Androgen receptor inhibition delays CRPC metastasis
medwireNews: The results of two independent trials presented at the 2018 ASCO Genitourinary Cancers Symposium suggest that the use of an androgen receptor (AR) inhibitor alongside androgen deprivation therapy (ADT) can delay metastasis in men with castration-resistant prostate cancer (CRPC).
One trial investigated apalutamide, while the other focused on enzalutamide, but in both cases the comparator was placebo and patients in the experimental and control arms continued to receive ADT. Both trials enrolled men with nonmetastatic (M0) disease who were at high risk for developing metastases, defined by a prostate specific antigen (PSA) doubling time of 10 months or less; in the enzalutamide trial, participants were also required to have a PSA level of at least 2 ng/mL at intake.
In the phase III SPARTAN (Selective Prostate Androgen Receptor Targeting with ARN-509) trial, which was published simultaneously in The New England Journal of Medicine, treatment with apalutamide 240 mg/day was associated with a significant 72% reduction in the risk for metastasis or death relative to placebo. And the median metastasis-free survival (MFS) time was 40.5 months for the 806 patients who were randomly assigned to the apalutamide group and 16.2 months for their 401 counterparts in the placebo group.
The improvement in MFS with apalutamide was observed across all prespecified subgroups, including by age, baseline PSA level, and PSA doubling time.
Apalutamide also significantly prolonged the time to symptomatic progression, with a hazard ratio of 0.45 relative to placebo, although the median duration was unreached in both groups.
Adverse events of grade 3–4 occurred in 45.1% of apalutamide-treated participants and 34.2% of those given placebo; hypertension (14.3 vs 11.8%) was the most frequent high-grade side effect in the apalutamide arm, followed by rash (5.2 vs 0.3%), fractures (2.7 vs 0.8%), and falls (1.7 vs 0.8%).
The incidence of serious adverse events was 24.8% and 23.1%, respectively, and a corresponding 10.6% and 7.0% of patients discontinued the assigned regimen due to toxicity.
Noting that metastases were detected by technetium-99m bone scans and computed tomography in the trial, Matthew Smith, from the Massachusetts General Hospital Cancer Center in Boston, USA, and co-researchers point out that “[i]t is possible that more sensitive imaging tests could have identified metastases at baseline in many of the patients.”
But they believe that the consistent improvement with apalutamide across subgroups “suggests that the clinical benefits of apalutamide extend to patients with a high disease burden.”
The findings of the second phase III trial were similar, such that the 933 men who were randomly allocated to receive enzalutamide 160 mg/day had a significant 71% lower risk for developing metastases or dying than the 468 who received placebo. The corresponding median MFS durations were 36.6 and 14.7 months, and again the benefits of AR inhibitor treatment were seen across all subgroups.
Enzalutamide-treated patients also had a significant 93% reduced risk for time to PSA progression, at a median of 37.2 versus 3.9 months for the placebo group.
Maha Hussain (Northwestern University, Chicago, Illinois, USA), who presented the results on behalf of her fellow PROSPER investigators, said that in this analysis conducted at a median follow-up 22 months, the median overall survival had not been reached in either study arm, but that enzalutamide was associated with a nonsignificant 20% reduced risk for death relative to placebo.
With regard to the toxicity profile, she noted that the occurrence of grade 3 or worse adverse events was “not really high,” at 31% and 23% in the enzalutamide and placebo study arms, respectively. Hypertension (5 vs 2%), fatigue (3 vs 1%), and hematuria (2 vs 3%) were the most frequent grade 3 or more severe toxicities in the enzalutamide group.
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