Could Docetaxel Have Role in Unfavorable-Risk Prostate Cancer?
Adding docetaxel to androgen deprivation therapy (ADT) plus radiation therapy (RT) failed to improve survival in unfavorable-risk prostate cancer, though the combination may hold benefit for certain patients, long-term results of a randomized trial found. While the regimen did not prolong overall survival (OS) among all men with unfavorable-risk nonmetastatic cancer after a median of 10 years follow-up, it did decrease the incidence of RT-induced cancer, reported Anthony D'Amico, MD, PhD, of Dana-Farber Cancer Institute in Boston, and colleagues. Exploratory analyses showed that men with prostate-specific antigen (PSA) levels <4 ng/mL appeared to have improved OS, previously unseen in randomized trials, driven by a reduction in prostate cancer-specific mortality, according to the findings in the Journal of Clinical Oncology. "There is a reduction in radiation-induced cancers, which is quite remarkable, because those cancers are usually lethal," D'Amico told MedPage Today. "And if men with PSA <4 really benefit from docetaxel by decreasing prostate cancer deaths, and also benefit from having less radiation-induced cancers, that's a double win for those men." The FDA approved docetaxel for use in men with metastatic castration-resistant prostate cancer (mCRPC) after an OS benefit was observed in randomized clinical trials. Other trials demonstrated prolonged OS when men with newly diagnosed mCRPC were treated with ADT plus docetaxel. However, D'Amico and colleagues noted that subsequent reports from six clinical trials, including NRG Oncology RTOG 0521 and STAMPEDE, of men with unfavorable-risk nonmetastatic cancer who had docetaxel added to radical prostatectomy or ADT and RT, had negative or inconclusive results. Thus docetaxel is not recommended when managing men with unfavorable-risk prostate cancer. The authors also pointed out that an OS benefit with a nonsignificant reduction in prostate cancer-specific mortality was seen in two of the trials where >80% of the patients had high-grade prostate cancer. There is a "plausible" hypothesis that accounts for that OS benefit and the nonsignificant reduction in prostate cancer-specific mortality, according to D'Amico's group. "There is a subgroup of men who have a low PSA <4, but a high-grade cancer," D'Amico explained. "These are men who don't make much PSA because they are already insensitive to testosterone. They have androgen sensitive disease, and that is exactly the disease that docetaxel increases survival in, in men with metastatic disease." D'Amico and colleagues performed a multicenter, international, randomized phase III trial from September 2005 to January 2015 in which 350 men with T1c-4N0M0 unfavorable-risk prostate cancer were assigned 1:1 to ADT and RT with or without docetaxel. They wanted to evaluate the effect add-on docetaxel had on OS and the incidence of RT-induced cancers, as well as how that effect on OS differed within PSA subgroups. After a median follow-up of 10.2 years, 89 of the participants died (44 in the docetaxel arm; 45 in the ADT-plus-RT-alone arm). Of these deaths, 42 were from prostate cancer (22 and 20, respectively). OS did not significantly increase in the docetaxel arm (a restricted mean survival time over 10 years of 9.11 with docetaxel vs 8.82 years without). However, the authors also found that fewer RT-induced cancers were observed in the docetaxel arm, with 10-year estimates of 0.61% versus 4.90% without the chemotherapy (age-adjusted HR 0.13, 95% CI 0.02-0.97). There was no significant difference in the cumulative incidence of all other second cancers (HR 0.89, 95% CI 0.50-1.60). The treatment effect of the addition of docetaxel to ADT plus RT on OS also differed in men with PSA levels <4 ng/mL versus men with PSAs of 4-20 ng/mL (adjusted HR 0.27 and 1.51, respectively), driven by less prostate-specific mortality in the docetaxel arm (0% vs 28.57%, respectively), the authors explained. "We looked into that PSA <4 subgroup and found there was a huge benefit there, but because the study wasn't designed to look specifically in that subgroup, it's hypothesis generating," D'Amico said. He added that his group is partnering with other trials (RTOG 0521 and STAMPEDE) for a meta-analysis to further explore that possible survival benefit in that small subset of patients. "This small group is not inconsequential," D'Amico pointed out. "This is the group of men who have the highest rate of deaths from prostate cancer. The vast majority -- more than 50% -- go on to die from prostate cancer when you just give them standard treatment. So this is a group with an unmet need, and if docetaxel really has an impact in this group, it will be practice changing." As for the finding of a reduction in RT-inducted cancers, D'Amico noted that docetaxel is a radiosensitizer, "and since radiation mutates cells, and it's those cells that go on to create new cancers, maybe docetaxel is potent enough to kill those cells that are mutated." "And this finding is not hypothesizing -- it is robust," he stressed. D'Amico and colleagues noted that the potential future availability of oral docetaxel, with its more favorable toxicity profile than IV docetaxel, "provides the opportunity to study oral docetaxel use to reduce the risk of RT-induced cancer with minimal patient impact and across a wide variety of cancers where RT and docetaxel use is part of the management approach." Mike Bassett is a staff writer focusing on oncology and hematology. He is based in Massachusetts.