Metastatic Hormone-Sensitive Prostate Cancer Sees Treatment Paradigm Shift

Lancet Oncologyconcluded that docetaxel should be considered the new standard of care for men with hormone-sensitive metastatic prostate cancer.^1,2One of the studies included in this meta-analysis was recently published in theNew England Journal of Medicine, and its conclusions are echoed in the meta - analysis.³

The primary objective of this study was to determine whether overall survival would be longer for patients receiving docetaxel therapy at the commencement of androgen deprivation therapy versus patients receiving ADT alone (NCT00309985). The study was designed to ensure it had 80% power to detect a 33% difference in overall survival (OS) between the two groups. Secondary objectives included PSA levels, median time to disease progression, median time to development of castration-resistant prostate cancer, and safety. The study enrolled and randomized patients from July 2006 through December 2012. The cut - off date for survival in the publication was December 23, 2013. All other data were from the database as of December 23, 2014.³

Inclusion criteria mandated all eligible patients had a pathological diagnosis of prostate cancer or a clinical presentation of prostate cancer with an elevated prostate-specific antigen (PSA) level. Presence of disease had to be confirmed radiologically, and ECOG performance status of 0, 1, or 2. Prior adjuvant therapy was allowed, subject to timing of duration (≤24 months) and of progression following cessation of therapy (>12 months). Patients were enrolled if they were already taking docetaxel provided they did not experience progression and the treatment had begun within 120 days before randomization. Indices of organ function had to prove adequate for treatment with docetaxel.³

The Patients

Patients randomized to ADT alone were seen every 3 months. For those randomized to the combination, patients were seen every 3 weeks during the course of docetaxel, and once every 3 months thereafter. PSA was measured at every visit. A PSA level of <0.2 ng/mL on two consecutive measurements &ge;4 weeks apart was taken to indicate a complete serologic response. An increase in PSA >50% more than the nadir attained following the start of ADT (2 consecutive increases &ge;2 weeks apart) was taken to indicate serologic progression. Imaging was conducted at baseline and at the time of documented castration resistance or as medically indicated.^3'

The study randomized 790 patients, 397 to receive ADT alone or to ADT with docetaxel (75 mg/m²) every 3 weeks for 6 cycles and premedicated with dexamethasone (8 mg oral). Dose modification for ADT was not allowed, and no more than two were allowed for docetaxel (down to 65 mg/m²or 55 mg/m²). Administration of growth factors was left to the discretion of the investigators. Patient characteristics were evenly distributed between the two groups. Approximately 70% of patients had an ECOG performance score of 0, about 65% presented with high-volume disease, and about 60% had a Gleason score of &ge;8.

The median age of the patients in the ADT group was 63 years (39-91) and 64 years (36-88) in the docetaxel and ADT group. The majority of patients (73%) had received no prior curative local therapy. For the patients who had begun ADT therapy before randomization, the median time interval between the start of therapy to randomization was similar between the study arms at 1.2 months and 1.3 months for the combination arm and the ADT monotherapy arm, respectively.³

Results

About 86% of patients in the combination group completed the 6 cycles of therapy, and 74% did not require dose modification. The median follow-up was 28.9 months. Median OS was 57.6 months versus 44.0 months for patients receiving ADT and docetaxel or ADT alone, respectively (HR for death in combination group, 0.61; 95% CI 0.47-0.80;P<.001), a difference of 13.6 months. When analyzing data for the subgroup of patients with high-volume disease, at the final analysis, median OS was again superior in the combination therapy group versus the ADT-alone group at 49.2 months and 32.2 months respectively (HR for death, 0.60; 95% CI, 0,45-0.81;P<.001). Median survival for patients with low-volume disease had not been reached in either study arm; however, all subgroups analyzed showed benefit with docetaxel treatment. A total of 85 patients died in the combination group versus 114 in the ADT-alone group, all designated as prostate cancer deaths.³

Secondary efficacy endpoints also showed a benefit in the combination arm. The percentage of patients receiving combination therapy who achieved a decrease in PSA to less than 0.2 ng/mL was significantly greater than those receiving ADT alone.³

Another advantage for the combination arm became apparent for the median time to development of castration-resistant prostate cancer. Median time to development was 20.2 months versus 11.7 months for the combination and ADT-alone groups, respectively, (HR combination group, 0.61; 95% CI, 0.51-0.72;P<.001), and similarly for median time to clinical progression at 33.0 months versus 19.8 months for the combination and ADT-alone groups respectively (HR, 0.61; 95% CI, 0.50-0.75;P< .001).³

The study reported treatment-related grade 3 or 4 allergic reactions in the combination therapy group along with grade 3 fatigue in 4%. Occurring at rates of 1% or less were grade 3 diarrhea, stomatitis, motor neuropathy, and sensory neuropathy. Neutropenic fever occurred in 6% of patients in the combination group, and 2% had grade 3 or 4 infection with neutropenia.³

Promising Paradigm

The authors concluded that docetaxel with ADT, prescribed as per the study protocol, led to significantly longer OS than in men treated with only ADT in men with metastatic hormone-sensitive prostate cancer. These data and others included in the recent meta-analysis support combination therapy of docetaxel with ADT for men with metastatic, hormone-sensitive prostate cancer.^1-3

References

1. Vale CI, Burdett S, Rydzewska LHM, et al.Lancet Oncol. 2015; pii: S1470-2045(15)00489-1. doi: 10.1016/S1470-2045(15)00489-1.
2. TargetedOnc.com. Metastatic hormone-sensitive prostate cancer should include docetaxel alongside ADT.http://www.targetedonc.com/news/metastatic-hormone-sensitive-prostate-cancer-docetaxel-adt. Accessed January 27, 2016.
3. Sweeney CJ, Chen YH, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer.N Engl J Med. 2015;373(8):737-746.