Triplet therapy with ARSI, docetaxel, ADT boosts survival in mHSPC

Adding androgen receptor signaling inhibitors (ARSI) to a treatment regimen consisting of docetaxel and androgen deprivation therapy (ADT) can lead to better survival outcomes in patients with metastatic hormone-sensitive prostate cancer (mHSPC), according to a recent meta-analysis.

Pooled results from five randomized controlled trials, with a cumulative sample size of 2,837 patients, showed that the triple combo regimen reduced the risk of death by 25 percent in this patient population (pooled hazard ratio [HR], 0.74, 95 percent confidence interval [CI], 0.65–0.84; p<0.001), as compared with the docetaxel-ADT regimen. [Eur Urol 2022;doi:10.1016/j.eururo.2022.08.002]

Similarly, adding ARSI to docetaxel and ADT slashed progression risk by more than half (pooled HR, 0.49, 95 percent CI, 0.42–0.58; p<0.001). Findings were not meaningfully changed when focusing on the subgroup of patients with de novo mHSPC, in whom add-on ARSI decreased the risk of death by nearly 30 percent (pooled HR, 0.72, 95 percent CI, 0.62–0.84; p<0.001).

“Taken together, our data signal that triplet therapy could improve distant oncologic outcomes in patients with mHSPC with a significant impact on long-term oncologic outcomes,” the researchers said.

In conducting the meta-analysis, the researchers retrieved studies from the online databases of PubMed, Web of Science, and Scopus. They also drew abstracts from recent major conferences, including the American Society of Clinical Oncology and European Society for Medical Oncology. Overall, 11 trials were eligible for inclusion, with a combined total of 7,679 patients.

The analysis’ primary outcome was overall survival, while secondary endpoints were progression-free survival and associated adverse events.

Effect varies by disease volume

Two studies stratified survival outcome data after triplet therapy between patients with high- vs low-volume disease. Pooled analysis of these showed that while add-on ARSI significantly decreased death risk in the former patient subgroup (pooled HR, 0.79, 95 percent CI, 0.63–0.99; p=0.039), it could not demonstrate such an effect in the latter (pooled HR, 0.79, 95 percent CI, 0.50–1.23; p=0.3).

In contrast, disease burden did not affect the impact of ARSI on disease progression.

In terms of safety, the researchers pooled three studies with a combined sample of 2,498 patients. Adding ARSI to a docetaxel-ADT regimen increased the likelihood of severe adverse events by nearly 30 percent (pooled odds ratio [OR], 1.28, 95 percent CI, 1.06–1.54; p=0.009).

Specifically, nonhaematologic side effects such as severe hypertension was significantly elevated among patients given add-on ARSI (pooled OR, 1.96, 95 percent CI, 1.42–2.70; p<0.001), while no such impact was reported for haematologic adverse events, such as severe neutropaenia and febrile neutropaenia.

Exposure-adjusted incidence rates of severe side effects also did not differ between the triplet vs doublet treatment groups.

“The efficacy of triplet therapy appears to be reliable in patients with high-volume disease, while the potential benefit in patients with low-volume disease is still controversial. However, triplet therapy had the highest likelihood of increased rates of adverse events,” the researchers said.

“Further studies with long-term follow-up are needed to select mHSPC patient populations, which are most likely to benefit from triplet therapy in terms of quality-adjusted survival,” they added.