trial.
At a median follow-up of 14.4 months, median rPFS was not reached in the enzalutamide arm and was 19.45 months in the placebo arm, indicating a 61% reduction in risk of radiographic progression or death with enzalutamide (HR, 0.39; 95% CI, 0.30-0.50; P <.0001),1 reported Andrew J. Armstrong, MD, at the 2019 Genitourinary Cancers Symposium.
“Significant benefits were noted in clinically important subsets of patients stratified by low and high disease volume and prior docetaxel chemotherapy, and significant improvements in all key secondary endpoints of efficacy [were realized],” said Armstrong, professor of medicine and associate professor of pharmacology and cancer biology, Department of Medicine, Duke University.
Enzalutamide plus ADT was also associated with a reduction in the risk of time to PSA progression by 81% (HR, 0.19; 95% CI, 0.13-0.26; P <.0001) and the time to initiation of new antineoplastic therapy by 72% (HR, 0.28; 95% CI, 0.20-0.40; P <.0001) compared with ADT alone.
An interim analysis of overall survival (OS) showed that the median OS has not been reached in either arm, with 39 deaths in the enzalutamide arm and 45 in the placebo arm. A final OS analysis will be conducted after approximately 342 deaths.
ADT has been the treatment mainstay for men with mHSPC but progression to castration-resistant disease is normally observed in 1 to 3 years. Combining ADT with docetaxel, abiraterone acetate (Zytiga), and radiation to the primary site in the face of oligometastatic disease has been shown to improve survival. The most recent studies in mHSPC, however, have excluded men who received prior docetaxel.2,3
The international, double-blind ARCHES trial enrolled 1150 patients with histologically verified mHSPC across North America, Europe, and the Asia-Pacific region who were randomized to receive enzalutamide at 160 mg daily or placebo. Men with both low- and high-volume disease, as well as patients who received recent treatment with docetaxel but did not have disease progression were enrolled.
Patients were allowed to receive prior ADT ≤3 months; those who received prior docetaxel could have had ADT for up to 6 months. The primary endpoint was rPFS, defined as the time to radiographic progression of disease either by soft tissue or confirmed bone scan criteria or death from any cause within 24 weeks of treatment discontinuation, whichever occurred first.
At initial diagnosis, 70% in the enzalutamide arm and 63% in the placebo arm had distant metastasis; 62% and 65%, respectively, had high disease volume; and 67% and 65%, respectively, had a Gleason score ≥8. Across the overall study population, approximately 18% of patients received prior docetaxel in the hormone-sensitive setting and the median duration of prior ADT at study entry was 1.6 months. Of those with confirmed metastases at screening, nearly half had bone only metastases with about 9% having soft tissue only metastases.
The 12-month event-free rate estimate for rPFS was 84% in the enzalutamide/ADT arm and 64% in the placebo/ADT arm, with a median that has not been reached for enzalutamide. At the data cutoff date of October 14, 2018, the majority of the events were radiographic progression events—77 in the enzalutamide arm and 185 in the placebo arm. With a median follow-up of 14.4 months, the median duration of therapy was 12.8 months for enzalutamide plus ADT versus 11.6 months for placebo plus ADT and “nearly 76% of patients remain on the study drug for enzalutamide and 58% remain on ADT alone,” Armstrong said.
Significant improvement in rPFS in favor of enzalutamide was observed across all subgroups analyzed, including by age, geographic region, Gleason score, disease localization and pattern of spread, volume of disease, and receipt of prior docetaxel.
Regarding the subgroup who had received prior docetaxel, Armstrong said, “This important, nearly 20% subset of patients, had a hazard ratio of 0.53 indicating a 47% improvement in the hazard of progression or death over time,” adding that the confidence intervals did not cross 1.0 (95% CI, 0.31-0.92).
“PSA progression is usually one of the first manifestations of castration resistance,” he said. The 12-month rate of freedom from PSA progression was 91% in the enzalutamide arm versus 63% in the placebo arm. Some 68.1% achieved an undetectable PSA with enzalutamide/ADT compared with 17.6% treated with placebo/ADT, a difference of 50.5% (P <.0001).
A complete response (disappearance of all lesions on imaging) was attained by 36.7% of enzalutamide-treated patients versus 23.1% of placebo recipients. The overall response rate favored enzalutamide over placebo (83.1% vs 63.7%; P <.0001).
The 12-month event-free rate estimate for time to initiation of new antineoplastic therapy was 94% versus 80% in the enzalutamide and placebo arms, respectively. The most common next therapy was docetaxel followed by abiraterone and then enzalutamide.
At data cutoff, adding enzalutamide to ADT did not have a significant impact on time to deterioration of urinary symptoms (HR, 0.88; 95% CI, 0.72-1.08; P = .2162) or the Functional Assessment of Cancer Therapy-Prostate (FACT-P) total score compared with placebo. “While we did not show a difference in the impact on urinary symptoms or FACT-P scores, most of these patients during 14.4 months of follow-up maintained a high level of quality of life,” Armstrong said.
The safety profile of enzalutamide was consistent with prior studies of the androgen receptor inhibitor. The proportion of patients who had to discontinue study was similar between enzalutamide and placebo (7.2% vs 5.2%) and the rate of grade ≥3 adverse events was also similar (24.3% vs 25.6%).
Following the unblinding at the end of double-blind treatment and the significant positive outcome on the primary endpoint, all patients in the placebo group are being offered enzalutamide in an open-label extension protocol.