A main question is whether the benefit in terms of OS and PFS seen between triplet therapy vs. docetaxel plus ADT holds true also vs. AAB plus ADT. In other words, is docetaxel needed? As a matter of fact, the two trials, ARASENS and PEACE-1, have used docetaxel and not AAB in the control arm, despite emerging evidence that AABs might be more effective than docetaxel in unselected mHSPC population in terms of both PFS and OS.3 To complicate the scenario, among those randomized control trials testing the use of single AAB, early (or even concomitant) docetaxel use was allowed in a non-uniform proportion of enrolled patients in the TITAN, ARCHES, and ENZAMET trials.4–6
To disentangle this question, we conducted a systematic review and meta-analysis on chemotherapy and AAB alone or combine for men with mHSPC.7 To do so, we relied on survival data reconstruction. We were able to digitalize the Kaplan-Meier curves for PFS and OS and to extrapolate quasi-individual survival data, i.e. for each individual the time from randomization to either censoring or event and the event or censoring itself (more info on the methods can be found here: https://twitter.com/AlbertoMartini_/status/1558473225063071744).
We then analyzed the data from triplet therapy vs. the current standard of care (either docetaxel or AAB). To have a deeper insight into the treatment landscape, we performed several sensitivity analyses, firstly separating AAB from docetaxel, to test the hypothesis that a difference might exist between the two treatments compared to triplet therapy. Second, given that three RCTs allowed the early use of docetaxel before AAB, that the shown effect size might be affected by this sequential therapy, and that the published Kaplan-Meier curves for early-docetaxel versus non-docetaxel subgroups were not available in all the studies, a sensitivity analysis was conducted by splitting AAB studies allowing early docetaxel use vs those not allowing early docetaxel. Additionally, a third sensitivity analysis was conducted on PFS alone, after the exclusion of ARASENS since this study did not report data on clinical or radiological PFS, but only on time to CRPC.
The method used in our meta-analysis is innovative and, different relative to the standard network meta-analysis based on Hazard Ratios does not rely on proportionality of hazard assumption, and allows the use of restricted mean survival time (RSMT), which translates into the clinically meaningful message of mean gained months of survival from the event (progression or death).
Ten trials were included involving 5,544 patients for assessing OS and 5,725 for PFS. Patients receiving triplet therapy exhibited similar OS compared to either treatment alone, with a RSMT at 48 months of 0.3 month (95% Confidence Interval [CI]: -0.7-1.2; p=0.6). Patients receiving triplet therapy exhibited longer PFS compared to AAB or chemotherapy alone, with RSMT at 48 months of 5.3 months (95%CI: 4.2-6.5; p<0.001).
In addition, we found that triplet therapy was associated with longer OS when compared to docetaxel (48-month RSMT: 2.6 months; 95%CI 1.8-3.4; p<0.001) but yielded similar OS when compared to AAB (48-month RSMT: -0.8 month; 95CI: -1.6–0.2; p=0.1). Similarly, triplet therapy was associated with longer PFS when compared to docetaxel (48-month RSMT: 10.3 months; 95CI: 9.0-11.6; p<0.001) but yielded similar PFS when compared to AAB (48-month RSMT: 1.1 months; 95CI: -0.2–2.3; p=0.1).
The sensitivity analysis showed a statistically significant difference in terms of OS in favor of AAB with or without early docetaxel versus triplet therapy or abiraterone alone or docetaxel alone, which has the lower OS. Regarding PFS, there was no statistically significant difference for AAB with or without early docetaxel versus triplet therapy. Yet, there was a significant difference in favor of triplet therapy or AAB with or without early docetaxel relative to abiraterone alone and docetaxel alone. Finally, excluding the ARASENS which did not report data on clinical or radiological PFS, but only on time to CRPC, triplet therapy yielded similar PFS compared to AAB alone plus ADT.
Several considerations might be raised from our results. First, the benefit in terms of gained months ( RSMT) for all the oncological outcomes determined by triplet therapy appeared clinically minimal compared to the current standard of care, also in view of increased economic costs for healthcare providers and adverse events rates. In addition, our findings suggest that the longer OS and PFS observed with triplet therapy relative to docetaxel alone could be driven by AAB, rather than combination itself. An intriguing hypothesis is that the OS and PFS benefit in favor of triplet therapy observed in the PEACE-1 and ARASENS trials might be driven by data from men with high-volume disease, despite we were not able to have data from Kaplan-Meier curves in these subgroups. In support of this hypothesis, subgroup analyses of the trials on docetaxel indicated that improved survival is evident only for men with high- volume disease (visceral disease, ≥ 4 bone metastases with ≥ 1 metastases outside of the vertebral bodies/pelvis).8–10
The main limitation of our study relied on the high heterogeneity of patient populations included in the different randomized trials, with high variability in the proportions of patients with high burden disease, with de-novo or metachronous mHSPC, and with different ECOG performance status.
In conclusion, our findings challenge the conclusions of the ARASENS and PEACE-1 trials which suggested combination therapy as the new standard of care for mHSPC and prompt further trials to better address the role of triplet therapy in mHSPC.
Written by: Giuseppe Fallara, MD, Department of Urology, IRCCS San Raffaele Scientific Institute, Milan, Italy
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- Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. New Engl J Med 2022; 386: 1132–42.
- Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 2022; 399: 1695–707.
- Naqvi SAA, Riaz ZB, Riaz A, et al. Triplet therapy in metastatic castration-sensitive prostate cancer: A systematic review and meta-analysis. J Clin Oncol 2022; 40: 136–136.
- Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. New Engl J Med 2019; 381: 121–31.
- Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 2019; 37: 2974–86.
- Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. New Engl J Med 2019; 381: 13–24.
- Fallara G, Robesti D, Nocera L, et al. Chemotherapy and Advanced Androgen Blockage, Alone or Combined, for Metastatic Hormone-Sensitive Prostate Cancer A systematic review and Meta-Analysis. Cancer Treat Rev 2022; 110: 102441.
- Kyriakopoulos CE, Chen Y-H, Carducci MA, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer: Long-Term Survival Analysis of the Randomized Phase III E3805 CHAARTED Trial. J Clin Oncol 2018; 36: JCO.2017.75.365.
- Gravis G, Fizazi K, Joly F, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol 2013; 14: 149–58.
- Clarke NW, Ali A, Ingleby FC, et al. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol 2019; 30: 1992–2003.
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