Dr. Chi presents the final analysis of the LATITUDE phase III study. The initial results were presented at ASCO 2017.
As a reminder, the structure of the study was as follows: 1,199 pts were randomized 1:1 to either abiraterone acetate (AA) 1 g daily with 5 mg prednisone daily + ADT or double placebo + ADT. Only high-risk men were included, and were defined as meeting at least two of three criteria: (i) Gleason score ≥8, (ii) presence of ≥3 lesions on bone scan, (iii) presence of measurable visceral lesions. The co-primary endpoints were OS and radiographic progression-free survival (rPFS). Secondary endpoints included time to: (i) pain progression, (ii) PSA progression, (iii) next symptomatic skeletal event, (iv) chemotherapy, and (v) subsequent prostate cancer therapy. The study was conducted at 235 sites in 34 countries in Europe, Asia-Pacific, Latin America, and Canada.
The full study protocol is reviewed below:
The final analysis was planned for when the total death events were approximately 852. However, it should be noted that at the time of this presentation, the final analysis was conducted after a median follow-up of 51.8 mo (~22 mo from the first interim analysis and presentation of results) and when 618 deaths were observed (275 [46%] in AA+P arm and 343 [57%] in placebo arm). The authors noted that the preplanned event size of 852 deaths was no longer relevant as a criterion for superiority was met.
The baseline characteristics were pretty evenly matched across both groups and have been previously published. At the time of this presentation, treatment was ongoing for 157 (26.3%) men in AA+P arm. But, 72 (12.0%) men crossed over from placebo arm to the AA+P arm, of which 59 (81.9%) remained on treatment. For patients who went on to a second life-extending therapy, more patients in the placebo arm (57%) reported moving to second therapy than men in the AA+P arm (30%). Docetaxel was the most common 2nd life-extending therapy in both arms.
In terms of primary outcome, AA+P treatment continued to show significant OS benefits compared to placebo alone (53.3 months vs. 36.5 months in the placebo, HR: 0.66, 95% CI: 0.56-0.78; p<0.0001). Compared to an HR 0.62 in the initial presentation, this is slightly attenuated, but still significant. The KM curve is found below:
This is compared to the results of the first two interim analyses below:
This OS benefit was consistent across subgroup analyses.
There were also significant improvements in secondary endpoints, including: time to pain progression (HR 0.72, p = 0.0002), time to SREs (0.75, p = 0.018), time to chemotherapy initiation (HR 0.51, p<0.0001), time to subsequent therapy (HR 0.45, p<0.0001), and PFS2. PFS2 was a unique assessment of LATITUDE that evaluated to time to progression on second therapy – and this too was statistically improved with initial AA+P therapy (HR 0.58, p <0.0001).
The secondary endpoints are summarized in the table below:
An important post-hoc analysis compared outcomes based on disease volume – as per CHAARTED criteria. While there was a significant improvement in OS in men with high-volume disease (49.7 vs. 33.3 months, HR 0.62, p < 0.0001), there was NO significant difference in OS in men with low-volume disease (median OS NR in either arm, HR 0.72, p = 0.12). It should be noted that only 243 men met the low-volume inclusion criteria, while 955 men met the high-volume criteria. Hence, the sample size may be too small to capture any significant difference in the low-volume metastatic disease burden – there appears to be a separation in the OS curves, but the data may be immature. KM curves are seen below:
In terms of tolerability, serious AEs were reported in 27% of men in AA+P arm but only 20% in placebo arm. Overall AE rates were similar in both arms. Grade 3/4 AEs of special interest (AA+P vs PBO; %) were hypertension (22 vs 11), hypokalemia (12 vs 2), hepatotoxicity (9 vs 4), cardiac disorders (4 vs 1) and fluid retention (1 vs 1). These are all consistent with AA+P use. Three treatment-related deaths were noted in both treatment arms.
Based on this final analysis, Dr. Chi noted that AA+P continues to demonstrate a significant OS advantage over than ADT alone in men with newly hormone naïve metastatic prostate cancer. These efficacy findings and AE profiles are consistent with the first and second interim analyses and reinforce AA+P as a standard of care. Clinical trial information: NCT01715285
He lastly pointed out that the final analysis has now been accepted into Lancet Oncology and should be available shortly.
Presented by: Kim N. Chi, MD
Co-Authors: Karim Fizazi, Namphuong Tran, Luis Enrique Fein, Nobuaki Matsubara, Alfredo Rodríguez Antolín, Mustafa Ozguroglu, Dingwei Ye, Susan Feyerabend, Andrew Protheroe, Giri Sulur, Yesenia Luna, Susan Li, Suneel Mundle
Author Affiliations: Department of Cancer Medicine, Gustave Roussy Cancer Campus, Paris-Sud University, France, Villejuif, France; Janssen Research & Development, Los Angeles, CA; Instituto de Oncología de Rosário, Rosário, Argentina; Division of Breast and Medical Oncology, National Cancer Center Hospital East, Chiba, Japan; Hospital Universitario 12 de Octubre, Madrid, Spain; Cerrahpaşa Medical Faculty, Istanbul University, Istanbul, Turkey; Fudan University Affiliated Cancer Hospital, Shanghai, China; Studienpraxis Urologie, Nurtingen, Germany; Oxford University Hospitals Foundation NHS Trust, Oxford, United Kingdom; Janssen Research & Development, Spring House, PA; Janssen Research & Development, Raritan, NJ; BC Cancer Agency - Vancouver Centre, Vancouver, BC, Canada
Written by: Thenappan Chandrasekar, MD (Clinical Instructor, Thomas Jefferson University) (twitter: @tchandra_uromd, @JEFFUrology) at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA