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Impact of DNA damage repair defects on response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer

Abstract

Purpose

Prostate-specific membrane antigen radioligand therapy (PSMA-RLT) is a novel treatment for castration-resistant prostate cancer (mCRPC). While the majority of patients responds to PSMA-RLT, with 10–15% having an exceptional response, approximately 30% of patients is unresponsive to PSMA-RLT. The molecular underpinning may in part explain these varying responses. This study investigated alterations in DNA damage repair (DDR) genes in tumour biopsies and their association with response to PSMA-RLT.

Methods

A predefined retrospective cohort study was performed in mCRPC patients of whom the tumours had undergone next-generation sequencing of 40 DDR genes and received Lu-177-PSMA and/or Ac-225-PSMA-RLT. The primary outcome of this study was to compare the progression free survival (PFS) after PSMA-RLT for patients with and without pathogenic DDR aberrations in their tumour. Secondary outcomes were prostate-specific antigen (PSA) response and overall survival (OS).

Results

A total of 40 patients were included of which seventeen had a tumour with a pathogenic DDR aberration (DDR+), of which eight had defects in BRCA1/2. DDR+ patients had an equal varying response to PSMA-RLT compared to those without pathological DDR anomalies (DDR-) in terms of PFS (5.9 vs. 6.4 months, respectively; HR 1.14; 95% CI 0.58-2.25; p = 0.71), ≥50% PSA response (59% vs. 65%, respectively; p = 0.75) or OS (11.1 vs. 10.7 months, respectively; HR 1.40; 95% CI: 0.68–2.91; p = 0.36).

Conclusion

In this study of a selected cohort, pathogenic DDR aberrations were not associated with exceptional responsiveness to PSMA-RLT. Translational studies in larger prospective cohorts are warranted to associate DDR gene defects with differential responses to PSMA-RLT.

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Fig. 1: Swimmerplot with patient history.
Fig. 2: Oncoplot with the pathogenic alterations.
Fig. 3: Waterfall plot of prostate-specific antigen response.
Fig. 4: Kaplan-Meier plots.

Data accessibility

The data that support the findings of this study are available from the corresponding author upon reasonable request.

References

  1. 1.

    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2019. CA: Cancer J Clin. 2019;69:7–34.

    Google Scholar 

  2. 2.

    Heidenreich A, Bastian PJ, Bellmunt J, Bolla M, Joniau S, van der Kwast T, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65:467–79.

    CAS  Article  Google Scholar 

  3. 3.

    Silver DA, Pellicer I, Fair WR, Heston WD, Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin Cancer Res. 1997;3:81–85.

    CAS  PubMed  Google Scholar 

  4. 4.

    Ghosh A, Heston WD. Tumor target prostate specific membrane antigen (PSMA) and its regulation in prostate cancer. J Cell Biochem. 2004;91:528–39.

    CAS  Article  Google Scholar 

  5. 5.

    Bravaccini S, Puccetti M, Bocchini M, Ravaioli S, Celli M, Scarpi E, et al. PSMA expression: a potential ally for the pathologist in prostate cancer diagnosis. Sci Rep. 2018;8:4254.

    Article  Google Scholar 

  6. 6.

    Wright GL Jr., Grob BM, Haley C, Grossman K, Newhall K, Petrylak D, et al. Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy. Urology. 1996;48:326–34.

    Article  Google Scholar 

  7. 7.

    Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [(177)Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19:825–33.

    CAS  Article  Google Scholar 

  8. 8.

    Heck MM, Tauber R, Schwaiger S, Retz M, D’Alessandria C, Maurer T, et al. Treatment outcome, toxicity, and predictive factors for radioligand therapy with 177177177Lu-PSMA-I&T in metastatic castration-resistant prostate cancer. Eur Urol. 2019;75:920–6.

    CAS  Article  Google Scholar 

  9. 9.

    Sathekge M, Bruchertseifer F, Vorster M, Lawal IO, Knoesen O, Mahapane J, et al. Predictors of overall and disease-free survival in metastatic castration-resistant prostate cancer patients receiving (225)Ac-PSMA-617 radioligand therapy. J Nucl Med: Off Publ, Soc Nucl Med. 2020;61:62–69.

    CAS  Article  Google Scholar 

  10. 10.

    Rahbar K, Ahmadzadehfar H, Kratochwil C, Haberkorn U, Schafers M, Essler M, et al. German multicenter study investigating 177Lu-PSMA-617 radioligand therapy in advanced prostate cancer patients. J Nucl Med. 2017;58:85–90.

    CAS  Article  Google Scholar 

  11. 11.

    Hofman MS, Emmett L, Sandhu S, Iravani A, Joshua AM, Goh JC, et al. [177177177Lu] Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397:797–804.

  12. 12.

    Sathekge M, Bruchertseifer F, Knoesen O, Reyneke F, Lawal I, Lengana T, et al. 225Ac-PSMA-617 in chemotherapy-naive patients with advanced prostate cancer: a pilot study. Eur J Nucl Med Mol Imaging. 2019;46:129–38.

    CAS  Article  Google Scholar 

  13. 13.

    Kratochwil C, Bruchertseifer F, Rathke H, Hohenfellner M, Giesel FL, Haberkorn U, et al. Targeted alpha-therapy of metastatic castration-resistant prostate cancer with (225)ac-psma-617: swimmer-plot analysis suggests efficacy regarding duration of tumor control. J Nucl Med. 2018;59:795–802.

    CAS  Article  Google Scholar 

  14. 14.

    Yadav MP, Ballal S, Sahoo RK, Tripathi M, Seth A, Bal C. Efficacy and safety of 225225225Ac-PSMA-617 targeted alpha therapy in metastatic castration-resistant prostate cancer patients. Theranostics. 2020;10:9364–77.

    CAS  Article  Google Scholar 

  15. 15.

    Jackson SP, Bartek J. The DNA-damage response in human biology and disease. Nature. 2009;461:1071–8.

    CAS  Article  Google Scholar 

  16. 16.

    Kan C, Zhang J. BRCA1 mutation: a predictive marker for radiation therapy? Int J Radiat Oncol, Biol, Phys. 2015;93:281–93.

    CAS  Article  Google Scholar 

  17. 17.

    Isaacsson Velho P, Qazi F, Hassan S, Carducci MA, Denmeade SR, Markowski MC, et al. Efficacy of Radium-223 in bone-metastatic castration-resistant prostate cancer with and without homologous repair gene defects. Eur Urol. 2019;76:170–6.

    CAS  Article  Google Scholar 

  18. 18.

    Lord CJ, Ashworth A. The DNA damage response and cancer therapy. Nature. 2012;481:287–94.

    CAS  Article  Google Scholar 

  19. 19.

    de Bono JS, Fizazi K, Saad F, Shore N, Sandhu SK, Mehra N, et al. 847PD Central, prospective detection of homologous recombination repair gene mutations (HRRm) in tumour tissue from >4000 men with metastatic castration-resistant prostate cancer (mCRPC) screened for the PROfound study. Ann Oncol. 2019;30:v325–55.

  20. 20.

    Robinson D, Van Allen EM, Wu YM, Schultz N, Lonigro RJ, Mosquera JM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161:1215–28.

    CAS  Article  Google Scholar 

  21. 21.

    Mateo J, Carreira S, Sandhu S, Miranda S, Mossop H, Perez-Lopez R, et al. DNA-repair defects and olaparib in metastatic prostate cancer. N Engl J Med. 2015;373:1697–708.

    CAS  Article  Google Scholar 

  22. 22.

    Castro E, Mejorada RL, Saez M, De Giorgi UFF, Aragón I, Romero Laorden N, et al. Impact of germline mutations in Homologous Recombination (HR) genes on the response to Radium-223 for metastatic castration prostate cancer. Ann Oncol. 109; 30 v325–55.

  23. 23.

    Kirova YM, Savignoni A, Sigal-Zafrani B, de La Rochefordiere A, Salmon RJ, This P, et al. Is the breast-conserving treatment with radiotherapy appropriate in BRCA1/2 mutation carriers? Long-term results and review of the literature. Breast Cancer Res Treat. 2010;120:119–26.

    Article  Google Scholar 

  24. 24.

    Castro E, Goh C, Leongamornlert D, Saunders E, Tymrakiewicz M, Dadaev T, et al. Effect of BRCA mutations on metastatic relapse and cause-specific survival after radical treatment for localised prostate cancer. Eur Urol. 2015;68:186–93.

    CAS  Article  Google Scholar 

  25. 25.

    Cornford P, Bellmunt J, Bolla M, Briers E, De Santis M, Gross T, et al. EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer. Eur Urol. 2017;71:630–42.

    Article  Google Scholar 

  26. 26.

    Weren RD, Mensenkamp AR, Simons M, Eijkelenboom A, Sie AS, Ouchene H, et al. Novel BRCA1 and BRCA2 tumor test as basis for treatment decisions and referral for genetic counselling of patients with ovarian carcinomas. Hum Mutat. 2017;38:226–35.

    CAS  Article  Google Scholar 

  27. 27.

    Kroeze LI, de Voer RM, Kamping EJ, von Rhein D, Jansen EAM, Hermsen MJW, et al. Evaluation of a hybrid capture-based pan-cancer panel for analysis of treatment stratifying oncogenic aberrations and processes. J Mol Diagn. 2020;22:757–69.

  28. 28.

    Cardinale J, Schafer M, Benesova M, Bauder-Wust U, Leotta K, Eder M, et al. Preclinical evaluation of (18)F-PSMA-1007, a new prostate-specific membrane antigen ligand for prostate cancer imaging. J Nucl Med. 2017;58:425–31.

    CAS  Article  Google Scholar 

  29. 29.

    Fendler WP, Calais J, Eiber M, Flavell RR, Mishoe A, Feng FY, et al. Assessment of 68Ga-PSMA-11 PET accuracy in localizing recurrent prostate cancer: a prospective single-arm clinical trial. JAMA Oncol. 2019;5:856–63.

    Article  Google Scholar 

  30. 30.

    Kratochwil C, Bruchertseifer F, Giesel FL, Weis M, Verburg FA, Mottaghy F, et al. 225Ac-PSMA-617 for PSMA-targeted alpha-radiation therapy of metastatic castration-resistant prostate cancer. J Nucl Med. 2016;57:1941–4.

    CAS  Article  Google Scholar 

  31. 31.

    Kratochwil C, Giesel FL, Stefanova M, Benesova M, Bronzel M, Afshar-Oromieh A, et al. PSMA-targeted radionuclide therapy of metastatic castration-resistant prostate cancer with 177Lu-Labeled PSMA-617. J Nucl Med. 2016;57:1170–6.

    CAS  Article  Google Scholar 

  32. 32.

    Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016;34:1402–18.

    Article  Google Scholar 

  33. 33.

    van der Velden DL, Hoes LR, van der Wijngaart H, van Berge Henegouwen JM, van Werkhoven E, Roepman P, et al. The Drug Rediscovery protocol facilitates the expanded use of existing anticancer drugs. Nature. 2019;574:127–31.

    Article  Google Scholar 

  34. 34.

    Morris MJ, Bono JSD, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39:LBA4-LBA4.

  35. 35.

    Kratochwil C, Fendler WP, Eiber M, Baum R, Bozkurt MF, Czernin J, et al. EANM procedure guidelines for radionuclide therapy with (177)Lu-labelled PSMA-ligands ((177)Lu-PSMA-RLT). Eur J Nuclear Med Mol Imaging. 2019; 46:2536–44.

  36. 36.

    Violet J, Jackson P, Ferdinandus J, Sandhu S, Akhurst T, Iravani A, et al. Dosimetry of (177)Lu-PSMA-617 in metastatic castration-resistant prostate cancer: correlations between pretherapeutic imaging and whole-body tumor dosimetry with treatment outcomes. J Nucl Med. 2019;60:517–23.

    CAS  Article  Google Scholar 

  37. 37.

    Edler von Eyben F, Singh A, Zhang J, Nipsch K, Meyrick D, Lenzo N, et al. (177)Lu-PSMA radioligand therapy of predominant lymph node metastatic prostate cancer. Oncotarget. 2019;10:2451–61.

    Article  Google Scholar 

  38. 38.

    van der Doelen MJ, Mehra N, van Oort IM, Looijen-Salamon MG, Janssen MJR, Custers JAE, et al. Clinical outcomes and molecular profiling of advanced metastatic castration-resistant prostate cancer patients treated with (225)Ac-PSMA-617 targeted alpha-radiation therapy. Urol Oncol. 2021. (in press).

  39. 39.

    Schulz A, Meyer F, Dubrovska A, Borgmann K. Cancer stem cells and radioresistance: DNA repair and beyond. Cancers. 2019;11:862.

  40. 40.

    Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–60.

    CAS  Article  Google Scholar 

  41. 41.

    Nikjoo S, Uehara WE, Wilson M, Hoshi DT, Goodhead H. Track structure in radiation biology: theory and applications. Int J Radiat Biol. 1998;73:355–64.

    CAS  Article  Google Scholar 

  42. 42.

    Ward JF. DNA damage and repair. Basic Life Sci. 1991;58:403–15. discussion 415-21.

    CAS  PubMed  Google Scholar 

  43. 43.

    Crumbaker M, Emmett L, Horvath LG, Joshua AM. Exceptional response to 177 lutetium prostate-specific membrane antigen in prostate cancer harboring DNA repair defects. JCO Precis Oncol. 2019;3:1–5.

    Google Scholar 

  44. 44.

    Kratochwil C, Giesel FL, Heussel CP, Kazdal D, Endris V, Nientiedt C, et al. Patients resistant against PSMA-targeting alpha-radiation therapy often harbor mutations in DNA-repair associated genes. J Nuclear Med. 2020;61:683–8.

  45. 45.

    Stover EH, Konstantinopoulos PA, Matulonis UA, Swisher EM. Biomarkers of response and resistance to DNA repair targeted therapies. Clin Cancer Res. 2016;22:5651–60.

    CAS  Article  Google Scholar 

  46. 46.

    Pouget JP, Lozza C, Deshayes E, Boudousq V, Navarro-Teulon I. Introduction to radiobiology of targeted radionuclide therapy. Front Med. 2015;2:12.

    Article  Google Scholar 

  47. 47.

    Khreish F, Ebert N, Ries M, Maus S, Rosar F, Bohnenberger H, et al. (225)Ac-PSMA-617/(177)Lu-PSMA-617 tandem therapy of metastatic castration-resistant prostate cancer: pilot experience. Eur J Nuclear Med Mol Imaging. 2020;47:721–8.

  48. 48.

    Feuerecker B, Tauber R, Knorr K, Heck M, Beheshti A, Seidl C, et al. Activity and adverse events of actinium-225-PSMA-617 in advanced metastatic castration-resistant prostate cancer after failure of lutetium-177-PSMA. Eur Urol. 2021;79:343–50.

  49. 49.

    Paschalis A, Sheehan B, Riisnaes R, Rodrigues DN, Gurel B, Bertan C, et al. Prostate-specific membrane antigen heterogeneity and DNA repair defects in prostate cancer. Eur Urol. 2019;76:469–78.

    CAS  Article  Google Scholar 

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Acknowledgements

We thank all the investigators of the study, the patients and their families.

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Affiliations

Authors

Contributions

Conceptualisation: Privé, Slootbeek, Laarhuis, van der Doelen, Gerritsen, Heskamp, Janssen, Nagarajah, Mehra Methodology: Privé, Slootbeek, van der Doelen, Heskamp, Janssen, Gerritsen, Nagarajah, Mehra Software: Privé, Slootbeek, Pamidimarri Naga; Validation: Privé, Slootbeek, Laarhuis, van der Doelen, Gerritsen, Nagarajah, Mehra Formal Analysis: Privé, Slootbeek, Laarhuis, van der Doelen, Gerritsen, Nagarajah, Mehra Investigation: Privé, van Kalmthout, Gotthardt, Janssen, Gerritsen, Nagarajah, Mehra Resources: de Keizer, Ezziddin, Kratochwil, Morgenstern, Bruchertseifer, Ligtenberg, Witjes, van Oort, Gotthardt, Janssen, Gerritsen, Nagarajah, Mehra Data Curation: Privé, Slootbeek, Laarhuis, Janssen, Gerritsen, Nagarajah, Mehra Writing – Original Draft: Privé, Laarhuis, Nagarajah, Mehra. Writing – Review & Editing: Slootbeek, van der Doelen, van Kalmthout, de Keizer, Ezziddin, Ligtenberg, Witjes, van Oort, Gotthardt, Heskamp, Janssen, Gerritsen, Nagarajah, Mehra Visualisation: Privé, Pamidimarri Naga Supervision: Gotthardt, Heskamp, Gerritsen, Nagarajah, Mehra Project Administration: Privé, Laarhuis, van der Doelen, Mehra.

Corresponding author

Correspondence to Niven Mehra.

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Competing interests

C. Kratochwil is co-inventor of some patents in the field of PSMA-targeting radio-ligand therapy. The other authors have declared that no competing interest exists for this study.

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Privé, B.M., Slootbeek, P.H.J., Laarhuis, B.I. et al. Impact of DNA damage repair defects on response to PSMA radioligand therapy in metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis (2021). https://doi.org/10.1038/s41391-021-00424-2

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