AUA 2023: First Update: Managing our Metastatic Hormone Sensitive Prostate Cancer Patients: Are We There Yet?

(UroToday.com) The 2023 American Urological Association (AUA) annual meeting held in Chicago, IL between April 28 and May 1st, 2023, was host to the International Prostate Forum, with Dr. Maha Hussain discussing the current management of patients with metastatic hormone sensitive prostate cancer (mHSPC).

Since 2015, we have seen the emergence of the treatment intensification approaches to the management of mHSPC patients, with doublet (ADT + docetaxel or androgen receptor signaling inhibitor [ARSI]) and triplet (ADT + docetaxel + abiraterone or darolutamide) approaches demonstrating survival benefits in this setting. The table below summarizes the current phase III trials that have demonstrated a survival benefit in this setting:

Published in 2015, the CHAARTED trial randomized mHSPC men to either ADT plus docetaxel (75 mg/m²) versus ADT alone. At a median follow-up of 29 months, the median OS was prolonged from 44 to 58 months with docetaxel treatment intensification (HR: 0.61, 95% CI: 0.47 – 0.80, p<0.001).¹

An updated report in 2018, at a median follow-up of 54 months, demonstrated OS benefits in the high-volume disease (HR: 0.63, 95% CI: 0.50 – 0.79), but not the low-volume disease group (HR: 1.04, 95% CI: 0.70 – 1.55).

Next, the LATITUDE trial randomized mHSPC patients to ADT + abiraterone acetate/prednisone versus ADT alone. The initial report in 2017 demonstrated an OS benefit in the intervention arm, with 3-year OS improved from 49 to 66% (HR: 0.62, 95% CI: 0.51 – 0.76).³

Updated analysis reported in 2019 at a median follow-up of 52 months, demonstrated a 34% decreased any-cause mortality rate with combination abiraterone/ADT with a median OS improvement from 37 to 53 months.⁴

The ENZAMET trial evaluated the combination of enzalutamide + ADT versus ADT + non-steroidal anti-androgen (an “active” control arm). The final OS data was recently published in The Lancet Oncology. At a median follow-up of 68 months, the 5-year OS was improved from 57% to 67% (HR: 0.70, 95% CI: 0.58 – 0.84).⁵

The ARCHES trial of enzalutamide + ADT versus ADT alone (no NSAA), demonstrated a 34% reduction in all-cause mortality rates (HR: 0.66, p<0.001), at a median follow-up of 45 months.⁶

Similar results were observed with the addition of apalutamide to ADT in the TITAN trial, with a 35% reduction in the hazard of all-cause mortality with the combination regimen (HR: 0.65, p<0.0001) after a median follow-up of 44 months.⁷

We next witnessed the emergence of triplet therapy regimens with the PEACE-1 trial that evaluated the addition of abiraterone acetate to ADT + docetaxel in mHSPC patients. This regimen was shown to have an OS benefit in the high-volume (HR: 0.72, 95% CI: 0.55 – 0.95, p=0.019), but not the low-volume group (HR: 0.83, 95% CI: 0.50 – 1.39, p=0.66).⁸

About 45% of patients in the ENZAMET trial had planned use of docetaxel following randomization. As such, some have argued that this was the first trial evaluating triplet therapy in this disease space. The most recent report published in 2023 included a pre-specified OS analysis by timing of presentation (synchronous or metachronous) in patients receiving docetaxel. This analysis suggests that the triplet combination of docetaxel/enzalutamide/ADT may be most beneficial in the patients with synchronous (i.e., de novo) metastatic disease (HR: 0.73, 95% CI: 0.55 – 0.99), with no observed benefit in the metachronous (i.e., recurrent) group (HR: 1.10, 95% CI: 0.65 – 1.86).⁵

ARASENS was the third trial to evaluate triplet therapy for mHSPC patients with patients randomized to docetaxel/ADT +/- darolutamide. This triplet combination demonstrated an OS benefit with a 32% decreased mortality rate (HR: 0.68, 95% CI: 0.57 – 0.80).⁹

   
Recently, survival outcomes from ARASENS stratified by CHAARTED volume and LATITUDE risk criteria were published in The Journal of Clinical Oncology. Among patients in the ARASENS cohort, 77% and 70% had CHAARTED high-volume and LATITUDE high-risk disease, respectively.   
As seen in the Kaplan Meier plots above, the OS benefit appears to be most pronounced in the CHAARTED high-volume cohort (HR: 0.69, 95% CI: 0.57 – 0.82), compared to those in the low-volume group (HR: 0.68, 95% CI: 0.41 – 1.13). Conversely, an OS benefit was observed in both the LATITUDE high (HR: 0.71, 95% CI: 0.58 – 0.86) and low risk groups (HR: 0.62, 95% CI: 0.42 – 0.90). Prolongation of time-to-castration was observed in all volume/risk groups.

Dr. Maha Hussain concluded this overview of treatment intensification in the mHSPC disease space as follows:

• Doublet therapy: ADT + docetaxel and ADT + ARSI are both superior to ADT alone
  • Docetaxel benefit observed mainly in high-volume disease patients
• Triplet therapy
  • PEACE-1 (docetaxel subgroup): Abiraterone + docetaxel + ADT improved OS compared to docetaxel + ADT
    • rPFS is improved for low-volume patients. OS data is not yet mature but there is a trend
  • ENZAMET (docetaxel subgroup): Enzalutamide + docetaxel + ADT versus docetaxel + ADT:
    • OS benefits with enzalutamide most pronounced in patients with synchronous mHSPC
  • ARASENS: Darolutamide + docetaxel + ADT versus docetaxel + ADT improved OS (benefit is observed across the disease volume and risk criteria)

Presented by: Maha Hussain, MD, FACP, FASCO, Genevieve Teuton Professor of Medicine in the Division of Hematology-Oncology, Department of Medicine, Northwestern University, Chicago, IL

Written by: Rashid K. Sayyid, MD, MSc – Society of Urologic Oncology (SUO) Clinical Fellow at The University of Toronto, @rksayyid on Twitter during the 2023 American Urological Association (AUA) Annual Meeting, Chicago, IL, April 27 – May 1, 2023

1. 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.
2. 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 Apr 10;36(11):1080-1087.
3. Fizazi K, Tran N, Fein L, et al. Abiraterone plus Prednisone in Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. 2017;377(4):352-360.
4. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): Final overall survival analysis of a randomized, double-blind, phase 3 trial. Lancet Oncol 2019 May;20(5):686-700.
5. Sweeney CJ, Martin AJ, Stockler MR, et al. Testosterone suppression plus enzalutamide versus testosterone suppression plus standard antiandrogen therapy for metastatic hormone-sensitive prostate cancer (ENZAMET): an international, open-label, randomised, phase 3 trial. Lancet Oncol 2023;24(4):323-334.
6. Armstrong AJ, Azad AA, Iguchi T, et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol 2022;40(15):1616-1622.
7. Chi KN, Chowdhury S, Bjartell A, et al. Apalutamide in patients with metastatic castration-sensitive prostate cancer: Final survival analysis of the randomized, double-blind, phase III TITAN study. J Clin Oncol. 2021 Jul 10;39(20):2294-2303.
8. Fizazi K, Foulon S, Carles J, Roubaud G, 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, randomized, phase 3 study with a 2 x 2 factorial design. Lancet. 2022 Apr 30;399(10336):1695-1707.
9. Smith MR, Hussain M, Saad F, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022 Mar 24;386(12):1132-1142.
10. Hussain M, Tombal B, Saad F, et al. Darolutamide plus androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase III ARASENS trial. J Clin Oncol. 2023 Feb 16