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

Background. Whether disease burden in patients with metastatic castration-sensitive prostate cancer (mCSPC) predicts treatment outcomes is unknown. We assessed apalutamide treatment effect in TITAN patients with mCSPC by disease volume, metastasis number and timing of metastasis presentation.

Methods. These protocol-defined and post hoc analyses of the phase III randomised TITAN study evaluated clinical outcomes in patients receiving 240 mg/day apalutamide (n = 525) or placebo (n = 527) plus androgen-deprivation therapy (ADT). Subgroups were defined by volume (high: visceral and ≥1 bone metastases or ≥4 bone lesions with ≥1 beyond vertebral column/pelvis), development of metastases per conventional imaging (synchronous: at initial diagnosis; meta-chronous: after localised disease) and oligometastases (≤5 bone-only metastases) or polymetastases (>5 in bone ± other locations or ≤5 in bone plus other locations). Overall survival (OS), radiographic or second progression-free survival, and time to prostate-specific antigen progression or castration resistance were assessed using Cox proportional hazards models.

Results. Of 1052 patients, 63 %, 81 %, 54 %, 27 %, 5.7 %, and 8.0 % had high-volume, synchronous, synchronous/high-volume, synchronous/low-volume, metachronous/high-volume, and metachronous/low-volume disease, respectively. The OS benefit favoured apalutamide plus ADT versus ADT alone in synchronous/high-volume (hazard ratio (HR) 0.68;  95 % confidence interval (CI) 0.53–0.87; p = 0.002), synchronous/low-volume (HR 0.65; 95 % CI 0.40–1.05; p = 0.08), metachronous/high-volume (HR 0.69; 95 % CI 0.33–1.44; p = 0.32) and metachronous/low-volume (HR 0.22; 95 % CI 0.09–0.55; p = 0.001) subgroups. Apalutamide improved other clinical outcomes regardless of subgroup, with similar safety profiles. Most favourable outcomes were observed in oligometastatic disease.

Conclusion. TITAN patients derived a robust benefit with apalutamide plus ADT regardless of disease volume and timing of metastasis presentation without differences in safety, supporting early apalutamide intensification in mCSPC.

1. Francini E., Gray K.P., Xie W. 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. DOI: 10.1002/pros.23645

2. Gillessen S., Attard G., Beer T.M. et al. Management of patients with advanced prostate cancer: report of the advanced prostate cancer consensus conference 2019. Eur Urol 2020;77(4):508–47. DOI: 10.1016/j.eururo.2020.01.012

3. Sweeney C.J., Martin A.J., Stockler M.R. et al. Overall survival of men with metachronous metastatic hormone-sensitive prostate cancer treated with enzalutamide and androgen deprivation therapy. Eur Urol 2021;80(3):275–9. DOI: 10.1016/j.eururo.2021.05.016

4. 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):1695–707. DOI: 10.1016/S0140-6736(22)00367-1

5. Gillessen S., Armstrong A., Attard G. et al. Management of patients with advanced prostate cancer: report from the Advanced Prostate Cancer Consensus Conference 2021. Eur Urol 2022;82(1):115–41. DOI: 10.1016/j.eururo.2022.04.002

6. Bossi A., Foulon S., Maldonado X. 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 2 × 2 design. Presented at: 2023 ASCO Annual Meeting, Chicago, IL, USA; 2023.

7. Armstrong A.J., Szmulewitz R.Z., Petrylak D.P. 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. DOI: 10.1200/JCO.19.00799

8. Armstrong A.J., Iguchi T., Azad A.A. et al. The efficacy of enzalutamide plus androgen deprivation therapy in oligometastatic hormone-sensitive prostate cancer: a post hoc analysis of ARCHES. Eur Urol 2023;84(2):229–41. DOI: 10.1016/j.eururo.2023.04.002

9. Armstrong A.J., Iguchi T., Azad A. 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. J Clin Oncol 2021;40(Suppl.6):115. DOI: 10.1200/JCO.2022.40.6_suppl.115

10. Armstrong A.J., Iguchi T., Azad A. et al. The efficacy of enzalutamide (ENZA) plus androgen deprivation therapy (ADT) on bone oligometastatic hormone-sensitive prostate cancer: a post hoc analysis of ARCHES. J Clin Oncol 2021;39(Suppl.15):5071. DOI: 10.1200/JCO.2021.39.15_suppl.5071

11. Azad A., Villers A., Alekseev B. et al. Efficacy of enzalutamide (ENZA) plus androgen deprivation therapy (ADT) in men with de novo (M1) metastatic hormone-sensitive prostate cancer (mHSPC) versus progression to mHSPC (M0): post hoc analysis of the phase III ARCHES trial. J Clin Oncol 2021;39(Suppl.6):102. DOI: 10.1200/JCO.2021.39.6_suppl.102

12. Armstrong A.J., Azad A.A., Iguchi T. et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2022;40(15):1616–22. DOI: 10.1200/JCO.22.00193

13. Azad A.A., Armstrong A.J., Alcaraz A. et al. Efficacy of enzalutamide in subgroups of men with metastatic hormone-sensitive prostate cancer based on prior therapy, disease volume, and risk. Prostate Cancer Prostatic Dis 2022;25(2):274–82. DOI: 10.1038/s41391-021-00436-y

14. Gravis G., Boher J.M., Chen Y.H. et al. Burden of metastatic castrate naive prostate cancer patients, to identify men more likely to benefit from early docetaxel: further analyses of CHAARTED and GETUG-AFU15 studies. Eur Urol 2018;73(6):847–55. DOI: 10.1016/j.eururo.2018.02.001

15. Gravis G., Boher J.M., Joly F. 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. DOI: 10.1016/j.eururo.2015.11.005

16. Kyriakopoulos C.E., Chen Y.H., Carducci M.A. et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: long-term survival analysis of the randomized phase, respectively III E3805 CHAARTED trial. J Clin Oncol 2018;36(11):1080–7. DOI: 10.1200/JCO.2017.75.3657

17. Tripathi A., Chen Y.H., Jarrard D.F. et al. Eight-year survival rates by baseline prognostic groups in patients with metastatic hormone-sensitive prostate cancer (mHSPC): an analysis from the ECOG-ACRIN 3805 (CHAARTED) trial. J Clin Oncol 2022;40(Suppl.16):5081. DOI: 10.1200/JCO.2022.40.16_suppl.5081

18. Vale C.L., Fisher D., Godolphin P. et al. Defining more precisely the effects of docetaxel plus ADT for men with mHSPC: meta-analysis of individual participant data from randomized trials. J Clin Oncol 2022;40(Suppl.16):5070. DOI: 10.1200/JCO.2022.40.16_suppl.5070

19. Vale C.L., Fisher D.J., Godolphin P.J. et al. Which patients with metastatic hormone-sensitive prostate cancer benefit from docetaxel: a systematic review and meta-analysis of individual participant data from randomised trials. Lancet Oncol 2023;24(7):783–97. DOI: 10.1016/S1470-2045(23)00230-9

20. Hussain M., Tombal B., Saad F. et al. Darolutamide plus androgen-deprivation therapy and docetaxel in metastatic hormone-sensitive prostate cancer by disease volume and risk subgroups in the phase III ARASENS trial. J Clin Oncol 2023:JCO2300041. DOI: 10.1200/JCO.23.00041

21. Sweeney C.J., Martin A.J., Stockler M.R. 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. DOI: 10.1016/S1470-2045(23)00063-3

22. Chi K.N., Agarwal N., Bjartell A. et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med 2019;381(1):13–24. DOI: 10.1056/NEJMoa1903307

23. Chi K.N., Chowdhury S., Bjartell A. 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. DOI: 10.1200/JCO.20.03488

24. Bjartell A., Agarwal N., Karsh L. et al. Relationships of sites and burden of metastases with long-term outcomes and molecular subtypes in TITAN. Abstr MP24-08. J Urol 2021;206(Suppl.3):e414–5. DOI: 10.1097/JU.0000000000002015.08

25. Bjartell A., Ye D., Agarwal N. et al. Apalutamide (APA) for metastatic castration-sensitive prostate cancer (mCSPC) in TITAN: outcomes in patients (pts) with de novo (D1) mCSPC vs. progression to mCSPC after localized disease (D0) at diagnosis. Eur Urol Open Sci 2020;19(Suppl.2):e863. DOI: 10.1016/S2666-1683(20)33159-1

26. Chowdhury S., Bjartell A., Merseburger A.S. et al. Apalutamide (APA) for metastatic castration-sensitive prostate cancer (mCSPC): outcomes in high-volume (HV) and low-volume (LV) disease from the titan final analysis (FA). Eur Urol 2021;79(Suppl.1):S1180–1. DOI: 10.1016/S0302-2838(21)01220-3

27. Scher H.I., Halabi S., Tannock I. et al. Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol 2008;26(7):1148–59. DOI: 10.1200/JCO.2007.12.4487

28. Chi K.N., Saad F., Chowdhury S. et al. Prostate-specific antigen (PSA) kinetics in patients (pts) with advanced prostate cancer treated with apalutamide: results from the TITAN and SPARTAN studies. J Clin Oncol 2020;38(Suppl.15):5541. DOI: 10.1200/JCO.2020.38.15_suppl.5541

29. Chowdhury C., Bjartell A., Agarwal N. et al. Apalutamide for metastatic castration-sensitive prostate cancer in TITAN: prognostic importance of prostate-specific antigen responses. J Urol 2020;203(4S):e250. DOI: 10.1097/JU.0000000000000844.011

30. Chowdhury S., Bjartell A., Agarwal N. et al. Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer. Ann Oncol 2023;34(5):477–85. DOI: 10.1016/j.annonc.2023.02.009

31. Armstrong A.J., Shore N.D., Szmulewitz R.Z. et al. Efficacy of enzalutamide plus androgen deprivation therapy in metastatic hormone-sensitive prostate cancer by pattern of metastatic spread: ARCHES post hoc analyses. J Urol 2021;205(5):1361–71. DOI: 10.1097/JU.0000000000001568

32. Davis I.D., Martin A.J., Stockler M.R. et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 2019;381(2):121–31. DOI: 10.1056/NEJMoa1903835

33. National Comprehensive Cancer Network. Prostate cancer. Version 1. 2023-September 16, 2022. Available at: https://www.nccn.org/professionals/physician_gls/pdf/prostate.pdf (accessed 15th November 2022).

34. Smith M.R., Hussain M., Saad F. et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med 2022;386(12):1132–42. DOI: 10.1056/NEJMoa2119115

35. Chi K.N., Merseburger A.S., Ozguroglu M. et al. The effect of prior docetaxel (DOC) treatment on efficacy and safety of apalutamide (APA) plus androgen deprivation therapy (ADT) in patients (pts) with metastatic castration-sensitive prostate cancer (mCSPC) from TITAN. J Clin Oncol 2022;40(Suppl.6):89. DOI: 10.1200/JCO.2022.40.6_suppl.089