The addition of mitoxantrone and prednisone to adjuvant androgen deprivation therapy after radical prostatectomy did not extend survival among men with high-risk prostate cancer, according to results of the randomized phase 3 SWOG S9921 trial.
The addition of mitoxantrone also appeared associated with a higher number of deaths due to other malignancies.
Adjuvant ADT may reduce the risk for death among men with high-risk prostate cancer after radical prostatectomy.
Hussain, MD, FACP, FASCO, deputy director of Robert H. Lurie Comprehensive Cancer Center at Northwestern University and a HemOnc Today Editorial Board Member, and colleagues hypothesized the addition of mitoxantrone and prednisone to adjuvant ADT may reduce mortality compared with ADT alone.
“This trial was designed to select high-risk prostate cancer based on the standards at the time of study design — criteria that are still predictive for high-risk disease by today’s standards,” Hussain told HemOnc Today. “In the 1990s, emerging data from randomized phase 3 trials indicated clear OS advantage to longer duration adjuvant androgen deprivation in combination with radiation in high-risk prostate cancer and in the setting of node-positive disease after radical prostatectomy, thus providing evidence to support the impact of ADT on systemic micrometastases.”
Hussain and colleagues conducted a phase 3 trial that included 961 men with high-risk prostate cancer, all of whom underwent radical prostatectomy within 120 days of trial enrollment.
All men had cT1-3N0M0 prostate cancer and had at least one high-risk factor after radical prostatectomy. Those factors included pathologic Gleason score of 8 or higher; pT3b, pT4 or N1 disease; pathologic Gleason score of 7 and positive margins; or any of the following preoperative findings for patients who received neoadjuvant ADT: preoperative PSA higher than 15 ng/mL, biopsy Gleason score higher than 7, or PSA higher than 10 ng/mL with biopsy Gleason score higher than 6.
Patients also were required to have a postoperative PSA level of 0.2 ng/mL or lower before receiving hormonal therapy.
Researchers randomly assigned patients to 2 years of adjuvant ADT alone, or in combination with mitoxantrone and prednisone.
OS served as the primary outcome.
Median follow-up was 11.2 years.
Researchers reported estimated 10-year OS of 87% among men assigned ADT alone — significantly higher than the pretrial estimate of 50% — and 86% for those assigned ADT plus mitoxantrone plus prednisone (HR = 1.06; 95% CI, 0.79-1.43).
Estimated 10-year DFS was 72% in each group.
Eighteen percent of patients assigned ADT alone and 22% assigned the experimental combination died of prostate cancer.
An additional 18% of those assigned ADT alone and 36% of those assigned the combination died of other cancers.
“Based on cumulative data supporting adjuvant ADT for high-risk patients undergoing external beam radiation therapy, pN1 postradical prostatectomy and the data from S9921 men with high-risk prostate cancer, postradical prostatectomy should be counseled regarding the pros and cons of considering 2 years of adjuvant ADT,” Hussain said. “Considering the observed long median survival among high-risk prostate cancer patients, it is critical to incorporate validated intermediate endpoints into future trial design for evaluation of systemic therapy; however, trials should have adequate follow up for OS.”
However, the findings are not sufficient to change practice, according to Oliver Sartor, MD, C.E. and Bernadine Laborde professor of cancer research at Tulane University and medical director of Tulane Cancer Center, who wrote an accompanying editorial.
“What do the authors of SWOG S9921 conclude?” Sartor wrote. “First, mitoxantrone provided no benefit. Second, the observed OS was improved relative to pretrial estimates. Third, only approximately 20% of the deaths were attributable to prostate cancer. Whether these better-than-expected observations were a result of patient selection, 2 years of ADT, stage migration or various postprotocol therapies cannot be ascertained.”
He also called the researchers’ decision to assign the control group to 2 years of ADT after radical prostatectomy “a controversial choice” because data to support it were not available at the time of trial initiation, nor are they available now.
“Should SWOG S9921 change practice? At this time, without the appropriate control group, one cannot conclude that these better-than-expected outcomes were attributable to ADT,” Sartor added. “Are they provocative? Yes. Are they practice changing? No.” – by Andy Polhamus
For more information:
Hussain, MD, FACP, FASCO,
can be reached at 303 E. Superior St., Suite 3-107, Chicago, IL 60611; email: firstname.lastname@example.org.
Disclosures: Hussain reports honoraria from OncLive and Sanofi; research funding to her institution from AstraZeneca, Bayer, Genentech, Pfizer and Prostate Cancer Clinical Trials Consortium; and travel, accommodations and expenses from Sanofi. Please see the study for all other author’s relevant financial disclosures. Sartor reports consultant/advisory roles with Advanced Accelerator Applications, AstraZeneca, Bavarian Nordic, Bayer, Blue Earth, Bristol-Myers Squibb, Constellation Pharmaceuticals, Dendreon, EMD Serono, Endocyte, Johnson & Johnson, Oncogenex and Sanofi; research funding to his institution from Bayer, Endocyte, Johnson & Johnson, Innocrin, Merck and Sanofi; and travel, accommodations and expenses from AstraZeneca, Bayer, Blue Earth, Johnson & Johnson, Medivation, Progenics and Sanofi.