KEY TAKEAWAYS
- This phase 3 study analyzed COU-AA-302 and ACIS trials to determine if TTrP and rPFS can be used as ICE.
- 2,016 mCRPC patients in COU and ACIS trials showed Abiraterone, with or without apalutamide, improved TTrP and OS.
- The treatment effect on rPFS & OS and TTrP & OS were correlated with average R2 of 0.84, 0.84, 0.85, and 0.86, respectively.
- TTrP and rPFS showed a positive correlation with OS in the overall cohort and Abi/Abi+apa groups.
- The study suggests that TTrP and rPFS can predict survival in chemo-naïve mCRPC patients. However, more studies are needed to confirm these findings. Also, these results may not apply to patients who have already received chemotherapy for mCRPC.
In randomized trials of treatment for mCRPC, rPFS is frequently employed as an Indicator for OS. However, the existing research on the effectiveness of rPFS as a surrogate for OS presents mixed findings. As TTrP does not count death as an event, it is unclear whether or not it constitutes an ICE for OS. To determine if TTrP and rPFS are suitable for use as ICE, they analyzed both COU-AA-302 and ACIS data simultaneously. Patients with metastatic castration-resistant prostate cancer (mCRPC) who had not previously received docetaxel were randomized to receive either abiraterone (abi) or a placebo in the COU trial. The ACIS study assigned a comparable patient group to receive either abi or abi plus apalutamide (abi+apa).
To assess whether the treatment’s impact on survival is mediated by its impact on radiographic progression, the investigators employed weighted Cox regression models and landmark analyses. The ICE was correlated with OS using a semiparametric Spearman test. To do this, we first estimated the treatment effect on ICE and OS at the center level for each of the 2 trials, and then we calculated the modified R2 between these center-level estimates. The technique of generating pseudo-trial centers was carried out 500 times, and the reported R2 is the mean across all 500 iterations, with negative associations removed.
A total of 2016 patients met the study’s inclusion criteria, 1053 from the COU and 963 from the ACIS. The TTrP and OS were better in those with Abi (HR 0.55 [95%CI 0.45-0.66]). (HR 0.80 [0.70-0.92]). Results with abi+apa were comparable (0.51 [0.41-0.64], 0.77 [0.65-0.91]). In the state arrival extended Markov proportional hazard model, radiographic advancement was associated with a significantly higher hazard of death (3.64 [1.54-8.62]), while prolonged TTrP was associated with a decreased hazard of death (0.94 [0.93-0.95]). The entire cohort found an association of 0.58 [0.54-0.63] between TTrP and OS and 0.68 [0.65-0.71] between rPFS and OS at the patient level.
The TTrP-OS and rPFS-OS correlations were (0.50-0.66) and (0.67-0.75) and (0.79-0.74) in the abi and abi+apa groups, respectively. Treatment effects on rPFS and OS and TTrP and OS were connected with average R2 values of 0.84, 0.84, 0.85, and 0.86 at the trial level. With respect to HRrPFS and HRTTrP, the mean surrogate threshold effect across 500 permutations was 0.78 and 0.70 in the ACIS trials and 0.54 and 0.45 in the COU-AA-302 trials, respectively. In chemo-naive patients with mCRPC, TTrP, and rPFS were observed to have a significant relationship with OS. At the trial level, we observed a moderate to the high relationship between the treatment effect on ICE and OS. Verifying these results will need larger-scale meta-analyses.
Source: https://meetings.asco.org/abstracts-presentations/216895
Clinical trial: https://clinicaltrials.gov/ct2/show/NCT02257736/
Roy S, Sun Y, Spratt D, Morgan S, Kim T, Malone J, Wallis C, Kishan A, Saad F, Malone S. Radiographic progression-free survival (rPFS) and time to radiographic progression (TTrP) as surrogate endpoints in docetaxel-naïve metastatic castrate resistant prostate cancer (mCRPC): A pooled analysis of COU-AA-302 and ACIS. J Clin Oncol 41, 2023 (suppl 6; abstr 136)
