medwireNews: The combination of enzalutamide and Lutetium-177-prostate-specific membrane antigen-617 (LuPSMA) has shown synergistic activity for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in the ENZA-p trial.
The phase II study was reported at the ESMO Congress 2023 in Madrid, Spain, by Louise Emmett, from St Vincent’s Hospital in Darlinghurst, New South Wales, Australia, who said that the addition of LuPSMA to enzalutamide demonstrated “strong evidence of enhanced anticancer activity” against a control that is an “active, life-prolonging treatment”.
The presenter explained that the PSMA receptor and the androgen receptor (AR) work on the same pathway in prostate cancer and that the PSMA receptor is upregulated when the AR is blocked, resulting in enzalutamide resistance in cells with high expression of PSMA receptors.
Noting that a proportion of participants in the PREVAIL trial of enzalutamide had early resistance or treatment failure, the investigators hypothesised that combining the two treatments would aid this patient population by targeting enzalutamide-resistant tumour cells and leaving low-expression cells that are more likely to respond to the AR inhibitor.
To test this hypothesis, the team recruited chemotherapy-naive patients who had a rising prostate-specific antigen (PSA) level of 5 ng/mL or higher, a positive positron emission tomography (PET) scan for PSMA, and at least two risk factors for resistance to enzalutamide. These criteria included metastasis within 3 years of diagnosis or de novo metastasis on diagnosis; visceral metastases or bone metastases at more than five sites; a PSA doubling time of less than 84 days; prior use of abiraterone or pain requiring opiates.
Louise Emmett noted that over half (59–61%) of patients in the trial had 20 or more PSMA-avid metastases or the presence of de novo metastases at diagnosis (52–58%) or had received docetaxel for hormone-sensitive disease (53–56%). But only a small proportion had previously been treated with abiraterone (11–14%).
The patients were randomly assigned to receive enzalutamide 160 mg alongside two or four doses of LuPSMA 7.5 GBq at 6-week intervals (n=83) or enzalutamide alone (n=79). The number of LuPSMA doses was determined by the presence or absence of persistent PSMA-positive disease at the day 92 PET scan and the majority (81%) of patients in the LuPSMA arm received four doses, the presenter said.
The primary endpoint of PSA progression-free survival (PFS) at the preplanned interim analysis, after a median follow-up of 20 months and 117 events, was “strongly positive” for the combination regimen, reported Louise Emmett. The median duration was 13.0 months versus 7.8 months with monotherapy, giving a significant hazard ratio (HR) of 0.43.
There was also a trend towards better radiographic PFS with LuPSMA plus enzalutamide (16 vs 12 months, HR=0.67) and statistically significant improvements in PSA response of at least 50% (93 vs 68%) and at least 90% (78 vs 37%).
Moreover, there were comparable rates of adverse events (AEs) in the LuPSMA plus enzalutamide and enzalutamide-only treatment arms, at grade 12 (85 vs 81%) and grade 4–5 (6 vs 4%), as well as for serious AEs (33 vs 35%), the investigator said. The higher rate of grade 3 events with the combination treatment (10 vs 4%) was attributed to haematological AEs such as anaemia.
The presenter summarised that toxicity could be minimised by continuing delivery of LuPSMA only to patients with PSMA-avid disease, while increasing the number of potential doses to six might further improve PFS for patients with a high burden of androgen-resistant clones.
Louise Emmett emphasized that this strategy might “become more important as we move this radiation treatment earlier in the disease paradigm to hormone-sensitive prostate cancer.”
She concluded that PFS and overall survival follow-up will continue until July 2024 and translational analysis is ongoing.
Discussing the presentation at the session, Daniel Heinrich, from Innlandet Hospital in Brummunddal, Norway, noted that the ENZA-p primary endpoint was “obviously positive” for this “feasible combination”, especially with the adaptive approach to dosing reducing accumulative AEs.
However, he added that approval of other mCRPC treatments has been based on overall survival and longer follow-up for this and other secondary endpoints is required.
Reference
LBA84 - Emmett L, Subramaniam S, Crumbaker M, et al. Enzalutamide and 177Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer (mCRPC): A randomised, phase II trial: ENZA-p (ANZUP 1901). Ann Oncol 2023;34:S2(S1325). DOI: 10.1016/j.annonc.2023.10.086
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