Adding docetaxel to androgen suppression and radiation therapy for selected men with high-risk localized prostate cancer (PCa) may improve disease-free survival (DFS) and decrease the risk of distant metastasis, according to a recent study.

The current standard of care for these patients is radiotherapy (RT) plus long-term androgen deprivation therapy (ADT). Seth A. Rosenthal, MD, of Sutter Medical Group and Sutter Cancer Centers, Sacramento, California, and colleagues conducted the multicenter randomized NRG Oncology RTOG 0521 study, which enrolled men between 2005 and 2009 with high-risk non-metastatic PCa and randomly assigned them to receive standard long-term ADT plus RT with or without adjuvant docetaxel.

The study included 612 patients with a median age of 66 years (range 46–83 years) and median PSA level of 15.1 ng/mL. Gleason score 9 or 10 cancer was presented in 53% of the cohort, and 27% had cT3 to cT4 disease. The median follow-up was 5.7 years for the evaluable 563 patients and 6.1 years for the 461 surviving patients.

Treatment was well tolerated in both arms. The 4-year overall survival (OS) rate was 93% for the docetaxel group compared with 89% in the standard-treatment arm, Dr Rosenthal’s team reported in the Journal of Clinical Oncology.1

The 6-year rate of distant metastasis was 9.1% in the docetaxel arm compared with 14% in the standard-treatment group. The 6-year DFS rate was 65.4% in the docetaxel arm compared with 54.9% in the standard-treatment arm. The median DFS time was 8.5 years for the docetaxel arm versus 6.9 years for standard-treatment group. Docetaxel recipients had a significant 40% decreased risk of distant metastasis and 24% decreased risk of disease progression compared with the standard-treatment group.

“Although there are multiple management options, on the basis of the results of this trial, adjuvant CT [chemotherapy] with docetaxel can be reasonably discussed with selected men with high-risk localized prostate cancer who are fit for CT,” the authors concluded.

Previous studies have shown that docetaxel-based chemotherapy may improve OS among men with castration-resistant and castration-sensitive PCa, the investigators noted.

“This well-designed study adds to the body of literature supporting the increased efficacy of docetaxel chemotherapy when used in aggressive prostate cancer that is naïve to treatment,” said David R. Wise, MD, PhD, a medical oncologist with the Perlmutter Cancer Center at New York University Langone Health, where he is assistant professor of medicine and urology.

Although the new study shows that docetaxel therapy leads to a statistically significant benefit in OS and metastasis-free survival, the findings must be weighed against docetaxel-related toxicity. In this study, only 1.4% of the patients in AS plus RT arm suffered grade 4 adverse events (AEs) compared to 25.9% in the docetaxel arm, Dr Wise pointed out. The difference between the 2 arms was primarily related to greater hematologic toxicity, while the rates of gastrointestinal and genitourinary AEs were not significantly different between the 2 arms. Two grade 5 AEs toxicities were reported in the docetaxel arm and were possibly or probably related to acute respiratory distress syndrome and multi organ failure.

“Toxicity due to overtreatment is a particularly vexing problem in this population of men with disease that can be cured with standard treatment,” Dr Wise told Renal & Urology News. “The use of docetaxel will therefore likely continue to be restricted to the subset of patients who are best able to tolerate chemotherapy and who also have the highest risk disease.”

Anthony V. D’Amico, MD, PhD, professor of radiation oncology at Harvard Medical School and chief of genitourinary radiation oncology at Brigham and Women’s Hospital and Dana Farber Cancer Institute in Boston, said several randomized trials have addressed the use of upfront adjuvant chemotherapy in men with localized PCa and produced conflicting results. The Scandinavian trial SPCG-13 (Scandinavian Prostate Cancer Group) failed to show any benefit in biochemical DFS in a cohort of 378 men with intermediate-risk or high-risk disease randomly assigned to AS (12 months) plus adjuvant chemotherapy (6 cycles of docetaxel) versus AS alone.2 The SPCG-12 study did show a benefit in relapse-free survival (RFS) for 459 high-risk patients randomly assigned to radical prostatectomy (RP) plus adjuvant chemotherapy (6 cycles of docetaxel) compared with RP alone,3 but did not demonstrate a reduction in distant metastasis or death from PCa. Moreover, investigators found the RFS benefit only in men with Gleason score 7 disease, which is counter intuitive. Meanwhile, men with higher Gleason scores may respond differently to adjuvant docetaxel, which may explain the findings from the current study, he said. “This study has a lot more advanced patients with 9 and 10 Gleason scores,” Dr D’Amico said. “There may be a benefit, but given the conflicting data we need biomarkers that tell us which patient population benefits before adopting its use.”

If a patient is motivated and has very high-risk disease, and he and his physician are concerned that  radiation and hormones will not be enough, then this approach may be worth discussing, Dr D’Amico said. “I am not as worried about potential toxicity,” he said. “If we can find a population that benefits based on biomarkers, then I think the side effects are acceptable given the extended experience our medical oncology colleagues now have in the use of this agent.”

Steven E. Canfield, MD, professor of surgery at McGovern Medical School at The University of Texas Health Science Center at Houston and chief of urology at Memorial Hermann-Texas Medical Center in Houston, said the role of upfront chemotherapy in localized PCa is not a new concept, but previous trials largely have shown this approach to be ineffective in most clinical settings of localized disease. The new findings should be interpreted cautiously, he said. “The current study is at odds with a number of recent trials asking a very similar question, which did not show benefit,” Dr Canfield said.

References

1.     Rosenthal SA, Hu C, Sartor O, et al. Effect of chemotherapy with docetaxel with androgen suppression and radiotherapy for localized high-risk prostate cancer: The randomized phase III NRG Oncology RTOG 0521 Trial. 2019; published online ahead of print.

https://doi.org/10.1200/JCO.18.02158

2.     Kellokumpu-Lehtinen PI, Hjalm-Erickson M, Astrom L, et al. A randomised phase III trial between adjuvant docetaxel and surveillance after radical radiotherapy for intermediate and high-risk prostate cancer: Results of SPCG-13 trial. J Clin Oncol 36, 2018 (suppl; abstr 5000).

     https://ascopubs.org/doi/10.1200/JCO.2018.36.15_suppl.5000

3.     Ahlgren GM, Flodgren P, Tammela TLJ, et al. Surveillance after radical prostatectomy for high-risk prostate cancer: Results from the prospective randomised, open-label phase III Scandinavian Prostate Cancer Group 12 trial. Eur Urol 2019;73:870-876.

https://www.europeanurology.com/article/S0302-2838(18)30021-6/fulltext