Dr Eleni Efstathiou from the Houston Methodist Cancer Center in Houston, USA delivered the state-of-the-art lecture in a thematic session on mHSPC management, which discussed the development of doublet and triplet therapy options for the upfront treatment of PCa.1 Given consistent survival benefits demonstrated by doublet therapy over ADT alone from mHSPC trials between 2015–2020, Dr Efstathiou believes there was “no question” that doublet therapy offers a longer duration of OS and failure-free survival than ADT alone (Figure 1).1,4,5
At EAU 2022, experts reviewed the state of the art for treating mHSPC, including discussing doublet vs triplet therapy for patients with the evolution of clinical trials1 and the future perspectives in management of mHSPC.2 A post-hoc analysis from the ARCHES study was also presented analyzing clinical outcomes for mHSPC patients whose PSA was reduced to undetectable levels and potential predictors for achieving the undetectable PSA level.3 Detailed highlights from these presentations are provided below.
State-of-the-art Lecture – Doublet vs Triplet in mHSPC: Requirements vs Choices in the Upfront Treatment of PCa1
Dr Eleni Efstathiou from the Houston Methodist Cancer Center in Houston, USA delivered the state-of-the-art lecture in a thematic session on mHSPC management, which discussed the development of doublet and triplet therapy options for the upfront treatment of PCa.1 Given consistent survival benefits demonstrated by doublet therapy over ADT alone from mHSPC trials between 2015–2020, Dr Efstathiou believes there was “no question” that doublet therapy offers a longer duration of OS and failure-free survival than ADT alone (Figure 1).1,4,5
Figure 1. Network comparisons of the effect of combination therapies compared with ADT alone4

Dr Efstathiou also pointed out that an incremental, stage-related change in survival benefits associated with the timing of inclusion of ASI therapy.1 Administering ASI therapy during the earlier stages of PCa (mHSPC) can increase survival compared with waiting until a patient has castration-resistant disease.1

Survival benefits (a 24–39% of reduction in risk of death) were driven by the doublet combination of ADT + ASI or docetaxel, despite clear differences among trials in terms of patients’ inclusion criteria and subsequent therapy (Table 1). From 2021, a 25–33% reduction in the risk of death was demonstrated in PEACE-1 and ARASENS with the triplet combination of abiraterone/darolutamide + docetaxel and ADT over docetaxel and ADT (Table 1).6,7

Table 1. Evolution of trials in mHSPC: 2015–2022 progress report with latest OS benefits released
With the evolution of mHSPC trials from doublet to triplet combination in 2015–2022, Dr Efstathiou concluded1:
1
Monotherapy with ADT is unethical for the average patient
2

Doublet therapy with ADT + enhanced ASI is a requirement

3

ADT and docetaxel is no-longer an acceptable choice based on recent trials

4
ADT and docetaxel + (enhanced) ASI therapy as a triplet is an acceptable and effective upfront treatment option, especially for de novo metastatic high-volume disease
“Earlier combinational treatment with ‘enhanced’ ASI therapy is a requirement for men with advanced HSPC” – Dr Eleni Efstathiou1
State-of-the-art Lecture – Future Perspectives in the Management of mHSPC
Dr Eugen Jan Karol Axcrona from the Department of Urology, Akershus University Hospital, Oslo in Norway discussed future perspectives in the management of mHSPC, focusing on the development of modern imaging (PSMA PET CT), genomics and biomarkers to optimize the upfront treatment strategy as follows.2
Is there a benefit in adding docetaxel or local treatment to MAB with a modern ARTA?
A shift beyond simple volume definition of PCa is required.2 Docetaxel seems to lose efficacy with lower volume, while local treatment loses efficacy with higher volume. Therefore, better biomarkers are required to guide treatment selection.2
Is there a benefit of metastatic targeted therapy for patients with oligometastatic disease?
Evidence in favour of this treatment is currently extrapolated from small phase 2 trials in patients with rising PSA, so more trials are necessary that will require an improved understanding of the prognostic value of new imaging modalities (e.g. PSMA PET CT).2 PSMA PET CT was recommended in the EAU guidelines as being more accurate for staging than CT and bone scan for high-risk localized disease, but no outcome data exists to inform subsequent management.2 PSMA PET CT may not be necessary for mHSPC patients with suspected high-volume disease on conventional imaging but this could be utilized in patients with potential low-volume disease particularly when planning local treatment.2 PSMA PET CT can help determine a proper volume definition to guide treatment decisions and can also act as a biomarker.2
What information is required to help develop novel targeted therapies?

PCa requires further classification to facilitate the development of more targeted treatment, but there are limits to what can be achieved.2 A genomic approach can be problematic because of genomic heterogeneity in both the primary PCa and distant metastatic lesions.2

Clinical trial data also needs to be supplemented with ‘big data from the real world’ using electronic health records and artificial intelligence to aid analysis.2

“PSMA PET CT should be incorporated in future studies in mHSPC, to secure a proper volume definition of diseases and give possibility to evaluate various treatments
– Dr Eugen Jan Karol Axcrona2

ARCHES Post-hoc Analysis – Clinical Outcomes of mHSPC Patients with PSA Decline to Undetectable Levels on Xtandi® + ADT

Prof. Arnulf Stenzl, the Medical Director of the Department of Urology from University of Tübingen in Germany, presented a post-hoc analysis evaluating the association of PSA decline to undetectable PSA levels (<0.2 ng/mL) and clinical outcomes in mHSPC patients from the Phase 3 ARCHES trial, which showed significantly rPFS and OS improvement by Xtandi® + ADT over placebo + ADT and determining predictors of PSA decline to undetectable levels for patients treated with Xtandi® + ADT through a stepwise multivariate analysis.3

Patients treated with Xtandi® + ADT were approximately four times more likely to achieve undetectable PSA than those treated with placebo + ADT.3 A reduced risk of death was observed in patients with undetectable PSA levels in both the Xtandi® arm (76% reduction; p<0.0001) and the placebo arm (65% reduction; p=0.0003) (Figure 2).3

Figure 2. Proportion of patients with undetectable PSA in the ARCHES trial
Patients in Xtandi® arm with undetectable PSA levels had improved rPFS, OS and secondary clinical outcomes compared with patients with detectable PSA levels after treatment (Table 2).3 In total, 42% and 70% of patients initially in the placebo arm received Xtandi® with the median time to crossover of 21.5 months and proven life-prolonging therapy subsequent to study treatment, respectively.12
Table 2. rPFS and OS outcomes for mHPSC patients with or without undetectable PSA levels3

Compared with patients with detectable PSA levels, patients on Xtandi® + ADT with undetectable PSA levels had higher FACT-P scores at baseline that were sustained over time and delayed deterioration in overall QoL, which was not observed in patients treated with placebo + ADT.3

An absence of metastatic disease at initial diagnosis (M0 vs M1: OR, 4.33; p=0.0013) and a low baseline PSA level
(<7.2 ng/mL) were identified as potential predictors for achieving undetectable PSA with Xtandi® + ADT.3

Improved rPFS, OS and other clinical outcomes in mHSPC patients who achieved undetectable PSA levels in which 4 times more patients treated with Xtandi® + ADT reached undetectable PSA levels than patients on placebo + ADT3
Abbreviations: Abi, abiraterone; ADT, androgen deprivation therapy; Apa, apalutamide; ARTA, androgen receptor-targeted agent; ASI, androgen-signaling inhibitors; Bis, bisphosphonate; Cel, celecoxib; CI, confidence interval; CrI, credible interval; CT, computerized tomography; Doc, docetaxel; FACT-P, Functional Assessment of Cancer Therapy – Prostate; HR, hazard ratio; MAB, maximum androgen blockade; mHSPC, metastatic hormone-sensitive prostate cancer; NE, not estimable; OR, odds ratio; OS, overall survival; PCa, prostate cancer; PET, positron emission tomography; PSA, prostate-specific antigen; PSMA, prostate-specific membrane antigen; QoL, quality of life; rPFS, radiographic progression-free survival.

References:
  1. Efstathiou E. Doublet vs triplet in mHSPC: Choices vs requirements in the upfront treatment of advanced prostate cancer. Presented at: 37th Annual European Association of Urology Congress; 1–4 July 2022; Amsterdam, The Netherlands.
  2. Axcrona EJK. Future perspectives in the management of mHSPC: Where are we heading to? Presented at: 37th Annual European Association of Urology Congress; 1–4 July 2022; Amsterdam, The Netherlands.
  3. Stenzl A, Shore ND, Villers A, et al. Clinical outcomes of patients with mHSPC with PSA decline to undetectable levels on enzalutamide: Post-hoc analysis of ARCHES. Presented at: 37th Annual European Association of Urology Congress; 1–4 July 2022; Amsterdam, The Netherlands.
  4. Chen J, Ni Y, Sun G, et al. Comparison of current systemic combination therapies for metastatic hormone-sensitive prostate cancer and selection of candidates for optimal treatment: a systematic review and Bayesian network meta-analysis. Front Oncol 2020;10:519388.
  5. Schulte B, Morgans AK, Shore ND, Pezaro C. Sorting through the maze of treatment options for metastatic castration-sensitive prostate cancer. Am Soc Clin Oncol Educ Book 2020;40:1-10.
  6. 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;399:1695-1707.
  7. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med 2022;386:1132-1142.
  8. Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373:737-746.
  9. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet 2016;387:1163-1177.
  10. Fizazi K, Tran NP, Fein L, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med 2017;377:352-360.
  11. James ND, Clarke NW, Cook A, et al. Abiraterone acetate plus prednisolone for metastatic patients starting hormone therapy: 5-year follow-up results from the STAMPEDE randomised trial (NCT00268476). Int J Cancer 2022;151:422-434.
  12. Armstrong AJ, Azad AA, Iguchi T, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2022;40:1616-1622.
  13. Davis ID, Martin AJ, Zielinski RR, et al. ENZAMET 5-year update – Xtandi® plus ADT provided a statistically significant Improvement in OS for patients with mHSPC over the active comparator. J Clin Oncol 2022;40(17_Suppl):LBA5004.
  14. Chi KN, 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;39:2294-2303.

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