Both men with high-risk non-metastatic prostate cancer and men with metastatic prostate cancer benefit from intensified hormone treatment

Three trials – PEACE-1, two combined STAMPEDE cohorts, and ARCHES – highlighted the benefits of treatment intensification with androgen receptor signalling inhibitors in patients with hormone-sensitive prostate cancer (HSPC).

Although treatment with androgen deprivation therapy (ADT) and local radiotherapy has improved outcome of patients with high-risk non-metastatic (M0) prostate cancer, post-treatment failure rates are high. In patients with metastatic prostate cancer, addition of abiraterone-acetate/prednisone (AAP) to ADT has proven to increase overall survival (OS). However, due to low numbers of events, no statistically significant benefit of addition of AAP to ADT was shown in patients with M0 prostate cancer [1]. To power the endpoint of metastases-free survival (MFS) in M0 patients, the STAMPEDE investigators combined M0 patients from 2 comparisons in the STAMPEDE platform protocol (NCT00268476), creating a cohort of 1,974 patients with M0 prostate cancer [2]. Patients were randomised 1:1 to ADT plus AAP (or ADT plus AAP plus enzalutamide) versus ADT alone. Of note, previous analysis of STAMPEDE showed that addition of enzalutamide to AAP did not prolong survival in men with metastatic castration-resistant prostate cancer [3]. Prof. Gerhardt Attard (UCL Cancer Institute, UK) presented the results of this analysis [4].

AAP-based therapy improved MFS, the primary endpoint (180 vs 306 events; HR 0.53; P<0.0001). At 6 years follow-up, AAP (± enzalutamide) improved MFS from 69% to 82% (see Figure 1). In addition, OS was improved by combining AAP (± enzalutamide) with ADT (HR 0.60; P<0.0001); 6-year OS rates improved from 77% to 86%; 6-year prostate cancer-specific survival improved from 85% to 93%. As expected, no extra benefit was observed from combining AAP/ADT with enzalutamide versus AAP/ADT. Extra toxicity from AAP addition was as expected, with no apparent synergistic adverse events from the combination. “These results clearly show that 2 years of AAP-based therapy significantly improves MFS and OS in men with high-risk M0 prostate cancer versus ADT alone. Therefore, this should be a new standard of care,” concluded Prof. Attard. “Adding enzalutamide to AAP increases toxicity, but has no discernible effect of efficacy.”

Figure 1: MFS in combined STAMPEDE cohorts [4]



The phase 3 PEACE-1 trial (NCT01957436) investigated the addition of AAP (± local radiotherapy) to ADT/docetaxel in men with de novo metastatic HSPC. A total of 355 patients was treated with ADT/docetaxel (“doublet”) and 355 patients were treated with AAP/ADT/docetaxel (“triplet”). Prof. Karim Fizazi (Institut Gustave Roussy, France) presented the results [5].

Like in non-metastatic men, both (radiographic) PFS and OS was improved with the addition of AAP. Median radiographic PFS was 4.5 years versus 2.0 years (HR 0.50; P<0.0001); median OS was not evaluable versus 4.4 years (HR 0.75; P=0.017). More benefit of AAP addition, both for radiographic PFS and OS, was observed in patients with high-volume metastatic burden compared with low-volume metastatic burden (median PFS: HR 0.47 vs 0.58, respectively; median OS: HR 0.72 vs 0.83, respectively). Prof. Fizazi concluded that “these results are practice changing: at least men with de novo, high-volume metastatic HSPC should be offered triple therapy.”

The randomised phase 3 ARCHES trial (NCT02677896) aimed to evaluate the efficacy and safety of the addition of enzalutamide to ADT in men with metastatic HSPC. Previous results from ARCHES showed that enzalutamide/ADT significantly reduced the risk of radiographic disease progression by 61% (P<0.001) and improved key secondary endpoints (time to PSA progression, time to initiation of new antineoplastic therapy, time to first symptomatic skeletal event, time to castration resistance, and reduced risk of pain progression), while maintaining a high quality of life versus placebo plus ADT [6]. Dr Andrew Armstrong (Duke Cancer Institute, NC, USA) presented final OS data from ARCHES [7].

In the study, 1,150 patients were randomised 1:1 to ADT/enzalutamide or ADT alone. After study unblinding, 184 patients (31.9%) randomised to ADT alone remained progression-free and crossed over tot ADT/enzalutamide. Median time to crossover was 21.5 months. Addition of enzalutamide significantly prolonged OS (HR 0.66; P<0.0001). After 4 years of follow-up, 71% of patients in the enzalutamide/ADT arm were still alive, versus 57% in the ADT alone arm (see Figure 2). Also, time to subsequent antineoplastic therapy was increased with enzalutamide/ADT versus ADT alone (HR 0.38). Benefit of enzalutamide was irrespectively of disease volume, prior local therapy, age, Gleason score, disease localisation, and PSA. Safety and toxicity were consistent with findings from the primary analysis.

Figure 2: OS in intention-to-treat population of ARCHES [7]



“The final analysis of ARCHES demonstrates that enzalutamide/ADT has a long-term survival benefit versus ADT alone in men with metastatic HSPC,” concluded Dr Armstrong.

1. James ND, et al. N Eng J Med. 2017;377:338–351.
2. Attard G, et al. Eur Urol. 2021;80:522-523.
3. Morris MJ, et al. J Clin Oncol. 2019;37:5008.
4. Attard G, et al. Abiraterone acetate plus prednisolone (AAP) with or without enzalutamide (ENZ) added to androgen deprivation therapy (ADT) compared to ADT alone for men with high-risk non-metastatic (M0) prostate cancer (PCa): Combined analysis from two comparisons in the STAMPEDE platform protocol. Abstract LBA4, ESMO Congress 2021, 16–21 September.
5. Fizazi K, et al. A phase 3 trial with a 2x2 factorial design in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): Overall survival with abiraterone acetate plus prednisone in PEACE-1. Abstract LBA5, ESMO Congress 2021, 16–21 September.
6. Armstrong AJ, et al. J Clin Oncol. 2019;37:2974–2986.
7. Armstrong AJ, et al. Final overall survival analysis from ARCHES: A phase 3, randomized, double blind, placebo-controlled study of enzalutamide plus androgen deprivation therapy in men with metastatic hormone sensitive prostate cancer. Abstract LBA25, ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November, 202119 November, 2021