Reduced risk for MACE with enzalutamide in prostate cancer compared to abiraterone acetate and apalutamide: Real-world evidence

PCa is the second most common type of cancer in men, estimated to have caused 375,304 deaths worldwide in 2020.1 ADT, a vital and efficacious component of PCa treatment, has been demonstrated to increase the risks of CVD-related deaths, non-fatal CVD, myocardial infarction and stroke.2 Hence, when cancer-related causes are ruled out, CVD is found to be the leading cause of death in PCa, attributed to heightened risks associated with ADT and accumulated stress.1,2 Dr Liu and colleagues examined real-world evidence from the open FAERS (US FDA Adverse Events Reporting System) database to assess PV, reporting rate and reaction outcomes of CV-related adverse events, particularly for MACE, in prostate cancer patients treated with three ARPI drugs: abiraterone acetate, apalutamide and enzalutamide.3 The data was collected between January 2014 and December 2022.3 The data was subjected to proportionate analysis (i.e., proportional reporting ratio, reporting odds ratio and information component) the higher the correlation between the specific drugs and adverse events, the higher the value of the indicators.3 A predetermined threshold value determined whether the PV signal had been detected.3 Traditional statistical analysis was also used, including logistic regression to compare constituent ratio of MACE and severe MACE, and ordinal logistic regression to compare severity of reaction outcomes for ordinal multiclassified data of MACE.3 The disproportionality analysis to compare MACE and other CV events in patients receiving ARPIs showed that abiraterone acetate had the highest PV signal, followed by apalutamide (Table 1).3 PV signal of MACE was not detected in enzalutamide but was detected in abiraterone acetate and apalutamide.3

The total number of MACE reports related to ARPI was 2,602 with the most reports due to enzalutamide (67.2%), followed by abiraterone acetate (28.2%) and apalutamide (4.6%).3 The most common MACE reported was non-fatal stroke (44.8%), CV death (34.3%) and non-fatal myocardial infarction (20.9%).3

The constituent ratio of MACE reported in patients administered with abiraterone acetate and apalutamide was significantly higher compared to enzalutamide, with no statistical differences between abiraterone acetate and apalutamide (Table 2).3 A similar observation was seen in cardiovascular death, nonfatal myocardial infarction and nonfatal stroke, which underlined the reduced risk of MACE and other CV-related adverse events with enzalutamide based on constituent ratio analysis.3

In the case of severe MACE, abiraterone acetate (OR, 0.01; 95% CI, 0.00–0.11; p<0.001) and apalutamide (OR, 0.0; 95% CI, 0.00–0.68; p=0.026) had significantly decreased incidence in comparison with enzalutamide, with no significant difference between abiraterone acetate and apalutamide (OR, 6.15; 95% CI, 0.12–311.24; p=0.365).3

Progress in PCa treatment has lowered cancer-related deaths, but have given rise to an increased risk of CVD-related mortality; thus, prioritising the reduction of CV-related deaths is crucial in treatment evaluations.1,2 This study is the first original study on disproportionality analysis of CV adverse events – especially MACE – in new-generation ARPIs using the FAERS database.3 However, it is subject to limitations such as the lack of follow-up data, reporting bias, and the possibility of missing data and errors in the database which may have affected the accuracy of the results.3 This report suggests that enzalutamide may be a potentially favourable option for PCa, especially in patients with additional CVD risks, however, larger prospective studies with longer follow-up periods are needed to confirm this.3

Enzalutamide was associated with the lowest risk for MACE and other CV-related adverse events in comparison with abiraterone acetate and apalutamide according to real-world evidence3

Optimal patient selection for treatment intensification in mHSPC and nmHSPC: A debate between doublet and triplet therapy

The 10th Joint Scientific Meeting of The Royal College of Radiologists & Hong Kong College of Radiologists and the 31st Annual Scientific Meeting of Hong Kong College of Radiologists were held on 18 and 19 November 2023. At the lecture supported by Astellas, Dr Anis Hamid shared insights into the role of triplet systemic therapy with ADT, docetaxel chemotherapy and next-generation hormonal agents in mHSPC and nmHSPC.

Evolution of mHSPC treatment over the last decade
The treatment landscape for prostate cancer has changed significantly in the last decade. The combination
of ADT plus docetaxel has been used in early stages of mHSPC and in non-metastatic settings.4-7 However,
treatment selection and optimal treatment sequencing remain as key challenges in the metastatic setting.
While it is uncertain whether all patients will benefit from systemic triplet therapy, emerging evidence has shown its role in mHSPC. The doublet and triplet combination of ADT, docetaxel, NHT such as abiraterone, enzalutamide, apalutamide and darolutamide, or EBRT have been evaluated in various clinical trials.4

Practice-changing data from CHAARTED
The survival benefit of ADT plus docetaxel in newly diagnosed mHSPC demonstrated in the phase 3 randomised CHAARTED trial has led to significant changes in clinical practice, including upfront chemohormonal therapy, which was previously offered at the onset of castration-resistant disease.6,8 CHAARTED also provided insights into the prognostic significance of risk stratification by volume of disease (high versus low) and presentation (metachronous versus synchronous).8 The prognostic gradient in mHSPC, driven by volume of disease and presentation, was confirmed in the STOPCAP M1 collaborative individual participant data meta-analysis.9

Clinical trials evaluating doublet therapies confirmed benefits of NHT plus ADT
Several clinical trials had confirmed the survival benefits of the addition of NHT to ADT over ADT alone in mHSPC. Notably, the survival benefits of NHT plus ADT were observed irrespective of docetaxel administration (Table 3).7,8,10-14

Clinical trials informing the use of systemic triplet therapy in mHSPC
With positive findings from clinical trials evaluating doublet therapies, the question arises on the advantages of systemic triplet therapy in mHSPC. At present, the ENZAMET, ARASENS and PEACE-1 trials provide evidence on the addition of enzalutamide, darolutamide and abiraterone, respectively, to an ADT plus docetaxel backbone to guide the use of systemic triplet therapy in mHSPC.12,15-17

The international, open-label, randomised phase 3 ENZAMET trial of ADT plus enzalutamide showed significant OS improvement over ADT plus a NSAA.12 The OS benefit was consistent across clinical subgroups, including volume of disease, presentation and concurrent docetaxel use.12 OS benefit of enzalutamide was also observed in patients aged 70 years and above irrespective of docetaxel use.12 With the addition of enzalutamide, patients without planned use of concurrent docetaxel had significantly improved PSA, PFS and prostate cancer-specific survival.12 The OS benefit in patients without or with planned use of concurrent docetaxel is shown in Figure 1.12

Adverse events leading to enzalutamide discontinuation were more common in older patients aged 70 years and above compared with younger patients, highlighting the importance of monitoring in older patients.18 While no prospective randomised trials have addressed whether the addition of docetaxel to ADT plus ARSI is superior to ADT plus ARSI alone, indirect evidence from exploratory analyses of ENZAMET have shown early improvements in prostate cancer-specific mortality and OS with triplet therapy in the synchronous, high-volume subgroup.12 This suggests the benefit of systemic triplet therapy over ADT plus ARSI alone in patients with synchronous, high-volume mHSPC.

Translating clinical data to clinical practice: Management considerations for patients with mHSPC
A 66-year-old retired teacher with no other significant personal history was diagnosed with intermediate-risk (Gleason score of 4+3) prostate cancer in 2010 (Figure 2).19 He underwent radical prostatectomy but experienced biochemical recurrence 3 years later, for which he received salvage radiation and a short-course ADT.19 In 2017, the patient was found to have a rising PSA of 11.5 ng/mL and PSMA PET scan revealed novel metastatic disease in the para-aortic, aortocaval, retrocaval and retrocrural regions.19

The patient was diagnosed with metachronous, low-volume mHSPC and ADT plus NHT was initiated. The decision to use doublet therapy took into consideration the best supportive care for this patient, the need for ADT, and systemic therapy intensification. As the patient has previously received salvage radiation, there was no clear role of giving radiation again. Nonetheless, radiotherapy could be considered for patients with intact prostate or untreated prostate cancer. Lastly, patient counselling on germline and somatic genomic profiling is increasingly important to inform treatment decision.

The importance of upfront intensification has been shown in clinical trials. Specifically, the ENZAMET trial of ADT plus enzalutamide has shown good disease control and prolonged OS in early disease states.12 Of those with metachronous low-volume disease not treated with docetaxel, the 5-year OS rate was 82% in the enzalutamide arm and 65% in the control arm, whereas in those with synchronous high-volume disease not treated with docetaxel, the 5-year OS rate was 56% in the enzalutamide arm versus 41% in the control arm.12 The trial also reported 40% non-prostate cancer deaths at 5-years in the metachronous low-volume group treated with enzalutamide.12

Clinical trials evaluating the benefit of treatment intensification in nmHSPC
The STAMPEDE trial, which used a multigroup, multistage platform design, demonstrated the benefit of early intensification in a high-risk non-metastatic setting.20 The study has a high-risk cohort, with 39% of patients having node-positive disease and a median PSA of 34 ng/mL.20 The MFS was significantly longer in patients receiving ADT plus abiraterone and prednisolone with or without enzalutamide than in those receiving ADT alone (HR, 0.53; 95% CI, 0.44–0.64; p<0.0001).20 The 6-year MFS was 82% in the combination therapy group versus 69% in the control group.20

The EMBARK trial is another study in the nmHSPC setting. It is a phase 3, randomised study evaluating androgen receptor blockade in patients with high-risk biochemical recurrence.21 The efficacy and safety of leuprolide alone was compared with enzalutamide plus leuprolide and enzalutamide monotherapy (Figure 3).21 The primary endpoint was MFS in the enzalutamide plus leuprolide group as compared with the leuprolide-alone group, whereas a key secondary endpoint is MFS in the enzalutamide monotherapy group as compared with the leuprolide-alone group.21

The role of biomarkers in refining treatment selection
The treatment landscape for mHSPC continues to evolve and biomarkers are increasingly important in informing treatment selection. Biomarker development in mHSPC leverages the knowledge from genomic profiling of both localised and metastatic prostate cancer.22 For instance, the transcriptional profiling of patients in the CHAARTED trial has shown that high Decipher risk and lower androgen receptor activity were associated with shorter OS regardless of disease volume and metastatic timing.22 This suggests the prognostic and predictive roles for transcriptional profiling in mHSPC.

Patients with mHSPC may benefit from treatment intensification; additional data is required to precisely stratify the patient population for targeted therapy19

Disclaimer: Information provided may contain information on unapproved indication. Information provided is for education only. Please always refer to your locally approved prescribing information before prescribing.

Abbreviations: ADT, androgen-deprivation therapy; ARPI, androgen receptor pathway inhibitors; BCR, biochemical recurrence; CI, confidence interval; CV, cardiovascular; CVD, cardiovascular disease; CT, computed tomography; DT, doubling time; EBRT, external beam radiotherapy; ECOG, Eastern Cooperative Oncology Group; FAERS, United States Food and Drug Administration Adverse Events Reporting System; FDA, Food and Drug Administration; HR, hazard ratio; HV, high-volume disease; MACE, major adverse cardiovascular events; mets, metastases; MFS, metastasis-free survival; mHSPC, metastatic hormone-sensitive prostate cancer; NA, not applicable; NHT, novel hormonal therapy; NR, not reached; NSAA, nonsteroidal antiandrogen agent; MRI, magnetic resonance imaging; OR, odds ratio; OS, overall survival; PBO, placebo; PCa, prostate cancer; PRR, proportional reporting ratio; PSA, prostate-specific antigen; PSMA-PET, prostate-specific membrane antigen positron emission tomography; PV, pharmacovigilance; ROR, reporting odds ratio; RP, radical prostatectomy; RT, radiotherapy; SoC, standard of care; US, United States; vs, versus; w, week.

References:

  1. Stabellini N, et al. Allostatic load and cardiovascular outcomes in males with prostate cancer. JNCI Cancer Spectrum 2023;7(2):pkad005.
  2. Chan JSK, et al. Temporal trends in cardiovascular burden among patients with prostate cancer receiving androgen deprivation therapy: A population-based cohort study. Br J Cancer 2023;128:2253–2260.
  3. Liu Y, et al. Cardiovascular adverse events associated with new-generation androgen receptor pathway inhibitors (ARPI) for prostate cancer: A disproportionality analysis based on the FDA Adverse Event Reporting System (FAERS). Clin Genitourinary Cancer 2023;21(5):594–601.
  4. Schulte B, et al. Sorting through the maze of treatment options for metastatic castration-sensitive prostate cancer. Am Soc Clin Oncol Educ Book 2020;40:198-207.
  5. Gravis G, et al. Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): A randomised, open-label, phase 3 trial. Lancet Oncol 2013;14:149-158.
  6. Sweeney CJ, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med 2015;373:737-746.
  7. Clarke NW, et al. Addition of docetaxel to hormonal therapy in low- and high-burden metastatic hormone sensitive prostate cancer: long-term survival results from the STAMPEDE trial. Ann Oncol 2019;30:1992-2003.
  8. Kyriakopoulos CE, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer: Long-term survival analysis of the randomized phase 3 E3805 CHAARTED trial. J Clin Oncol 2018;36:1080-1087.
  9. Vale CL, 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;24:783-797.
  10. Fizazi K, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): Final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol 2019;20:686-700.
  11. James N, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med 2017;377:338-351.
  12. Sweeney CJ, 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;24:323-334.
  13. Armstrong AJ, et al. Improved survival with enzalutamide in patients with metastatic hormone-sensitive prostate cancer. J Clin Oncol 2022;40:1616-1622.
  14. Chi KN, 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.
  15. Smith MR, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Eng J Med 2022;386:1132-1142.
  16. Hussain M, 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;41:3595-3607.
  17. Fizazi K, 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 Oncol 2022;399:1695-1707.
  18. Horvath LG, et al. Effects of enzalutamide on overall survival +/- early docetaxel in participants aged less than 70 yrs versus greater than or equal to 70 years in ENZAMET (ANZUP 1304). Ann Oncol 2023;34(suppl_2):S954-S100010.1016/annonc/annonc1334.
  19. Hamid AA. Optimal patient selection for treatment intensification in mHSPC: A debate between doublet and triplet therapy. Presented at: 10th Joint Scientific Meeting of The Royal College of Radiologists & Hong Kong College of Radiologists and the 31st Annual Scientific Meeting of Hong Kong College of Radiologists; 18–19 November 2023; Hong Kong.
  20. Attard G, et al. Abiraterone acetate and prednisolone with or without enzalutamide for high-risk non-metastatic prostate cancer: a meta-analysis of primary results from two randomised controlled phase 3 trials of the STAMPEDE platform protocol. Lancet 2022;399:447-460.
  21. Freedland SJ, et al. Improved outcomes with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med 2023;389:1453-1465.
  22. Hamid AA, et al. Transcriptional profiling of primary prostate tumor in metastatic hormone sensitive prostate cancer and association with clinical outcomes: Correlative analysis of the E3805 CHAARTED trial. Ann Oncol 2021;32:1157-1166.

You may refer to the abbreviated prescribing information here.

We respect your privacy policy. For more information, please view our privacy policy. All adverse events should be reported to pv@hk.astellas.com.

Astellas Pharma Hong Kong Co. Ltd.
Unit 1103-08, 11/F,
Tower 1, Grand Century Place,
193 Prince Edward Road West, Mongkok, Kowloon.
Tel: (852) 2377 9801 | Fax: (852) 2856 1440

MAT-HK-XTD-2024-00008