During the proffered paper session focusing on prostate genitourinary malignancy at the European Society for Medical Oncology (ESMO) 2022 congress, Gerhardt Attard, MD, PhD, FRCP, the John Black Charitable Foundation Endowed Chair in Urological Cancer Research at University College London, offered results of a phase 3 trial as a component of the STAMPEDE platform trial. The presentation focused on comparing patients with newly diagnosed metastatic hormone-sensitive prostate cancer (mHSPC) undergoing initiation of androgen-deprivation therapy (ADT) with either abiraterone acetate plus prednisolone (AAP) or enzalutamide (ENZ) plus AAP.
Treatment Options for mHSPC
Current treatment options for patients with mHSPC include cytotoxic docetaxel1 chemotherapy regimens and use of androgen synthesis inhibitors such as AAP2 or androgen-receptor antagonists such as apalutamide3 and ENZ.4,5 At ESMO 2021, a presentation of updated results from the ARCHES trial (ADT+placebo vs ADT+ENZ), which provided support for using ENZ in the mHSPC setting, included findings on overall survival (OS), time to subsequent antineoplastic therapy, and safety outcomes. Patients enrolled in the original ARCHES5 trial all had mHSPC confirmed by bone scan, cross-sectional computed tomography/magnetic resonance imaging, and histologic confirmation. Patients were stratified by disease volume (low vs high) and prior docetaxel exposure (0, 1-5, or 6 cycles) before the trial was initiated. Patients in the ADT+ENZ arm of ARCHES enjoyed a significant OS improvement of 34% at 48 months compared with those in the placebo arm (71% vs 57%). Further subgroup analyses also demonstrated that patients, regardless of prior docetaxel exposure, received benefit. However, patients with visceral metastatic disease had worse outcomes.
ARCHES also demonstrated that ADT+ENZ was relatively safe, with the only major safety issues being a higher rate of hypertension and some concerns about cognitive impairment. Cardiovascular risks appeared to be low. Professor Attard began his presentation by noting that addition of AAP or ENZ to standard ADT for mHSPC has been shown to improve outcomes. He cited data demonstrating that treatment with AAP+ENZ6 in the metastatic castration-resistant prostate cancer (mCRPC) setting did little to demonstrate any improvement in OS despite a higher rate of adverse events (AEs) compared to use of ENZ alone. However, the AAP+ENZ combination did yield improvement in radiographic progression-free survival (rPFS). Despite these findings, the role of such a combination in the mHSPC setting remains unknown. Prof Attard briefly reviewed the STAMPEDE platform patient population by explaining that those enrolled in the trial are stratified into 2 groups: the M1 group (mHSPC) based on imaging, or the M0 group based on high-risk localized disease. Patients with significant cardiovascular disease are excluded. (A full description is available at stampedetrial.org.)
Phase 3 Trial Layouts
To further underscore the importance of the STAMPEDE platform, Prof Attard referred to the investigators’ presentation at ESMO 2021,7 which demonstrated the utility of combining AAP with ENZ in the high-risk M0 setting. The primary endpoint of that analysis was metastasis-free survival (MFS), which improved by 47% with AAP with or without ENZ compared with standard ADT (hazard ratio [HR], 0.53; 95% CI, 0.44-0.64). Further substratification comparing patients who received AAP+ENZ with those given AAP alone demonstrated no discernible clinical benefit.
Moving forward, Prof Attard explained the layout of the two phase 3 trials being compared in his group’s analysis. Standard of care (SOC) was defined as standard ADT with or without addition of docetaxel. A total of 501 participants in the AAP-alone trial were enrolled and treated between 2011-2013. In comparison, the AAP+ENZ trial enrolled and treated 462 participants between 2014- 2016. Prof Attard emphasized the lack of an overlapping control group between the 2 arms. The primary outcome of the analysis was OS. Characteristics of patients in both trials were well balanced. The median age was 68 years (interquartile range [IQR], 63-72) and the median prostate-specific antigen value was and 96 ng/mL (IQR, 26-346). Most patients had de novo mHSPC at diagnosis (94%), with a minority of patients (6%) diagnosed with disease after initial therapy. Prof Attard also explained that both trials had robust data at follow-up (AAP, 95.8 months; AAP+ENZ, 71.7 months).
STAMPEDE Trial Results
Prof Attard next reviewed the results of the trials. Both demonstrated significant OS benefit (HR, 0.62 for AAP and 0.65 for AAP+ENZ), but there was no significant difference in benefit between them. The subgroup analysis in each trial also demonstrated some interesting findings. In the AAP-only trial, there was a significant difference in OS between patients aged 70 (HR, 0.52 vs 0.83; P=0.002); however, no such difference was seen in the AAP+ENZ trial. A similar difference was seen in patients using nonsteroidal anti-inflammatory drugs (NSAIDs) or aspirin. In the AAP-only trial, patients taking aspirin or NSAIDs on a regular basis had a lower OS than those that who did not use these medications (0.78 vs 0.56; P=0.037); however, similar to the subgroup analysis for age, no difference was seen in the AAP+ENZ trial (0.63 vs 0.68; P=0.576). Prof Attard mentioned that, despite these findings, there is currently no biological explanation for this interaction between NSAIDs or aspirin and AAP or ENZ.
The final OS-related subgroup analysis that Prof Attard discussed concerned the utility of docetaxel. Specifically, later in the AAP+ENZ trial, investigators had the option of co-administering docetaxel with AAP+ENZ to investigate the potential for any significant drug to drug interactions between cytotoxic chemotherapy and AAP+ENZ. The current data suggest there are no significant interactions.
Regarding secondary outcomes, Prof Attard remarked that MFS was similar between the AAP (HR, 0.50) and AAP+ENZ trials (HR, 0.52), suggesting no significant treatment effect differences. He also discussed the findings on AEs with the medication combinations. Briefly, he explained that although AEs were similar between the AAP and AAP+ENZ trials, patients in the latter trial experienced them more frequently. Fatigue, transaminitis, and hypertension were noted in both groups, but hypertension occurred more frequently in the AAP+ENZ trial.
In concluding remarks, Prof Attard reviewed several key data points. Comparison of patients in the original SOC vs SOC+AAP trial, showed that the addition of AAP in these patients resulted in an 18% survival benefit at 84 months of follow-up (48% vs 30%, as demonstrated by event-free survival). The data from this analysis provide conclusive evidence that there is no discernible clinical benefit when using AAP+ENZ in the mHSPC setting, as the OS improvements mentioned above are durable with just AAP (in addition to SOC) at >7 years after treatment.
Akhil Abraham Saji, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include urology education and machine learning applications in urologic care. He is a founding and current member of the EMPIRE Urology New York AUA section team.
- Kyriakopoulos CE, Chen YH, 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(11): 1080-1087. doi: 10.1200/ JCO.2017.75.3657
- Fizazi K, Tran N, Fein L, et al; for the LATITUDE Investigators. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4): 352-360. doi: 10.1056/NEJMoa1704174
- Chi KN, Agarwal N, Bjartell A, et al; for the TITAN Investigators. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13-24. doi: 10.1056/NEJMoa1903307
- Davis ID, Martin AJ, Stockler MR, et al; for the ENZAMET Trial Investigators and the Australian and New Zealand Urogenital and Prostate Cancer Trials Group. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi: 10.1056/NEJMoa1903835
- 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(32): 2974-2986. doi: 10.1200/ JCO.19.00799
- Morris MJ, Heller G, Bryce AH, et al. Alliance A031201: a phase III trial of enzalutamide (ENZ) versus enzalutamide, abiraterone, and prednisone (ENZ/AAP) for metastatic castration resistant prostate cancer (mCRPC). J Clin Oncol. 2019;37(15 suppl):abstract 5008. doi: 10.1200/JCO.2019.37.15_suppl.5008
- Attard G, Brown LC, Clarke N, et al. Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (M0) prostate cancer (PCa): combined analysis from two comparisons in the STAMPEDE platform protocol. Ann Oncol. 2021;32(suppl):S1298. Abstract LBA4. doi: 10.1016/j.annonc.2021.08.2098