Triplet vs SOC Explored in Metastatic Prostate Cancer

In the metastatic hormone-sensitive prostate cancer (mHSPC) setting, treatment approaches are rapidly evolving, sparking ongoing debate among clinicians about the efficacy of doublet vs triplet therapy. During the Debates and Didactics in Hematology and Oncology Conference held July 25 to 28, 2024, at Sea Island, Georgia, Bassel Nazha, MD, MPH; and Jordan Ciuro, MD, discussed the advantages and disadvantages of triplet vs doublet approaches.¹

Triplet therapy, composed of androgen deprivation therapy (ADT), androgen receptor pathway inhibitors (APRIs), and docetaxel, “is the most effective therapy and it is the one we should consider first in patients with mHSPC,” said Nazha, an assistant professor, Department of Hematology and Medical Oncology, Emory University School of Medicine, and medical oncologist at Winship Cancer Institute of Emory University, both in Atlanta, Georgia.

Ciuro, an assistant professor of medicine, Medical College of Georgia, and a medical oncologist at Augusta University Medical Center, both in Augusta, Georgia, argued that “there is still a role for doublet therapy in metastatic castrate- sensitive prostate cancer.”

Nazha opened the discussion acknowledging that the use of ADT and ARPIs is currently the most common approach in this setting. But the addition of docetaxel leads to improved survival through intensification of treatment, a multitargeted strategy, and comprehensive disease control.

“Importantly, a triplet therapy approach targets early disease resistance through nonoverlapping mechanisms,” Nazha said.² The landmark phase 3 trials supporting the use of triplet therapy are the PEACE-1 trial (NCT01957436; Visual Synopsis) and the ARASENS trial (NCT02799602).^3,4

PEACE-1 determined whether the addition of abiraterone acetate (Zytiga) with or without local radiation and standard of care (SOC) improves outcomes. At the time of the trial, the SOC was ADT monotherapy; however, the protocol was amended during the trial to allow for docetaxel use.⁵

“Findings from PEACE-1 demonstrated impressive improvement in overall survival [OS] and in progression-free survival [PFS],” Nazha said. As a comparison, Nazha noted that the OS for the CHAARTED trial (NCT00309985), evaluating ADT plus docetaxel, was 58 months and the OS for the LATITUDE trial (NCT01715285),⁶ evaluating ADT plus abiraterone, was 50 months.

ARASENS also showed a benefit associated with triplet therapy—median OS was not reached—and that benefit was consistent across prespecified subgroups, Nazha said.

This level 1 evidence for OS benefit from PEACE-1 and ARASENS demonstrates the superiority of triplet therapy over doublet therapy, according to Nazha.

“For fit patients with hormone-sensitive prostate cancer, I believe it is most viable to give the most effective therapy first, and that is triplet therapy,” Nazha concluded.

The Case for Doublet Therapy

Ciuro acknowledged that “there is still a continued role for doublet therapy in metastatic castrate-sensitive disease.”

Perhaps the biggest wild card is prostate cancer’s inherent heterogeneity, Ciuro noted. “No single treatment modality should apply to all patients,” Ciuro said. “We know that there are various subtypes within this disease type, such as high-volume disease based on the CHAARTED data⁵ and high-risk disease based on the LATITUDE trial,” Ciuro said.

Patients enrolled in CHAARTED had low-volume (defined as 3 or fewer bone metastases) and high-volume (defined as 4 or more bone metastases with 1 or more spread outside the axial skeleton) disease. Patients enrolled in LATITUDE had highrisk disease (defined as 2 or more risk factors: Gleason score of 8 or greater, 3 or more bone metastases, and visceral metastasis).

To begin, Ciuro noted that the investigators in the PEACE-1 trial included patients with de novo mHSPC, a particularly aggressive form of the disease. Next, she reviewed the baseline characteristics, noting that patients evaluated in PEACE-1 were generally younger, with no one older than 70 years; visceral involvement was observed in 12% to 13% in each respective arm, treated with ADT and abiraterone; and over 60% had high disease burden.

“Although Dr Nazha showed an OS benefit with the triplet arm, knowing that this is a heterogeneous population, how are these results affected when the population is stratified by volume of disease?” asked Ciuro. “In PEACE-1, it seems as though the OS benefit must be driven by those with high-volume disease,” Ciuro said. In patients who received ADT plus docetaxel with low-volume metastatic burden, the HR was 0.83 (95% CI, 0.501.39; P = .66). In patients treated with ADT with docetaxel in patients with high-volume metastatic burden, the HR was 0.72 (95% CI, 0.55-0.95; P = .019).⁷

Evaluating the ARASENS trial, Ciuro said the patient demographics indicated a younger patient population who were fit but who also had high-volume disease (77%) and high-risk disease (70%).⁸

“We truly need a trial evaluating the benefit of chemotherapy added to doublet therapy, that is, chemotherapy plus an APRI and ADT vs placebo plus an APRI and ADT. We do not have that data at the moment,” Ciuro said.

Should triplet therapy be the new SOC for all patients with mHSPC? “Right now, I would say no, although there is utility for this treatment intensification but we need to tailor it for the right patient cohort,” Ciuro said.

REFERENCES:

1. Nazha B, Ciuro J. Triplet vs doublet in M1 castration-sensitive prostate cancer. Presented at: Debates and Didactics in Hematology and Oncology Conference;July 25-28, 2024; Sea Island, GA. Accessed August 12, 2024. https://bioascend.com/ddho/

2. Hussain M, Fizazi K, Shore ND, et al. Metastatic hormone-sensitive prostate cancer and combination treatment outcomes: areview. JAMA Oncol. 2024;10(6):807-820. doi:10.1001/jamaoncol.2024.0591

3. 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

4. Hussain MHA, Tombal BF, Saad F, et al. Efficacy and safety of darolutamide (DARO) in combination with androgen-deprivation therapy (ADT) and docetaxel (DOC) by disease volume and disease risk in the phase 3 ARASENS study. J Clin Oncol. 2023;41(supp 6):15-15. doi:10.1200/JCO.2023.41.6_suppl.15

5. Sweeney CJ, Chen Y-H, 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

6. 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

7. 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

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