medwireNews: Phase 2 data point to the potential of switch maintenance with darolutamide in men with metastatic castration-resistant prostate cancer (CRPC) that has not progressed after taxane therapy.
The men had also received at least one androgen-receptor pathway inhibitor (ARPI) before taxane treatment, and the benefit of darolutamide appeared to be greater for those who had a complete or partial radiologic response to the latest ARPI rather than stable or progressive disease, notes the team.
The double-blind SAKK 08/16 trial enrolled 90 men who had nonprogressive disease after receiving docetaxel (86.7–95.6%) or cabazitaxel (4.4–13.3%), and had previously received abiraterone (60.0%), enzalutamide (31.1%), or both (8.9%).
The primary endpoint of radiographic progression-free survival (PFS) at 12 weeks was achieved by 64.7% of the 45 patients who were randomly assigned to receive maintenance darolutamide 600 mg twice a day alongside best supportive care.
This was significantly higher than the rate of 52.2% observed among their 45 counterparts who instead received placebo plus best supportive care.
The median radiographic PFS times were 5.5 and 4.5 months, respectively, and equated to a 46% reduction in the risk for radiographic progression or death with the use of darolutamide.
Maintenance darolutamide was also associated with significant improvements in event-free survival and time to prostate-specific antigen (PSA) progression relative to placebo, at medians of 5.4 versus 2.9 months and 2.7 months versus 1.9 months, respectively, and corresponding hazard ratios (HRs) of 0.46 and 0.48.
The proportion of participants who achieved a PSA decline of at least 50% was also significantly higher in the darolutamide group, at 22% versus 4%.
And overall survival (OS) also favored the darolutamide group, at a median of 24.0 months compared with 21.3 months in the placebo group, but the between-group difference was not statistically significant, report Silke Gillessen (Istituto Oncologico della Svizzera Italiana, Bellinzona, Switzerland) and co-researchers.
And they highlight that the efficacy benefits of darolutamide did not come at the cost of increased toxicity. Treatment-related adverse events (TRAEs) of grade 3 occurred in an identical 2% of patients in each group and there were no grade 4 or 5 TRAEs in either group.
Nevertheless, the researchers point out that the overall magnitude of the radiographic PFS benefit with darolutamide in the total study population was “marginal,” and “unlikely to be clinically relevant, only consisting of a 1-month improvement,” especially in light of “the significant financial impact of darolutamide maintenance.”
They write in the Journal of Clinical Oncology: “It thus appears crucial to identify those patients who would most likely benefit from darolutamide maintenance therapy,” adding that subgroup analyses from the trial provided a clue about this.
Specifically, radiographic PFS was significantly improved with maintenance darolutamide versus placebo in the subgroup of men who had a radiologic response to the most recent ARPI (n=29), with an HR for radiographic progression or death of 0.35, and there was a trend toward improved OS (nonsignificant HR=0.26).
No such improvement in either endpoint was observed, however, among men with stable or progressive disease as the best response to the latest ARPI (n=61).
In conclusion, Gillessen and colleagues caution that the study findings should be regarded as hypothesis-generating due to the “rather small” size.
“They must be further confirmed in a larger trial conducted in patients selected with respect to their latest response to ARPI treatment.”
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