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Current Systemic Therapy in Men with Metastatic Castration-Sensitive Prostate Cancer

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Abstract

Purpose of Review

This review aims to explore the evolving landscape of treatments available for metastatic castration-sensitive prostate cancer (mCSPC) patients.

Recent Findings

In less than a decade, evidence was chronologically provided that (1) systemic treatment intensification with docetaxel improves outcomes, including survival, in men with mCSPC, (2) then that these outcomes are also improved when a second-generation androgen receptor pathway inhibitor (ARPI) is combined with androgen deprivation therapy (ADT), and (3) using a “triplet systemic therapy,” which consists in the combination of ADT, an ARPI and docetaxel, further improves outcomes, including survival. Radiotherapy to the prostate combined with ADT alone is now recommended in men with low-volume mCSPC. Combining prostate radiotherapy and intensified systemic treatment including abiraterone may be synergistic as suggested in the PEACE-1 trial. Also, the role of metastases-directed local therapies (mostly stereotactic radiotherapy) is currently being assessed in phase 3 trials. Finally, the integration of biomarkers (e.g. BRCA2 gene alterations, PTEN loss, PSMA expression) for decision making is not currently established, though trials are also currently underway. Importantly, most evidence currently available was obtained in men with de novo metastases, while for those with metastatic relapse after definitive local treatment, the role of treatment intensification is less well established.

Summary

Treatment intensification is nowadays the standard of care for patients with de novo mCSPC as it leads to outcomes improvement, including survival, and the standard of care is evolving almost on a yearly basis.

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Data availability

No datasets were generated or analysed during the current study.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Sung H et al. 2021 Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: a cancer journal for clinicians 71(3): p. 209–49.

  2. Chowdhury S, et al. Causes of death in men with prostate cancer: an analysis of 50 000 men from the Thames Cancer Registry. BJU Int. 2013;112(2):182–9.

    PubMed  Google Scholar 

  3. Patrikidou A, et al. Who dies from prostate cancer? Prostate Cancer Prostatic Dis. 2014;17(4):348–52.

    CAS  PubMed  Google Scholar 

  4. Schröder FH, et al. Prostate-cancer mortality at 11 years of follow-up. N Engl J Med. 2012;366(11):981–90.

    PubMed  PubMed Central  Google Scholar 

  5. Huggins C, Hodges CV. Studies on prostatic cancer. I. The effect of castration, of estrogen and androgen injection on serum phosphatases in metastatic carcinoma of the prostate. CA Cancer J Clin. 1972;22(4):232–40.

    CAS  PubMed  Google Scholar 

  6. Mollica V, et al. Molecular mechanisms related to hormone inhibition resistance in prostate cancer. Cells. 2019;8(1):43.

    CAS  PubMed  PubMed Central  Google Scholar 

  7. Sweeney CJ, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373(8):737–46.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Fizazi K, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377(4):352–60.

    CAS  PubMed  Google Scholar 

  9. Davis ID, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381(2):121–31.

    CAS  PubMed  Google Scholar 

  10. Armstrong AJ, 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):2974–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Chi KN, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381(1):13–24.

    CAS  PubMed  Google Scholar 

  12. Fizazi K, et al. Darolutamide in nonmetastatic, castration-resistant prostate cancer. N Engl J Med. 2019;380(13):1235–46.

    CAS  PubMed  Google Scholar 

  13. Gravis G, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial. Lancet Oncol. 2013;14(2):149–58.

    CAS  PubMed  Google Scholar 

  14. Gravis G, et al. Androgen deprivation therapy (ADT) plus docetaxel versus ADT alone in metastatic non castrate prostate cancer: impact of metastatic burden and long-term survival analysis of the randomized phase 3 GETUG-AFU15 trial. Eur Urol. 2016;70(2):256–62.

    CAS  PubMed  Google Scholar 

  15. James ND, 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):1163–77.

    CAS  PubMed  PubMed Central  Google Scholar 

  16. Vale CL, et al. Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data. Lancet Oncol. 2016;17(2):243–56.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Kyriakopoulos CE, 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):1080–7.

    CAS  PubMed  PubMed Central  Google Scholar 

  18. Clarke NW, et al. Addition of docetaxel to hormonal therapy in low-and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol. 2019;30(12):1992–2003.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. James ND, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. 2017;377(4):338–51.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Fizazi K, 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.

    CAS  PubMed  Google Scholar 

  21. James N, et al. 611O Abiraterone acetate plus prednisolone for hormone-naïve prostate cancer (PCa): long-term results from metastatic (M1) patients in the STAMPEDE randomised trial (NCT00268476). Ann Oncol. 2020;31:S509.

    Google Scholar 

  22. Armstrong AJ,  et al. Overall survival (OS) in patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC) treated with enzalutamide (ENZA) + androgen deprivation therapy (ADT) by high or low disease volume and progression to mHSPC (M0 at diagnosis) or de novo mHSPC (M1 at diagnosis): Post hoc analysis of the phase 3 ARCHES trial. JCO. 2022;40:115–115.

  23. Sweeney CJ, 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.

    CAS  PubMed  Google Scholar 

  24. Chi KN, 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.

    CAS  PubMed  Google Scholar 

  25. Gravis G, et al. Prognostic factors for survival in noncastrate metastatic prostate cancer: validation of the glass model and development of a novel simplified prognostic model. Eur Urol. 2015;68(2):196–204.

    PubMed  Google Scholar 

  26. Francini E, et al. Time of metastatic disease presentation and volume of disease are prognostic for metastatic hormone sensitive prostate cancer (mHSPC). Prostate. 2018;78(12):889–95.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Vale CL et al. Defining more precisely the effects of docetaxel plus ADT for men with mHSPC: meta-analysis of individual participant data from randomized trials. JCO.2022;40:5070–5070.

  28. Hoyle AP, et al. Abiraterone in “high-” and “low-risk” metastatic hormone-sensitive prostate cancer. Eur Urol. 2019;76(6):719–28.

    CAS  PubMed  Google Scholar 

  29. Merseburger AS, et al. Apalutamide plus androgen deprivation therapy in clinical subgroups of patients with metastatic castration-sensitive prostate cancer: a subgroup analysis of the randomised clinical TITAN study. Eur J Cancer. 2023;193:113290.

    CAS  PubMed  Google Scholar 

  30. Feyerabend S, et al. Survival benefit, disease progression and quality-of-life outcomes of abiraterone acetate plus prednisone versus docetaxel in metastatic hormone-sensitive prostate cancer: a network meta-analysis. Eur J Cancer. 2018;103:78–87.

    CAS  PubMed  Google Scholar 

  31. Rydzewska LH, et al. Adding abiraterone to androgen deprivation therapy in men with metastatic hormone-sensitive prostate cancer: a systematic review and meta-analysis. Eur J Cancer. 2017;84:88–101.

    CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang L, et al. Comparison of systemic treatments for metastatic castration-sensitive prostate cancer: a systematic review and network meta-analysis. JAMA Oncol. 2021;7(3):412–20.

    PubMed  PubMed Central  Google Scholar 

  33. Wenzel M, et al. Overall survival after systemic treatment in high-volume versus low-volume metastatic hormonesensitive prostate cancer: systematic review and network meta-analysis. Eur Urol Focus 2022;8(2):399–408.

  34. Mori K, et al. Systemic therapies for metastatic hormone-sensitive prostate cancer: network meta-analysis. BJU Int. 2022;129(4):423–33.

    CAS  PubMed  Google Scholar 

  35. • Fizazi K 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. The Lancet. 2022;399(10336):1695–707. of importance because first demonstrated the benefit of a triplet therapy.

    CAS  Google Scholar 

  36. •• Smith MR, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132–42. of importance because confirmed the use of triplet therapy.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Davis ID et al. Updated overall survival outcomes in ENZAMET (ANZUP 1304), an international, cooperative group trial of enzalutamide in metastatic hormone-sensitive prostate cancer (mHSPC). JCO. 2022;40:LBA5004-LBA5004.

  38. Ciccarese C, et al. Triplet therapy with androgen deprivation, docetaxel, and androgen receptor signalling inhibitors in metastatic castration-sensitive prostate cancer: a meta-analysis. Eur J Cancer. 2022;173:276–84.

    CAS  PubMed  Google Scholar 

  39. Gillessen S. et al. Management of patients with advanced prostate cancer. Part I: intermediate-/high-risk and locally advanced disease, biochemical relapse, and side effects of hormonal treatment: report of the Advanced ProstateCancer Consensus Conference 2022. Eur Urol. 2022;83(3):267–293.

  40. Boevé LM, et al. Effect on survival of androgen deprivation therapy alone compared to androgen deprivation therapy combined with concurrent radiation therapy to the prostate in patients with primary bone metastatic prostate cancer in a prospective randomised clinical trial: data from the HORRAD trial. Eur Urol. 2019;75(3):410–8.

    PubMed  Google Scholar 

  41. Parker CC, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353–66.

    PubMed  PubMed Central  Google Scholar 

  42. Bossi A et al. Prostate irradiation in men with de novo, low-volume, metastatic, castration-sensitive prostate cancer (mCSPC): Results of PEACE-1, a phase 3 randomized trial with a 2x2 design. JCO. 2022;41:LBA5000-LBA5000.

  43. Kohli M, et al. Clinical and genomic insights into circulating tumor DNA-based alterations across the spectrum of metastatic hormone-sensitive and castrate-resistant prostate cancer. EBioMedicine. 2020;54:102728.

    PubMed  PubMed Central  Google Scholar 

  44. Van der Eecken K, et al. Tissue-and blood-derived genomic biomarkers for metastatic hormone-sensitive prostate cancer: a systematic review. Eur Urol Oncol. 2021;4(6):914–23.

    PubMed  Google Scholar 

  45. Mateo J, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373(18):1697–708.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Mateo J, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21(1):162–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  47. de Bono J, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020;382(22):2091–102.

    PubMed  Google Scholar 

  48. Rathkopf DE, et al. AMPLITUDE: A study of niraparib in combination with abiraterone acetate plus prednisone (AAP) versus AAP for the treatment of patients with deleterious germline or somatic homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC). JCO. 2021;39:TPS176–TPS176.

  49. Agarwal N, et al. 645TiP TALAPRO-3: a phase III, double-blind, randomized study of enzalutamide (ENZA) plus talazoparib (TALA) vs placebo plus ENZA in patients (pts) with DDR gene mutated metastatic castration-sensitive prostate cancer (mCSPC). Ann Oncol. 2021;32:S672–3.

    Google Scholar 

  50. Sarker D, et al. Targeting the PI3K/AKT pathway for the treatment of prostate cancerPI3K pathway in prostate cancer. Clin Cancer Res. 2009;15(15):4799–805.

    CAS  PubMed  Google Scholar 

  51. Buttigliero C, et al. Understanding and overcoming the mechanisms of primary and acquired resistance to abiraterone and enzalutamide in castration resistant prostate cancer. Cancer Treat Rev. 2015;41(10):884–92.

    CAS  PubMed  Google Scholar 

  52. Carver BS, et al. Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. Cancer Cell. 2011;19(5):575–86.

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Mulholland DJ, et al. Cell autonomous role of PTEN in regulating castration-resistant prostate cancer growth. Cancer Cell. 2011;19(6):792–804.

    CAS  PubMed  PubMed Central  Google Scholar 

  54. Jamaspishvili T, et al. Clinical implications of PTEN loss in prostate cancer. Nat Rev Urol. 2018;15(4):222–34.

    CAS  PubMed  PubMed Central  Google Scholar 

  55. Sweeney C, et al. Ipatasertib plus abiraterone and prednisolone in metastatic castration-resistant prostate cancer (IPATential150): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2021;398(10295):131–42.

    CAS  PubMed  Google Scholar 

  56. Schiewer MJ, Augello MA, Knudsen KE. The AR dependent cell cycle: mechanisms and cancer relevance. Mol Cell Endocrinol. 2012;352(1–2):34–45.

    CAS  PubMed  Google Scholar 

  57. Hamilton E, Infante JR. Targeting CDK4/6 in patients with cancer. Cancer Treat Rev. 2016;45:129–38.

    CAS  PubMed  Google Scholar 

  58. Shapiro GI. Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol. 2006;24(11):1770–83.

    CAS  PubMed  Google Scholar 

  59. Liu G, et al. A phase II trial of flavopiridol (NSC# 649890) in patients with previously untreated metastatic androgen-independent prostate cancer. Clin Cancer Res. 2004;10(3):924–8.

    CAS  PubMed  Google Scholar 

  60. • Sartor O, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091–103. Of importance as it showed the efficacy of PSMA-lutetium in prostate cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Sandhu S, et al. Prostate cancer. The Lancet. 2021;398(10305):1075–90.

    CAS  Google Scholar 

  62. Fizazi K, et al. Final analysis of the ipilimumab versus placebo following radiotherapy phase III trial in postdocetaxel metastatic castration-resistant prostate cancer identifies an excess of long-term survivors. Eur Urol. 2020;78(6):822–30.

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Petrylak DP et al. Pembrolizumab plus docetaxel for patients with metastatic castration-resistant prostate cancer (mCRPC): Randomized, double-blind, phase 3 KEYNOTE-921 study. JCO. 2023:41:19–19.

  64. Guan X, et al. Androgen receptor activity in T cells limits checkpoint blockade efficacy. Nature. 2022;606(7915):791–6.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Gratzke C, et al. 1772MO Pembrolizumab (pembro) plus enzalutamide (enza) and androgen deprivation therapy (ADT) for patients (pts) with metastatic hormone-sensitive prostate cancer (mHSPC): Randomized double-blind phase III KEYNOTE-991 study. Ann Oncol. 2023;34:S957–8.

    Google Scholar 

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Authors and Affiliations

  1. Department of Medical Oncology, Centres Hospitaliers Universitaires Helora, La Louvière, Belgium

    Guillaume Grisay

  2. Department of Cancer Medicine, Institut Gustave Roussy, University of Paris-Saclay, Villejuif, France

    Pernelle Lavaud & Karim Fizazi

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  1. Guillaume Grisay
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  2. Pernelle Lavaud
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Correspondence to Guillaume Grisay.

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Grisay, G., Lavaud, P. & Fizazi, K. Current Systemic Therapy in Men with Metastatic Castration-Sensitive Prostate Cancer. Curr Oncol Rep 26, 488–495 (2024). https://doi.org/10.1007/s11912-024-01509-6

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