Hussain et al1 reported on the randomized double-blind phase III trial ARASENS, in which patients with metastatic hormone-sensitive prostate cancer received androgen deprivation therapy (ADT) and docetaxel plus either darolutamide or placebo.1,2 Treatment intensification with darolutamide increased overall survival (OS) in the intention-to-treat population (hazard ratio [HR], 0.68 [95% CI, 0.57 to 0.80]; P < .0001) and in the post hoc defined subgroup with high-volume disease (visceral metastases and/or ≥4 bone metastases with ≥1 beyond the vertebral column/pelvis; HR, 0.69 [95% CI, 0.57 to 0.82]).1 Results were also suggestive of survival benefit in the smaller subgroup of patients with low-volume disease (HR, 0.68 [95% CI, 0.41 to 1.13]).1 It was also found that patients in the darolutamide-containing triplet therapy arm had improvement in the clinically relevant secondary end point of time to castration-resistant prostate cancer (CRPC) compared with placebo, in patients with high-volume disease (HR, 0.41 [95% CI, 0.34 to 0.49]), and in those with low-volume disease (HR, 0.21 [95% CI, 0.14 to 0.33]).1 Interpretation of these important findings needs to be nuanced, however.

Time to CRPC has been prolonged with darolutamide versus placebo. However, it should be clarified that, despite using the same term CRPC, disease state is different in the two groups. Although patients in the control arm have been exposed to ADT, those in the darolutamide arm have progressed while being additionally exposed to a second-generation androgen pathway inhibitor (API), a disease state with poorer prognosis.

The authors state that “the improvement in survival with darolutamide was observed despite more than 70% of patients in the placebo group receiving subsequent life-prolonging systemic therapies.” Details on subsequent therapies are presented in Appendix Table A1, online only.1 Among patients who entered follow-up after discontinuation of trial drugs, 75.6% (374 of 495) in the placebo group and 56.8% (179 of 315) in the darolutamide group had received one or more subsequent systemic antineoplastic therapies. One would expect that the number of subsequent lines is higher in the placebo group. However, the number of subsequent lines per patient is 1.66 (620/374) in the placebo group and 1.84 (330/179) in the darolutamide group.1 Thus, taking also into account darolutamide treatment, patients with progression in the experimental arm had received on average 2.84 drugs in addition to ADT and docetaxel, whereas those in the placebo arm received only 1.66 drugs in addition to ADT and docetaxel. This difference can blur interpretation of OS data. One may also question why 18% of patients in the placebo arm were rechallenged with docetaxel,1 with no information on whether they did receive an API (eg, abiraterone acetate or enzalutamide) at any time after progression. Since OS was the primary end point, it would have been important that adequate subsequent therapies be defined beforehand and reasons for nonadherence (unavailability, cost, fitness, toxicity, etc) be explained.

Intensification with triplet therapies in hormone-sensitive metastatic prostate cancer must be weighed carefully. Although ARASENS showed good efficacy with darolutamide + ADT + docetaxel1 and PEACE-1 showed good efficacy with abiraterone acetate + ADT + docetaxel,3 the specific role of docetaxel within triplet regimens cannot be answered by these trials. Through indirect comparisons, a recent network meta-analysis concluded that, as compared with a doublet therapy of ADT + an API, the benefit with docetaxel-containing triplet regimens as regards OS was uncertain, whereas adverse events were increased.4

Novel therapies, such as radioligand therapy targeting prostate-specific membrane antigen (PSMA) with 177Lu-PSMA-617 and poly (ADP-ribose) polymerase (PARP) inhibitors,5,6 which offered excellent results with low toxicity in heavily pretreated patients, are now being actively investigated in the earlier setting, including in taxane-naïve patients. For example, in BRCA-altered patients who had disease progression after treatment with an API for CRPC or hormone-sensitive disease, the PARP inhibitor rucaparib resulted in improved imaging-based progression-free survival compared with the use of docetaxel or an alternative API (median, 11.2 months v 6.4 months; HR, 0.50 [95% CI, 0.36 to 0.69]).6 Hence, one disadvantage of upfront treatment intensification with docetaxel-containing triplet therapies is that it might hamper the implementation of novel sequencing strategies. The opinion of the authors on these points would be appreciated.

© 2023 by American Society of Clinical Oncology
Triplet Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer

The following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to or

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

No potential conflicts of interest were reported.

1. 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 41:3595-3607, 2023 LinkGoogle Scholar
2. Smith MR, Hussain M, Saad F, et al: Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med 386:1132-1142, 2022 Crossref, MedlineGoogle Scholar
3. 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 399:1695-1707, 2022 Crossref, MedlineGoogle Scholar
4. Riaz IB, Naqvi SAA, He H, et al: First-line systemic treatment options for metastatic castration-sensitive prostate cancer: A living systematic review and network meta-analysis. JAMA Oncol 9:635-645, 2023 Crossref, MedlineGoogle Scholar
5. Sartor O, de Bono J, Chi KN, et al: Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med 385:1091-1103, 2021 Crossref, MedlineGoogle Scholar
6. Fizazi K, Piulats JM, Reaume MN, et al: Rucaparib or physician's choice in metastatic prostate cancer. N Engl J Med 388:719-732, 2023 Crossref, MedlineGoogle Scholar



DOI: 10.1200/JCO.23.00686 Journal of Clinical Oncology 41, no. 22 (August 01, 2023) 3873-3874.

Published online May 31, 2023.

PMID: 37257146

ASCO Career Center