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Comparative effectiveness of first-line systemic treatments for metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis

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Abstract

Objectives

No head-to-head trials had been performed to estimate the relative effectiveness of poly ADP-ribose polymerase inhibitor (PARPi) and androgen receptor signaling inhibitor (ARSi) in the first-line treatment for metastatic castration-resistant prostate cancer (mCRPC). We aimed to perform a systematic review and network meta-analysis to evaluate the comparative effectiveness of various systemic treatment agents for patients with mCRPC.

Methods

A comprehensive literature search was conducted for abstracts and full-text articles from the database’s inception through April 27, 2023. The study concentrated on assessing radiographic progression-free survival (rPFS) for both overall and homologous recombination repair mutation (HRRm) population, with overall survival (OS) as the secondary measure. Under the Bayesian framework, the overall effect was pooled using the fixed-effects model in base case analysis. Scenario analysis using restricted mean survival time (RMST) methods was performed to test the robustness of the results.

Results

Nine studies with 6,830 patients and 8 unique treatment options were included. Network meta-analysis demonstrated that talazoparib in combination with enzalutamide (TALA + ENZA; overall population, hazard ratio [HR], 0.20; 95% credible interval [CrI]: 0.16–0.26; RMST, 3.51; 95% confidence interval [CI] 2.46–4.60; HRRm population, HR, 0.15; 95% CrI: 0.09–0.23; RMST, 4.14; 95% CI 2.84–5.39) was superior to other treatments in the first-line setting in terms of rPFS. The results of Bayesian framework and RMST models showed consistent efficacy ranks. When extrapolated to overall survival benefit, within the Bayesian framework, olaparib plus abiraterone acetate and prednisone (OLAP + AAP) achieved the highest OS benefit for the overall population, which was not statistically significant when compared to TALA + ENZA. However, TALA + ENZA achieved the highest OS benefit at 3 years by applying RMST.

Conclusions

We suggest that talazoparib in combination with enzalutamide is probably a preferred treatment agent for the overall population and HRRm patients with mCRPC. Given the limitations of network framework and the modeling assumptions undertaken to finalize the analyses, results should be cautiously interpreted.

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Availability of data and materials

The datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Abbreviations

AAP:

Abiraterone acetate plus prednisone

ADT:

Androgen-deprivation therapy

APA:

Apalutamide

ARSi:

Androgen receptor signaling inhibitor

BIC:

Bicalutamide

BICR:

Blinded independent central review

BSC:

Best support care

BSP:

Bone sialoprotein

CI:

Confidence interval

CrI:

Credible interval

DDR:

DNA damage response and repair

ENZA:

Enzalutamide

FDA:

Food and Drug Administration

HR:

Hazard ratio

HRRm:

Homologous recombination repair mutation

HSP90:

Heat shock protein 90

INV:

Investigator

IPD:

Individual patient data

KM:

Kaplan–Meier

mCRPC:

Metastatic castration-resistant prostate cancer

MMR:

Mismatch repair

NCCN:

National Comprehensive Cancer Network

NHEJ:

Non-homologous end-joining

NMA:

Network meta-analysis

NIRA:

Niraparib

OLAP:

Olaparib

OS:

Overall survival

OSF:

Open Science Framework

OPN:

Osteopontin

PARPi:

Poly ADP-ribose polymerase inhibitor

PH:

Proportional hazard

PRISMA:

Preferred Reporting Items for Systematic Reviews and Meta-analyses

PROSPERO:

International Prospective Register of Systematic

RCT:

Randomized controlled trial

rPFS:

Radiographic progression-free survival

SABR:

Stereotactic ablative radiotherapy

TALA:

Talazoparib

References

  1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424. https://doi.org/10.3322/caac.21492.

    Article  PubMed  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 CANCERS in 185 Countries. CA Cancer J Clin. 2021;71(3):209–49. https://doi.org/10.3322/caac.21660.

    Article  CAS  PubMed  Google Scholar 

  3. Chen W, Zheng R, Baade PD, Zhang S, Zeng H, Bray F, et al. Cancer statistics in China, 2015. CA Cancer J Clin. 2016;66(2):115–32. https://doi.org/10.3322/caac.21338.

    Article  PubMed  Google Scholar 

  4. Ma C, Ye D, Li C, Zhou F, Yao X, Zhang S, et al. Epidemiologic characteristics of prostate cancer and analysis of first-line endocrine therapy in advanced stage. Chin J Surg. 2008;12:921–5.

    Google Scholar 

  5. Zhu Y. Expert consensus on the diagnosis and treatment of denervation-resistant prostate cancer in China. Chin Surg Miscell J. 2016;54(7):481–4.

    Google Scholar 

  6. Attard G, Murphy L, Clarke NW, Sachdeva A, Jones C, et al. Abiraterone acetate plus prednisolone with or without enzalutamide for patients with metastatic prostate cancer starting androgen deprivation therapy: final results from two randomised phase 3 trials of the STAMPEDE platform protocol. Lancet Oncol. 2023;24(5):443–56. https://doi.org/10.1016/S1470-2045(23)00148-1.

    Article  CAS  PubMed  Google Scholar 

  7. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351(15):1513–20. https://doi.org/10.1056/NEJMoa041318.

    Article  CAS  PubMed  Google Scholar 

  8. Pritchard CC, Mateo J, Walsh MF, De Sarkar N, Abida W, Beltran H, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443–53. https://doi.org/10.1056/NEJMoa1603144.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Shah S, Rachmat R, Enyioma S, Ghose A, Revythis A, et al. BRCA mutations in prostate cancer: assessment, implications and treatment considerations. Int J Mol Sci. 2021;22(23):12628. https://doi.org/10.3390/ijms222312628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Boussios S, Rassy E, Shah S, Ioannidou E, Sheriff M, et al. Aberrations of DNA repair pathways in prostate cancer: a cornerstone of precision oncology. Expert Opin Ther Targets. 2021;25(5):329–33. https://doi.org/10.1080/14728222.2021.1951226.

    Article  PubMed  Google Scholar 

  11. Yang S, Liu X. Progress of drug therapy for metastatic denervation-resistant prostate cancer. J Med Res. 2022;51(11):4–9.

    Google Scholar 

  12. Agarwal N, Azad AA, Carles J, Fay AP, Matsubara N, Heinrich D, et al. Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial. Lancet. 2023;S0140–6736(23):01055–63. https://doi.org/10.1016/S0140-6736(23)01055-3.

    Article  Google Scholar 

  13. Clarke NW, Armstrong AJ, Thiery-Vuillemin A, Oya M,Shore ND, Procopio G, et al. (2023) Final pre-specified overall survival in PROpel: abiraterone and olaparib versus abiraterone and placebo as first-line therapy for metastatic castration-resistant prostate cancer. ASCO GU. https://ascopubs.org/doi/abs/https://doi.org/10.1200/JCO.2023.41.6_suppl.LBA16.

  14. Chi KN, Rathkopf D, Smith MR, et al. Niraparib and abiraterone acetate for metastatic castration-resistant prostate cancer. J Clin Oncol. 2023;41(18):3339–51. https://doi.org/10.1200/JCO.22.01649.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Wei Y, Zhang T, He Y, Efstathiou E, Attard G, Olmos D, et al. Preliminary efficacy and safety study of fluzoparib in the treatment of metastatic desmoplasia-resistant prostate cancer. Chin J Cancer. 2021;31(07):561–6. https://doi.org/10.19401/j.cnki.1007-3639.2021.07.001.

    Article  CAS  Google Scholar 

  16. Ghose A, Moschetta M, Pappas-Gogos G, Sheriff M, Boussios S. Genetic aberrations of DNA repair pathways in prostate cancer: translation to the clinic. Int J Mol Sci. 2021;22(18):9783. https://doi.org/10.3390/ijms22189783.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ryan CJ, Smith MR, Fizazi K, Saad F, Mulders PF, Sternberg CN, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152–60. https://doi.org/10.1016/S1470-2045(14)71205-7.

    Article  CAS  PubMed  Google Scholar 

  18. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371(5):424–33. https://doi.org/10.1056/NEJMoa1405095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Saad F, Efstathiou E, Attard G, Flaig TW, Franke F, Goodman OB Jr, et al. Apalutamide plus abiraterone acetate and prednisone versus placebo plus abiraterone and prednisone in metastatic, castration-resistant prostate cancer (ACIS): a randomised, placebo-controlled, double-blind, multinational, phase 3 study. Lancet Oncol. 2021;22(11):1541–59. https://doi.org/10.1016/S1470-2045(21)00402-2.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Penson DF, Armstrong AJ, Concepcion R, Agarwal N, Olsson C, Karsh L, et al. Enzalutamide versus bicalutamide in castration-resistant prostate cancer: the STRIVE Trial. J Clin Oncol. 2016;34(18):2098–106. https://doi.org/10.1200/JCO.2015.64.9285.

    Article  CAS  PubMed  Google Scholar 

  21. Higano CS, Cheng HH. Poly-ADP ribose polymerase inhibitor and androgen receptor signaling inhibitor for all comers for first-line treatment of metastatic castration-resistant prostate cancer: is gene sequencing out? Curr Opin Urol. 2023;33(5):396–403. https://doi.org/10.1097/MOU.0000000000001114.

    Article  PubMed  Google Scholar 

  22. NCCN (2022) The NCCN Clinical Practice Guidelines in Oncology: Prostate Cancer(version 1.2023) [EB/OL]. http://www.nccn.org.

  23. National Health Commission of the People's Republic of China. Guidelines for the diagnosis and treatment of prostate cancer [EB/OL]. http://www.nhc.gov.cn/yzygj/s7659/202204/a0e67177df1f439898683e1333957c74/files/64eb7728ee494e299a77846fff09840e.pdf.

  24. Pan J, Zhao J, Ni X, Gan H, Wei Y, Wu J, et al. The prevalence and prognosis of next-generation therapeutic targets in metastatic castration-resistant prostate cancer. Mol Oncol. 2022;16(22):4011–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Saxby H, Boussios S, Mikropoulos C. Androgen receptor gene pathway upregulation and radiation resistance in oligometastatic prostate cancer. Int J Mol Sci. 2022;23(9):4786. https://doi.org/10.3390/ijms23094786.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Saxby H, Mikropoulos C, Boussios S. An update on the prognostic and predictive serum biomarkers in metastatic prostate cancer. Diagnostics (Basel). 2020;10(8):549. https://doi.org/10.3390/diagnostics10080549.

    Article  CAS  PubMed  Google Scholar 

  27. Fang M, Nakazawa M, Antonarakis ES, Li C. Efficacy of Abiraterone and enzalutamide in pre- and postdocetaxel castration-resistant prostate cancer: a trial-level meta-analysis. Prostate Cancer. 2017;2017:8560827. https://doi.org/10.1155/2017/8560827.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Iannantuono GM, Chandran E, Floudas CS, et al. Efficacy and safety of PARP inhibitors in metastatic castration-resistant prostate cancer: a systematic review and meta-analysis of clinical trials. Cancer Treat Rev. 2023;120: 102623. https://doi.org/10.1016/j.ctrv.2023.102623.

    Article  CAS  PubMed  Google Scholar 

  29. Hutton B, Salanti G, Caldwell DM, Choo-Wosoba H, Butera G, Roselli M, et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann Intern Med. 2015;162(11):777–84. https://doi.org/10.7326/M14-2385.

    Article  PubMed  Google Scholar 

  30. Ai J (2023) Comparative effectiveness of poly ADP-ribose polymerase inhibitor and androgen receptor signaling inhibitor in the first-line treatment for metastatic castration-resistant prostate cancer: a network meta-analysis. Accessed Sep 7, 2023. https://osf.io/axpuk.

  31. Ai J. Comparative effectiveness of poly ADP-ribose polymerase inhibitor and androgen receptor signaling inhibitor in the first-line treatment for metastatic castration-resistant prostate cancer: a network meta-analysis. Accessed Sep 26, 2023. https://www.crd.york.ac.uk/prospero

  32. Higgins JP, Altman DG, Gøtzsche PC, Jüni P, Moher D, Oxman AD, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ. 2011;343:d5928. https://doi.org/10.1136/bmj.d5928.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Chen J, Zhang Y, Zhang X, Zhao J, Ni Y, Zhu S, et al. Comparison of systemic treatments for metastatic castration-resistant prostate cancer after docetaxel failure: a systematic review and network meta-analysis. Front Pharmacol. 2022;12:789319. https://doi.org/10.3389/fphar.2021.789319.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Pak K, Uno H, Kim DH, Tian L, Kane RC, Takeuchi M, et al. Interpretability of cancer clinical trial results using restricted mean survival time as an alternative to the hazard ratio. JAMA Oncol. 2017;3(12):1692–6. https://doi.org/10.1001/jamaoncol.2017.2797.

    Article  PubMed  Google Scholar 

  35. Lombardi P, Filetti M, Falcone R, Di Bidino R, Iacovelli R, Ciccarese C, et al. New first-line immunotherapy-based combinations for metastatic renal cell carcinoma: a systematic review and network meta-analysis. Cancer Treat Rev. 2022;106:102377. https://doi.org/10.1016/j.ctrv.2022.102377.

    Article  CAS  PubMed  Google Scholar 

  36. Fisher D (2019) IPDMETAN: Stata module for performing two-stage IPD meta-analysis. Stata Software Components. Available at: https://econpapers.repec.org/software/bocbocode/S457785.htm.

  37. Therneau GTM. Proportional hazards tests and diagnostics based on weighted residuals. Biometrika. 1994;81(3):515–26.

    Article  Google Scholar 

  38. Guyot P, Ades AE, Ouwens MJ, Welton NJ. Enhanced secondary analysis of survival data: reconstructing the data from published Kaplan-Meier survival curves. BMC Med Res Methodol. 2012;12:9. https://doi.org/10.1186/1471-2288-12-9.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Petit C, Blanchard P, Pignon JP, Lueza B. Individual patient data network meta-analysis using either restricted mean survival time difference or hazard ratios: is there a difference? A case study on locoregionally advanced nasopharyngeal carcinomas. Syst Rev. 2019;8(1):96. https://doi.org/10.1186/s13643-019-0984-x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Guyatt G, Oxman AD, Akl EA et al. GRADE guidelines: 1. Introduction GRADE evidence profiles and summary of findings tables. J Clin Epidemiol 2011; 64: 383–94.

  41. Pu YS, Ahn H, Han W, Huang SP, Wu HC, Ma L, et al. Enzalutamide in chemotherapy-naïve metastatic castration-resistant prostate cancer: an Asian multiregional. Random Study Adv Ther. 2022;39(6):2641–56. https://doi.org/10.1007/s12325-022-02140-2.

    Article  CAS  PubMed  Google Scholar 

  42. Beer TM, Armstrong AJ, Rathkopf D, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer: extended analysis of the phase 3 PREVAIL study. Eur Urol. 2017;71(2):151–4. https://doi.org/10.1016/j.eururo.2016.07.032.

    Article  CAS  PubMed  Google Scholar 

  43. Oya M, Armstrong AJ, Thiery-Vuillemin A, Shore N, Procopio G, Arslan C, et al. (2022) Biomarker analysis and updated results from the Phase III PROpel trial of abiraterone (abi) and olaparib (ola) vs abi and placebo (pbo) as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). ESMO 2022. https://d27mnwjqm5ztsa.cloudfront.net/4d4d150a-bf20-4c76-945a-ce2a670c3c99/031898bb-a199-4394-b7fa-aa1c6f7a6a2a/031898bb-a199-4394-b7fa-aa1c6f7a6a2a_source__v.pdf.

  44. Rathkopf DE, Smith MR, de Bono JS, Logothetis CJ, Shore ND, de Souza P, et al. Updated interim efficacy analysis and long-term safety of abiraterone acetate in metastatic castration-resistant prostate cancer patients without prior chemotherapy (COU-AA-302). Eur Urol. 2014;66(5):815–25. https://doi.org/10.1016/j.eururo.2014.02.056.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Shore ND, Chowdhury S, Villers A, Klotz L, Siemens DR, Phung D, et al. Efficacy and safety of enzalutamide versus bicalutamide for patients with metastatic prostate cancer (TERRAIN): a randomised, double-blind, phase 2 study. Lancet Oncol. 2016;17(2):153–63. https://doi.org/10.1016/S1470-2045(15)00518-5.

    Article  CAS  PubMed  Google Scholar 

  46. Armstrong AJ, Lin P, Tombal B, Saad F, Higano CS, Joshua AM, et al. Five-year survival prediction and safety outcomes with enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer from the PREVAIL Trial. Eur Urol. 2020;78(3):347–57. https://doi.org/10.1016/j.eururo.2020.04.061.

    Article  CAS  PubMed  Google Scholar 

  47. Fizazi K, Azad A, Matsubara N, Carles J, Fay AP, Giorgi UD, et al. TALAPRO-2: Phase 3 study of talazoparib (TALA) + enzalutamide (ENZA) versus placebo (PBO) + ENZA as first-line (1L) treatment for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) harboring homologous recombination repair (HRR) gene alterations. https://doi.org/10.1200/JCO.2023.41.16_suppl.5004.

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Authors' Contributions

JA and TZ had full access to all of the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. The work reported in the paper has been performed by the authors, unless clearly specified in the text. Conception and design: JA, TZ. Acquisition, analysis, or interpretation of data: JA, LJ, XW. Drafting of the manuscript: JA, XH. Critical revision of the manuscript for important intellectual content: XY, JJ. Statistical analysis: JA, LJ, XH. Obtained funding: TZ. Administrative, technical, or material support: JJ, TZ. Supervision: TZ.

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers 72274079). Role of the sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

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  1. Jiahuan Ai and Liuying Jian contributed equally to this work.

Authors and Affiliations

  1. College of Pharmacy/Southern Institute of Pharmacoeconomics and Health Technology Assessment, Jinan University, Guangzhou, 510632, China

    Jiahuan Ai, Liuying Jian, Xiaoqin Wen, Xiaotong Huo, Xuanyi Yang, Jie Jiang & Tiantian Zhang

  2. Guangzhou Huabo Biopharmaceutical Research Institute, Guangzhou, 510010, China

    Tiantian Zhang

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Ai, J., Jian, L., Wen, X. et al. Comparative effectiveness of first-line systemic treatments for metastatic castration-resistant prostate cancer: a systematic review and network meta-analysis. Clin Transl Oncol (2024). https://doi.org/10.1007/s12094-024-03506-4

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