As such, several novel agents initially approved for use in metastatic castration-resistant prostate cancer (mCRPC), such as taxane chemotherapy and androgen receptor pathway inhibitors (ARPIs), now have demonstrable survival benefits in metastatic hormone-sensitive prostate cancer (mHSPC).1 Parallel efforts to improve survival in the high-risk localised and locally advanced disease setting have led to several trials evaluating the benefit of combination therapy in addition to standard-of-care surgery or radiotherapy with androgen deprivation therapy (ADT). Our narrative collaborative review synthesises the available evidence on combination treatment approaches for locally advanced and mHSPC while also addressing ongoing challenges and clinical considerations.
A doublet approach with an ADT backbone and an ARPI is now considered standard treatment for mHSPC following several landmark trials demonstrating a radiographic progression-free survival (rPFS) benefit with combination therapy compared to ADT alone.2-7 Of note, a significant improvement in overall survival (OS) has only been demonstrated for abiraterone, enzalutamide, and apalutamide in combination with ADT and not yet for darolutamide. The selection of a specific ARPI is influenced by a number of factors, including a patient’s symptom burden, concurrent comorbidities, regular medications, and potential drug interactions, in addition to local availability and cost. In select subgroups, an upfront triplet regimen incorporating docetaxel may be considered. The PEACE-1, ARASENS, and ENZAMET trials show a consistent benefit for triplet treatment with abiraterone, darolutamide, and enzalutamide, respectively, over an ADT + docetaxel doublet in patients with synchronous mHSPC.2,8,9 Although an OS benefit extends only to those with synchronous high-volume disease on subgroup analysis in the PEACE-1 and ARASENS trials (longer follow-up is awaited for the low-volume disease subgroups). Notably, direct comparative data between a triplet approach and the current standard of an ADT + ARPI doublet remains absent. As such, the role of triplet therapy remains uncertain, with the benefit possibly apparent in select patients with synchronous, high-volume metastatic disease.
Additionally, prostate irradiation remains a key component of standard management in patients with synchronous low-volume mHSPC receiving ADT + an ARPI. Though there has so far been no demonstrable improvement in OS in this cohort (longer follow-up is awaited from the PEACE-1 trial), the addition of prostate radiotherapy leads to improved rPFS as well as improved time to serious genitourinary events.
Emerging evidence also supports the use of an ARPI in addition to ADT and standard local therapy in select high-risk patients categorized as non-metastatic on conventional imaging.10 Several trials evaluating other combinations with ARPIs, radiotherapy, and ADT are ongoing and importantly, will help to refine which patients should be considered for intensified treatment with an ARPI beyond the higher-risk STAMPEDE criteria.
This may only herald the beginning for combination therapies in prostate cancer therapy, however, as an array of novel therapeutic strategies are currently being evaluated in clinical trials. These involve incorporating agents such as poly(ADP-ribose) polymerase inhibitors, AKT inhibitors, and targeted radioligand therapy such as [177Lu]Lu-PSMA in combination with standard treatment. Additionally, for oligometastatic HSPC, metastasis-directed and ADT-sparing approaches are being explored in several trials utilising stereotactic ablative body radiotherapy.
With ongoing survival gains, the need for robust biomarkers to enhance risk stratification and optimise treatment selection is increasingly urgent, as better patient selection for intensified regimens—or treatment de-escalation—may mitigate unnecessary treatment-related toxicity. This is particularly pertinent with the integration of the PSMA-PET, which has led to the earlier detection of metastatic disease. A discord exists between the optimal imaging modality to use to assess the prostate cancer disease burden, with uptake of PSMA-PET increasing in the real-world, but conventional imaging used for most pivotal clinical trials. More contemporary trials now incorporate PSMA-PET imaging, which, together with revised PET-based progression endpoints, provides important evidence to refine clinical decision-making and treatment algorithms.
Written by: Louise Kostos & Arun Azad
Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
References:
- Gillessen S, Turco F, Davis ID, Efstathiou JA, Fizazi K, James ND, et al. Management of Patients with Advanced Prostate Cancer. Report from the 2024 Advanced Prostate Cancer Consensus Conference (APCCC). European Urology. 2024.
- Sweeney CJ, Martin AJ, Stockler MR, Begbie S, Cheung L, Chi KN, 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):323-34.
- Chi KN, Chowdhury S, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, 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;39(20):2294-303.
- Armstrong AJ, Azad AA, Iguchi T, Szmulewitz RZ, Petrylak DP, Holzbeierlein J, et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2022;40(15):1616-22.
- Saad F, Vjaters E, Shore N, Olmos D, Xing N, Gomes AJPdS, et al. Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial. Journal of Clinical Oncology.0(0):JCO-24-01798.
- Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, 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 randomised, double-blind, phase 3 trial. Lancet Oncol. 2019;20(5):686-700.
- James ND, de Bono JS, Spears MR, Clarke NW, Mason MD, Dearnaley DP, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338-51.
- Fizazi K, Foulon S, Carles J, Roubaud G, McDermott R, Fléchon A, 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):1695-707.
- Smith MR, Hussain M, Saad F, Fizazi K, Sternberg CN, Crawford ED, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. N Engl J Med. 2022;386(12):1132-42.
- Attard G, Murphy L, Clarke NW, Cross W, Jones RJ, Parker CC, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. The Lancet. 2022;399(10323):447-60.