A new U.S. Department of Veterans Affairs (VA) study suggests that African American men and men with a higher tumor stage may benefit from adjuvant chemotherapy following radical prostatectomy.1 According to prespecified analysis of these two “high–risk” subgroups, patients with ≥ T3b disease had a statistically significant 18-month improvement in progression-free survival vs the standard of care population, and the benefit of docetaxel increased to almost 2 years in the African American subgroup.
Although there was no statistically significant improvement in progression-free survival for the entire intent-to-treat population, the study was underpowered to detect the expected treatment effect; patient accrual was stopped due to “resource issues” before reaching the planned sample size, the researchers reported.
Prespecified subgroup analyses suggest potential benefit for patients with higher risk pathology and African American ancestry, supporting ongoing and planned trials of systemic chemotherapy for hormone-sensitive prostate cancer.— Daniel W. Lin, MD
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“Prespecified subgroup analyses suggest potential benefit for patients with higher risk pathology and African American ancestry, supporting ongoing and planned trials of systemic chemotherapy for hormone-sensitive prostate cancer,” said Daniel W. Lin, MD, Chief of Urologic Oncology at the University of Washington’s Department of Urology. “Given the high failure rates of established treatments for localized prostate cancer, knowing whom to treat with adjuvant chemotherapy is a real step forward in the effort to improve outcomes.”
As Dr. Lin reported at the 2016 American Urological Association Annual Meeting, prostate cancer is the leading cause of cancer in men, affecting one in seven in the United States and one in five in the African American population. Moreover, of the 130,000 men who opt for radical prostatectomy to treat this disease, 20% to 30% will be found to have locally advanced or high-grade disease, leaving them at risk for relapse.
“At least half of high-risk prostate cancer will recur following prostatectomy, so there’s definitely room for us to improve,” said Dr. Lin. “There are conflicts about what to do after surgery in men with high-risk disease.”
Study Details
Researchers from VA centers across the United States sought to examine the efficacy of early adjuvant chemotherapy in patients who had radical prostatectomy but were at high risk for relapse based on clinical and pathologic parameters. Patients at high risk for relapse after prostatectomy were randomized to undergo either observation (standard of care) or chemotherapy, where docetaxel and prednisone were administered every 3 weeks for 18 weeks (without hormonal therapy).
High risk was defined as disease not confined to the prostate, positive surgical margins associated with Gleason grade 8 to 10, or a baseline prostate-specific antigen (PSA) level > 20 ng/mL. All patients underwent lymphadenectomy, and node-positive patients were excluded. Additionally, all patients had an undetectable PSA after surgery.
Although 297 men were randomized, the planned sample size was over 400. “Unfortunately, accrual to the study was stopped for resource issues before reaching the planned sample size,” said Dr. Lin. “As a result, the study was underpowered to detect the expected treatment effect.”
At least one-third of patients had Gleason grade 8 to 10 disease, which is much higher than in previous studies in the adjuvant setting, Dr. Lin remarked. In addition, one-third of patients had pathologic stage T3b or greater tumors, also indicative of a higher risk group.
“Interestingly, 25% of patients were African American,” said Dr. Lin. “No other study has had such a high African American population.”
Clinical Practice Implications
Patients were observed via PSA testing for 1 to 5 years. For the population as a whole, treatment with adjuvant chemotherapy showed no statistically significant improvement in progression-free survival (hazard ratio [HR] = 0.82, P = .24). Although the hazard ratio was not significant, receiving docetaxel after surgery delayed recurrence by almost 10 months. In patients treated with docetaxel, median progression-free survival was 55.5 months vs 45.6 months on standard of care.
Despite missing the primary endpoint, the trial may still influence clinical practice, as benefit in progression-free survival was seen in African American men (HR = 0.54, P = .05) and men with higher-risk pathology (HR = 0.57, P = .03). “When you look at progression-free survival over time, the addition of docetaxel delayed recurrence in ‘super high–risk’ patients by 18 months, which is significant,” revealed Dr. Lin.
Adjuvant Chemotherapy Following Radical Prostatectomy
- Adjuvant chemotherapy using docetaxel and prednisone following radical prostatectomy was well tolerated.
- Prespecified subgroup analyses suggest potential benefit for patients with higher risk pathology (≥ T3b) and African American ancestry.
- There was no statistically significant improvement in progression-free survival for the entire intent-to-treat population, but the study was underpowered to detect the expected treatment effect.
Furthermore, the magnitude of benefit with docetaxel increased to almost 2 years in the African American population. The median progression-free survival was 55.5 months with docetaxel compared with 32.7 months without. “This was very striking,” acknowledged Dr. Lin. “African Americans who received docetaxel not only delayed their treatment by almost 2 years, but the curves also flatten out, suggesting cure in a subset of men.”
In addition, adjuvant chemotherapy was well tolerated by patients, despite the large number of blood-related adverse events (46%). “We expect the hematologic issues with chemotherapy,” admitted Dr. Lin. “Importantly, only 2% of patients had febrile neutropenia, and there was only one grade 5 treatment-related infection.”
‘An Incomplete Story’
As Dr. Lin reported, the study was dropped due to resource issues at the VA, leaving behind “an incomplete story.” However, the good thing about the VA, said Dr. Lin, is its impressive electronic medical record. “Anywhere patients go within the VA system, we’ll have follow-up,” he added. "We hope to add to the story with longer follow-up in the future."
That said, Dr. Lin cautioned against interpretation of these results as a negative phase III trial because it was underpowered. “In some ways, this could be viewed as a large phase II trial in this setting,” he explained, “and it did show a signal. The hazard ratio of 0.82 is the same ratio as many trials, such as the original docetaxel trial, which have gone on to approval. If you just look at the effect size, it lends some credibility to the fact that chemotherapy can and does work in this setting.”
“At the same time,” added Dr. Lin, “if this study were well powered, we still might not have an overall effect. Nevertheless, we can’t say that just because we didn’t have an overall effect in an underpowered study, that there is no impact…. That’s an important nuance.”
Future Research
Additional translational endpoints of the trial include detailed genetic analysis of both tumor tissue and germline DNA, to improve future patient selection. “Maybe we can find the signature of who’s going to respond to docetaxel or who should get standard of care,” Dr. Lin observed.
Finally, whether to add androgen-deprivation therapy to this regimen—and if so, in what sequence—remains a controversial question. “Many don’t think it makes sense to put them together, but in mouse and in vitro models, there does appear to be a synergistic effect,” said Dr. Lin, who noted there are potential plans for a follow-up trial using both hormonal therapy and chemotherapy together in this clinical setting. ■
Disclosure: Dr. Lin reported no potential conflicts of interest.
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