ADT-Based Combinations Have Become Standard Therapy for Metastatic Castration-Sensitive Prostate Cancer

Robert Dreicer, MD, MS, MACP, FASCO

Overwhelming evidence has pointed to the use of androgen deprivation therapy (ADT) in combination with 1 or 2 other agents as the standard of care for patients with metastatic castration-sensitive prostate cancer (mCSPC), according to Robert Dreicer, MD, MS, MACP, FASCO.

Evidence from clinical trials exploring ADT in doublets or triplets with various agents, such as chemotherapy or androgen receptor (AR) inhibitors, has demonstrated combination therapies provide more benefits than ADT alone, Dreicer said. He noted optimal treatment selection should be determined by disease and non-disease factors of each patient, not comparative trial evidence.

“It’s not to say that no patients should be managed with primary ADT,” Dreicer, deputy director, UVA Cancer Center, director, Solid Tumor Oncology in the Division of Hematology/Oncology, and a professor of medicine and urology, University of Virginia Health System, said in a presentation at the 15th Annual Interdisciplinary Prostate Cancer Congress^® and Other Genitourinary Malignancies.¹ “The reality is [ADT alone] should be the rare exception [rather] than the rule. It should not be the other way around, given the benefit that we’ve been seeing [with combinations].”

Four agents are currently approved for the treatment of patients with mCSPC. Docetaxel was approved based on findings from the phase 2/3 STAMPEDE trial (NCT00268476) and phase 3 CHAARTED trial (NCT00309985).^2,3 Abiraterone acetate (Zytiga) received approval based on the results of the phase 3 LATITUDE (NCT01715285) and STAMPEDE trials.^4,5 Additionally, apalutamide (Erleada) was approved based on data from the phase 3 TITAN trial (NCT02489318)⁶, and enzalutamide (Xtandi) earned approval based on findings from the phase 3 ARCHES (NCT02677896) and ENZAMET (NCT02446405) trials.^7,8

Defining mCSPC involves several factors, which can affect treatment decisions, Dreicer noted. Hormone- or castration sensitive does not always mean a patient is naïve to hormonal therapy. Additionally, mCSPC is a heterogeneous disease state, where it can be classified as de novo or recurrent metastatic disease. Additionally, mCSPC can be defined as oligometastatic or polymetastatic, and imaging can be conducted through conventional means with a CT scan or next-generation imaging with a PSMA-based PET/CT scan or use of fluciclovine F18 and other PET agents.

Furthermore, mCSPC can also be classified as high- or low-volume disease. High-volume disease features the presence of visceral metastases, plus 4 or more bone lesions with at least 1 beyond the vertebral bodies and pelvis.⁹ Moreover, high-risk disease can be identified in patients who have 2 of 3 of the following: a Gleason score of 8 or more; at least 3 lesions on the bone scan; and the presence of visceral metastases.⁴

Treatment combinations with ADT backbones have demonstrated overall survival (OS) benefits across multiple trials, both in high-volume/high-risk and low-volume/low-risk disease, Dreicer said. “AR pathway inhibitors from a number of different compounds showed a profound impact on OS,” Dreicer added.

Chemohormonal therapy with ADT plus docetaxel produced OS benefits in both the CHAARTED and STAMPEDE trials. In CHAARTED, the addition of docetaxel elicited a median OS of 57.6 months vs 44.0 months with ADT alone (HR, 0.61; 95% CI, 0.47-0.80; P < .001).⁹ Furthermore, in STAMPEDE a median OS of 81 months (interquartile range [IQR], 41–not reached [NR]) was achieved with docetaxel plus ADT vs 71 months (IQR, 32-NR) with ADT alone (HR, 0.78; 95% CI, 0.66-0.93; P = .006).²

However, long-term follow-up from CHAARTED demonstrated a bigger benefit of ADT plus docetaxel for patients with high-volume disease.³ For patients with high-volume disease, the median OS was 51.2 months for ADT plus docetaxel vs 34.4 months for ADT alone (HR, 0.63; 95% CI, 0.50-0.79; P < .001). Conversely, patients with low-volume disease had a median OS of 63.5 months with docetaxel plus ADT; the median OS was NR for ADT alone (HR, 1.04; 95% CI, 0.70-1.55; P = .86).

“As we talk about treatment selections, we don’t have a lot of ways to separate making treatment decisions, but there is, at least with [docetaxel], a way to decide who may be a great candidate,” Dreicer explained.

Abiraterone also demonstrated an OS benefit in LATITUDE and STAMPEDE. In LATITUDE, the OS for ADT plus abiraterone and prednisone was NR compared with 34.7 months for ADT plus placebo (HR, 0.62; 95% CI, 0.51-0.76; P < .001).⁴

In STAMPEDE, the cohort treated with ADT plus abiraterone and prednisolone experienced 184 deaths compared with 262 in the ADT-alone group (HR, 0.63; 95% CI, 0.52-0.76; P < .001).5 Additionally, the cohorts of ADT plus docetaxel and ADT plus abiraterone and prednisolone produced a HR of 1.16 for OS (95% CI, 0.82-1.65; P = .40).¹⁰

“Although this is not a formal statistical comparison, it does involve similar patients accrued over a frame of time and gives some confidence that you’re not picking 1 drug that is better or worse than the other,” Dreicer said.

Several factors affect therapeutic decisions for patients with mCSPC. Regarding clinical factors, fitness for chemotherapy, AR inhibitors, and abiraterone should be considered. Frailty and comorbidities can define a patient’s fitness for an AR inhibitor, and blood sugar, cardiac history, and liver disease can play a role in a patient’s fitness for abiraterone. Patients with low-volume disease are more suited for an AR inhibitor or abiraterone, and patients with high-volume disease could benefit from docetaxel, an AR inhibitor, or abiraterone, Dreicer noted.

Patient preference can also affect therapy decisions, Dreicer added. Duration of therapy, aversion to pills or chemotherapy, quality of life (QOL), and economics all play a role.

“We do have good long-term follow-up from many of these studies with regard to QOL,” Dreicer said. “Fortunately, these therapies can be safely administered without meaningful impact on QOL.”

Research continued into possible combinations with ADT with the addition of enzalutamide in ENZAMET.⁸ Notably, this trial stratified patients based on high- or low-volume disease, and prior treatment with docetaxel was permitted. Patients received either ADT plus enzalutamide or ADT plus bicalutamide, nilutamide, or flutamide. At 36 months, 80% (95% CI, 75%-83%) of patients in the enzalutamide arm were still alive compared with 72% (95% CI, 68%-76%) in the non-enzalutamide arm (HR, 0.67; 95% CI, 0.52-0.86; log-rank P = .002).

Other trials have explored the addition of a third agent to ADT and docetaxel. The phase 3 PEACE-1 trial (NCT01957436) evaluated 4 arms of patients with de novo mCSPC. Patients were randomized to either ADT and docetaxel alone; ADT and docetaxel plus abiraterone and prednisone; ADT and docetaxel plus radiotherapy; or ADT, docetaxel, abiraterone, prednisone, and radiotherapy.¹¹ The abiraterone arm generated a median OS of 5.7 months (95% CI, 5.1–not evaluable [NE]) compared with 4.7 months (95% CI, 4.3-5.3) for the ADT and docetaxel alone arm (HR, 0.82; 95% CI, 0.69-0.98; P = .030).

The phase 3 ARASENS trial (NCT02799602) explored the addition of darolutamide (Nubeqa) to ADT and docetaxel vs ADT and docetaxel alone. Darolutamide reduced the risk of death by 32.5%, with that arm achieving a median OS that was NE (95% CI, NE-NE) compared with 48.9 months (95% CI, 44.4-NE) in the placebo plus ADT and docetaxel arm (HR, 0.68; 95% CI, 0.57-0.80; P < .001).¹²

As more agents have been added to the ADT backbone, median OS has improved for this patient population. Based on the results from PEACE-1 and ARASENS, the survival rates for those triplets are expected to exceed ADT alone, ADT plus docetaxel, and ADT plus abiraterone, Dreicer said.

The progress that is being made with additional [treatment] intensification is real,” Dreicer said. “We are just going to have to figure out which of the patients make sense [for each regimen to determine optimal treatment].”

References

1. Dreicer R. Initial therapy for management: metastatic prostate cancer. Presented at: New York GU 15th Annual Interdisciplinary Prostate Cancer Congress® and Other Genitourinary Malignancies; March 11-12, 2022; virtual. Accessed March 12, 2022.
2. 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
3. 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
4. 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
5. 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
6. 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
7. 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
8. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121-131. doi:10.1056/NEJMoa1903835
9. 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
10. Sydes MR, Spears MR, Mason MD, et al. Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Ann Oncol. 2018;29(5):1235-1248. doi:10.1093/annonc/mdy072
11. Fizazi K, Maldonado X, Foulon S, et al. A phase 3 trial with a 2x2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): first results of PEACE-1. J Clin Oncol. 2021;39(suppl 15):5000. doi:10.1200/JCO.2021.39.15_suppl.5000
12. Smith MR, Hussain MHA, Saad F, et al. Overall survival with darolutamide versus placebo in combination with androgen-deprivation therapy and docetaxel for metastatic hormone-sensitive prostate cancer in the phase 3 ARASENS trial. J Clin Oncol. 2022;40(suppl 6):13. doi:10.1200/JCO.2022.40.6_suppl.013