Patients with high-risk, nonmetastatic prostate cancer saw no survival advantage and no delay in metastases with the addition of adjuvant docetaxel to androgen deprivation therapy (ADT), a randomized trial found.
With a median follow-up of over 10 years, the time to radiologic progression was 8.9 years for ADT plus docetaxel compared with 9.0 years for ADT alone (HR 1.03, 95% CI 0.74-1.43) in a patient population with androgen-dependent disease, according to researchers led by Stéphane Oudard, MD, PhD, of Georges Pompidou Hospital in France.
Based on these results, “docetaxel may not be as suitable in a high-risk setting as in a metastatic setting,” they concluded in JAMA Oncology.
Patients assigned to adjuvant docetaxel had a non-significant 15% improvement in prostate-specific antigen (PSA) relapse, the study’s primary endpoint. With a median follow-up of 30.0 months, the median PSA progression-free survival was 20.3 months for the combination arm compared with 19.3 months for ADT alone (HR 0.85, 95% CI 0.62-1.16, P=0.31).
The phase III trial included 254 men with androgen-dependent, nonmetastatic prostate cancer with rising PSA levels. All patients had undergone primary local therapy for their prostate cancer and were considered at high risk for metastases. The patients were randomly assigned to 1 year of ADT with or without docetaxel.
All patients in both arms had a PSA decline of 50% or more compared with their baseline level, with the majority of patients in both arms experiencing this decline by 12 weeks.
The overall survival results are not yet mature. All-cause deaths occurred in about one-third of patients treated with (32.0%) or without (36.8%) docetaxel.
In an editorial published with the study, Nicholas J. Vogelzang, MD, of Comprehensive Cancer Centers of Nevada in Las Vegas, wrote that Oudard and colleagues’ results add another clue to answer the question of whether disease burden is more important than androgen dependence in selecting patients for adjuvant therapy.
Specifically, he contrasts the results of this current trial in androgen-dependent, nonmetastatic disease, which showed no advantage for adjuvant docetaxel, with trials of enzalutamide (Xtandi) and apalutamide (Erleada) in androgen-independent, nonmetastatic disease, which showed more than a doubling in median metastases-free survival compared with placebo.
According to Vogelzang, this difference suggests that androgen environment “trumps disease burden” when selecting therapy.
“The powerful role that the androgen receptor (AR) and its inhibition plays in earlier-stage disease was not clear in 1999-2003, but is now apparent with the apalutamide and enzalutamide trial results,” Vogelzang wrote. “I believe that it is not until the cancer has evolved to a significant fraction of cells that are independent of AR (and by implication, independent of second-generation androgen-receptor inhibitors) that taxane therapy (either adjuvant or for established disease) improves survival.”
This theory, according to Vogelzang, would explain the negative results of SWOG S9921 in androgen-dependent, nonmetastatic disease prostate cancer, where no advantage was seen with adjuvant mitoxantrone combined with ADT, and the negative results of patients with androgen-dependent, metastatic, low-volume disease in CHAARTED and the GETUG-AFU 15 trial, where adding docetaxel to ADT did not improve survival.
Based on these current findings and those from the SWOG trial, Vogelzang currently recommends adjuvant ADT for 1 to 2 years in high-risk patients. However, in young patients with node-positive disease and detectable PSA after radical prostatectomy, he does recommend adjuvant taxane therapy based on the idea that disease in these very poor risk patients could see “early evolution to AR independence.”
In general, however, he noted that adjuvant taxane therapy for low-volume disease should be a “selectively considered” option.
“There may be patients for whom adjuvant taxane therapy is useful — I simply do not know which patients they are,” Vogelzang said.
Oudard and colleagues conducted several exploratory analyses of baseline attributes and their effect on PSA and radiologic progression-free survival. For PSA progression-free survival, HRs were in favor of combination treatment for all baseline attributes examined. For radiologic progression-free survival, patients with more than three high-risk factors had a significantly shorter survival compared with three or less risk factors (HR 0.54, 95% CI 0.34-0.86, P=0.008), but no association with treatment arm was found.
The most common grade 3/4 hematologic adverse effects in the combination arm were neutropenia (48.0%), febrile neutropenia (8.0%), and thrombocytopenia (3.0%).
The study was funded by Sanofi and Ipsen, and the Association pour la Recherche de Thérapeutiques Innovantes en Cancérologie.
Oudard and colleagues have received consulting fees from various industry entities.
Vogelzang has received personal fees from Arvinas, AstraZeneca, Janssen, and Pfizer/Medivation/Astellas, has performed legal consulting for Novartis, and owns stock options in Caris.