Treatment intensification for high-risk localized prostate cancer: The time has come

Michael S. Cookson, MD, MMHC

Improved outcomes in men with advanced prostate cancer have been anchored to advances in hormonal therapy over the past 80 years. It is acknowledged that the pioneering work of Charles Huggins, MD, and Clarence V. Hodges, MD, in 1941 set the path for our understanding of androgen responsiveness of prostate cancer and the role of androgen deprivation therapy (ADT) in treatment of those with advanced and metastatic disease.¹

Approximately 50 years ago, the development of long-acting luteinizing hormone–releasing hormone (LHRH) agonists revolutionized the hormonal treatment of prostate cancer, allowing men treatment that could avoid the stigma associated with surgical castration and allow for intermittent therapy in certain clinical scenarios.² The development of first-generation nonsteroidal antiandrogens was another advancement that not only provided a mechanism to suppress the flare associated with LHRH agonists but also allowed for trials of combined androgen blockade with the addition of an antiandrogen as compared with LHRH or orchiectomy alone. However, the modest survival benefit of adding these antiandrogens to conventional testosterone suppression tempered widespread enthusiasm.^1,2

Although use of docetaxel chemotherapy was associated with benefit among men with castration-resistant prostate cancer, the real excitement for its use became evident when it was studied earlier in the disease state. The combination of chemotherapy and ADT in men with newly diagnosed metastatic disease was truly dramatic in its impact. The addition of docetaxel combined with LHRH therapy was a game changer, as it dramatically improved outcomes for men with newly diagnosed metastatic prostate cancer. Two trials—CHAARTED (NCT00309985) and STAMPEDE (NCT00268476)—both demonstrated improved overall survival with the addition of chemotherapy as compared with traditional ADT.^3,4 Shortly thereafter, the addition of androgen-targeted therapies combined with traditional LHRH demonstrated improved overall survival as compared to LHRH therapy alone. Both the LATITUDE (NCT01715285) and STAMPEDE trials demonstrated survival benefit with the addition of an androgen synthesis inhibitor (abiraterone [Zytiga] and prednisone) to traditional LHRH therapy.^5,6 Also, the addition of second-generation androgen receptor blockers (enzalutamide [Xtandi] and apalutamide [Erleada]) plus LHRH resulted in significant improved survival as compared with the LHRH therapy.^7,8 Currently, in the United States, there has been a tendency toward treatment with chemotherapy for those patients with high-volume metastatic burden, as well as androgen receptor–targeted therapy for those who have lower-volume metastatic disease and who are less fit for chemotherapy.

That brings us to the current state, where new data have revealed that patients with metastatic prostate cancer benefit from treatment intensification or triple therapy. In the PEACE-1 trial (NCT01957436), it was shown that the combination of docetaxel, LHRH, and abiraterone was superior to docetaxel plus LHRH therapy alone.⁹ In addition, the ARASENS trial (NCT02799602) demonstrated the combination of docetaxel, LHRH, and darolutamide (Nubeqa) was superior to docetaxel plus LHRH therapy, with significantly improved overall survival.¹⁰ Still to be decided is how to select patients for this treatment intensification coupled with the timing of the sequencing, of course weighing the potential increase in adverse effects.

These advances in androgen receptor–targeted therapy coupled with now chemotherapy are important and have significantly improved outcomes for men with metastatic disease. Over the years, we have improved the quality of life of men with advanced prostate cancer and have been able to extend the length of their lives by years. However, as exciting as these improvements have been, we are still facing the reality that we are not yet curing advanced or metastatic prostate cancer. We have seen the most impressive outcomes when 2 principles are adhered to: (1) treatment earlier in the disease state and (2) intensifying the treatment regimen.

However, earlier is a relative term and, in my opinion, not early enough. What we still need to trial is the use of treatment intensification or triple therapy in men with high-risk localized and/or locally advanced disease. The use of novel prostate-specific membrane antigen PET scans will allow for more accurate staging, and the opportunity for biomarker incorporation will allow for future patient selection. These studies could come in the form of neoadjuvant or adjuvant therapy prior to either surgery or radiation. The table is now set for a run at the elusive cure for men with truly high-risk disease. I certainly hope we don’t have to wait another half century to see this promise delivered to our patients.

References

1. Garnick MB. Hormonal therapy in the management of prostate cancer: from Huggins to the present. Urology. 1997;49(suppl 3A):5-15. doi:10.1016/s0090-4295(97)00163-5

2. Crawford ED. Hormonal therapy in prostate cancer: historical approaches. Rev Urol. 2004;6(suppl 7):S3-S11.

3. 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. doi:10.1056/NEJMoa1503747

4. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177. doi:10.1016/S0140-6736(15)01037-5

5. 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. doi:10.1056/NEJMoa1704174

6. James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate cancer not previously treated with hormone therapy. N Engl J Med.2017;377(4):338-351. doi:10.1056/NEJMoa1702900

7. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med.2014;371(5):424-433. doi:10.1056/NEJMoa1405095

8. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med.2019;381(1):13-24. doi:10.1056/NEJMoa1903307

9. 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(10336):1695-1707. doi:10.1016/S0140-6736(22)00367-1

10. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. New Engl J Med.2022;386(12):1132-1142. doi:10.1056/NEJMoa2119115