Key Highlights
  • Patients with mCRPC that started from de novo mHSPC have poorer survival outcomes in comparison with patients that progressed from nmHSPC.1
  • Doublet therapy of ADT plus ARPI in mHSPC improves patients’ overall survival across all subgroups.1,2
  • Enzalutamide doublet therapy confers superior survival benefit in comparison with SoC in mHSPC.3–6
mCRPC patients that progressed from de novo mHSPC are at a significant risk for mortality and require interventions to delay disease progression
Clinical Associate Professor Daniel Shevrin from the NorthShore University Health System, USA, shared updates from the Treatment Registry Outcomes in CRPC Patients (TRUMPET) database. TRUMPET is a prospective, observational multicentre registry based in the USA that enrolled male adults with M0/M1 CRPC who began first- or second-line treatment.1

The group examined the clinical outcomes of 353 patients with M1 mCRPC who were initially diagnosed with either de novo mHSPC (n=199) or nmHSPC (n=254).1 Patients with mCRPC (that developed from de novo mHSPC) were shown to have a shorter time to metastatic disease progression as well as higher PSA levels in comparison with patients with mCRPC (that developed from nmHSPC) (Table 1).1
Table 1. Characteristics of patients at baseline mCRPC1
Although no difference was observed in either the rPFS or PSA progression between both groups, patients with mCRPC that progressed from de novo mHSPC had a shorter time to opioid initiation (OI), shorter mean survival (6.6 months), and 37% increased risk of mortality (Table 2).1 Clearly, this patient population urgently needs intervention to delay their disease progression from mHSPC to CRPC and improve their prognosis.1
Table 2. Median time to treatment outcome of the de novo mHSPC and nmHSPC groups1
The study included a sub analysis of 44 (22.1%) patients with de novo mHSPC who received treatment intensification with doublet therapy (ADT plus docetaxel or abiraterone) at initial diagnosis.1 The results showed a trend for survival improvement; the median time to death for patients who received treatment intensification was 47.7 months (95% CI; 22.18, NE) in comparison to 37.3 months (95% CI; 28.35, 43.01) for the non-intensified group.1
Treatment intensification in patients with de novo mHSPC improved survival benefits1
Treatment intensification with ARPI in mHSPC: Benefits, barriers, and the future
Professor Neeraj Agarwal from the Huntsman Cancer Institute, University of Utah, USA, spoke on the advances in mHSPC management, real-world data and its application for improving PCa outcomes.2
Is triplet therapy superior to doublet therapy?
In the past decade, clinical trials have explored the optimal treatment strategy for mHSPC i.e., continuous ADT, the addition of docetaxel, doublet therapy (ADT plus ARPI) and triplet therapy (ADT plus ARPI plus docetaxel).2 The majority of patients across all subgroups (i.e., disease volume, de novo or metachronous status, PSA level and Gleason score) have improved overall survival benefit (with risk reduction between 30% to 40%) from doublet therapy with the exception of those with visceral metastases (approximately 10% of patients with mHSPC) (Table 3).2
Table 3. Trials assessing doublet therapy (ADT plus ARPI)3
Triplet therapy has also been shown to improve overall survival in patients with mHSPC with risk reduction ranging from 25% to 32% in the PEACE-1 and ARASENS trials, respectively (Table 4).2 ENZADA, a single arm phase III study, demonstrated that triplet therapy with ADT plus enzalutamide plus docetaxel was well-tolerated and effective in improving the 52-week PSA response in patients with mHSPC.3 However, a survival benefit was not evident in patients with metachronous disease in the ARASENS trial and those with low-volume disease in the PEACE-1 study.2 Only patients with high-volume disease who are fit for chemotherapy should be considered for triplet therapy.2
Table 4. Trials with triplet therapy (ADT plus docetaxel plus ARPI)2
These compelling evidence places triplet therapy alongside doublet therapy in Category 1 evidence of the NCCN guidelines; however, no clinical trials to date have demonstrated the superiority of triplet therapy over doublet therapy.2 Consequently, ADT monotherapy has been displaced except for in exceptional circumstances (e.g., life expectancy <2 years).2
Despite the evidence, these data are not yet translated into real-world application for mHSPC; studies in Europe and the US showed that treatment intensification is not common practice.2 A survey of urologists and medical oncologists revealed a host of issues impeding them from considering treatment intensification in this patient population (Table 5).2
Table 5. Why clinicians do not choose intensified ADT2
Physicians may find it difficult to keep up to date with the latest medical literature or attend conferences where these data are presented.2 Improving access to the latest evidence via digital media, hybrid conferences and the use of electronic medical records incorporated with AI-based decision-making tools could help to address this dilemma.2
Many patients are proactive in selecting their treatment options and strategizing their desired clinical outcomes; at least 1 in 5 patients indicated that they do not rely solely on their clinicians’ recommendations in their treatment journey.2 Partnering with patients and their advocates to increase awareness of evidence-based treatment may hold the key to increasing the adoption of treatment intensification.2
The role of biomarkers in personalizing ADT intensification
PSA remains a cornerstone biomarker for assessing treatment response in PCa; patients who do not attain the optimal PSA response after initiating doublet therapy have inferior clinical outcomes in comparison with patients who do.2 Professor Agarwal postulated that patients who do not achieve the desired PSA response after starting ADT and/or ARPI doublets may benefit from adding docetaxel to their regimen.2
The use of docetaxel may be optimised in patients using selected genetic biomarkers.2 For instance, the presence of one or more tumour-suppressor genes (i.e., PTEN, RBI, TP53) may improve the patients’ prognosis with the addition of docetaxel4 while the SPOP mutation is associated with better treatment response to ADT plus ARPI therapy but not ADT plus docetaxel.5
Research into new biomarkers and genomic markers in patients with mHSPC has also shown promise for personalised treatment strategies. Several upcoming and on-going clinical trials are incorporating biomarker assessment in patients with mHSPC (Table 6).2
Table 6. Clinical trials in mHSPC patients and potential genetic biomarkers2
ADT and ARPI doublet therapy is now a mainstay of mHSPC treatment for all patients with the exception of those with visceral metastasis or other high-risk genomic features.2 Clinicians and patients alike should be made aware of its benefit in improving the survival of patients with mHSPC alongside judicious use of appropriate biomarkers to tailor the treatment approach (Figure 1).2,6
Figure 1. Potential precision therapy approaches in mHSPC6
Doublet therapy of ADT with ARPI stands to benefit most patients with mHSPC. Advocacy and better biomarkers selection can help to expand its use for the future of prostate cancer2
Recap of the ARCHES and ENZAMET trials
Enzalutamide plus ADT improves treatment outcome in patients with mHSPC
Enzalutamide is a potent ARPI that has demonstrated significant survival benefits in treating mCRPC and nmCRPC.7 Two multinational phase III studies – ARCHES and ENZAMET – assessed enzalutamide in the first-line setting of mHSPC.7–9
ARCHES recruited patients with mHSPC who were randomised to either enzalutamide plus ADT, or placebo plus ADT (SoC).7,9 ENZAMET enrolled patients with mHSPC who received either enzalutamide plus ADT or SoC.8 Patients were stratified by disease volume and prior docetaxel therapy.7-9 Both trials demonstrated the value of deploying enzalutamide with ADT as first-line treatment in mHSPC (Table 7).7-9
Table 7. ARCHES and ENZAMET trials outcomes7-9

Enzalutamide plus ADT was generally well-tolerated across both studies, demonstrating that enzalutamide doublet therapy has a role not just in mCRPC, but also in mHSPC.7–9

Enzalutamide doublet therapy confers superior survival benefit in comparison with SoC7–9
Abbreviations: ADT, androgen deprivation therapy; AI, artificial intelligence; AKT, protein kinase B; ARPI, androgen receptor pathway inhibitors; ASCO 23, American Society of Clinical Oncology Symposium 2023; BICR, blinded independent central review; BiTEs, bispecific T cell engagers; CAR T-cell, chimeric antigen receptor T-cell; CDK4/6, cyclin D kinase 4/6; CI, confidence interval; CRPC, castration-resistant prostate cancer; DDR, DNA damage repair; HR, hazard ratio; HRR, homologous recombinant repair; M0, cancer has not metastasized; M1, cancer has metastasized; mCRPC, metastatic castration-resistant prostate cancer; mHSPC, metastatic hormone-sensitive prostate cancer; mos, months; MSI, microsatellite instability; NCCN, National Comprehensive Cancer Network; NE, not estimable; NHT, novel hormonal therapy; nmCRPC, non-metastatic castration-resistant prostate cancer; nmHSPC, non-metastatic hormone-sensitive prostate cancer; NR, not reached; OI, opiate-initiation; OS, overall survival; PARPi, poly (ADP-ribose) polymerase inhibitor; PCa, prostate cancer; PD-1, programmed cell death protein 1; PET, positron emission topography; PFS, progression-free survival; PIK3A, phosphatidylinositol 3-kinase; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; PTEN, phosphatase and tensin homologue; RB1, retinoblastoma 1; rPFS, radiographic progression-free survival; SoC, standard of care; SPOP, speckle-type POZ protein; SUV, standard uptake value; TMB, tumour mutational burden; TP53, tumour protein 53; USA, United States of America; vs, versus.
References:
  1. Shevrin DH, et al. Outcomes of patients (pts) with de novo metastatic hormone-sensitive prostate cancer (mHSPC) who progressed to metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TRUMPET registry. Presented at: American Society of Clinical Oncology Genitourinary Symposium 2023; 16–18 February 2023; San Francisco, CA, USA. Poster e17085.
  2. Agarwal N. Treatment of metastatic hormone-sensitive prostate cancer: When more is more. Presented at: American Society of Clinical Oncology Genitourinary Symposium 2023; 16–18 February 2023; San Francisco, CA, USA. Presentation 214998.
  3. Burgess EF, et al. ENZAlutamide, Docetaxel, and Androgen deprivation (ENZADA) for metastatic castrate sensitive prostate cancer. Presented at: American Society of Clinical Oncology Genitourinary Symposium 2023; 16–18 February 2023; San Francisco, CA, USA. Poster 5072.
  4. Valez MG, et al. Differential impact of tumor suppressor gene (TP53, PTEN, RB1) alterations and treatment outcomes in metastatic hormone-sensitive prostate cancer. Prostate Cancer Prostatic Dis 2022;25(3):479–483.
  5. Swami U, et al. SPOP mutations as a predictive biomarker for androgen receptor axis-targeted therapy in de novo metastatic castration sensitive prostate cancer. Clin Cancer Res 2022;28(22):4917–4925.
  6. Hamid A, et al. Metastatic hormone sensitive prostate cancer: Toward an era of adaptive and personalised treatment. 2023 ASCO Educational Book. http://ascopubs.org/doi/full/10.1200/EDBK_390166. Accessed on 12 September 2023.
  7. Armstrong AJ, et al. ARCHES: A randomised, phase III study of androgen deprivation therapy with enzalutamide or placebo in men with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2019;37:2974–2986.
  8. Davis ID, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Eng J Med 2019;381:121–131.
  9. Armstrong AJ, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2022;40:1616–1622
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