A randomised phase III PSMAfore study met the primary endpoint, showing significant prolongation of time to radiographic progression or death with 177Lu-PSMA-617 compared with androgen receptor pathway inhibitor (ARPI) change in taxane-naive patients with metastatic castration resistant prostate cancer (mCRPC) who had disease progression on a previous ARPI. In addition, 177Lu-PSMA-617 was more effective than a change of ARPI in prolonging the time to prostate specific antigen (PSA) progression, symptomatic skeletal events, deterioration in health-related quality of life (HRQoL), and worsening of pain, with a favourable safety profile. Overall survival (OS) was similar with 177Lu-PSMA-617 and ARPI change.
The results of the primary endpoint of radiographic progression-free survival (rPFS), the planned third interim analysis of the key secondary endpoint of OS, and several other secondary and exploratory endpoints are published by Prof. Michael J Morris of the Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center in New York, NY, USA and colleagues on 15 September 2024 in The Lancet along poster presentation at the ESMO Congress 2024 on symptomatic skeletal events, time to worsening in HRQoL and pain from the third interim analysis of the PSMAfore study.
The authors wrote in the background that for patients who have disease progression on a first-line ARPI, selection of the next appropriate therapy can be controversial. Evidence has shown that taxane-based chemotherapy is the most active therapy in this population. However, real-world data indicate that many patients and physicians select alternative therapies to avoid side-effects that can negatively impact QoL or because of a patient health status that renders taxanes medically inappropriate. A change of ARPI is a common second-line therapeutic strategy among patients for whom it is considered appropriate to delay taxane-based chemotherapy.
The VISION study showed the efficacy of 177Lu-PSMA-617 in patients with mCRPC who had received taxanes, with significant prolongation of imaging-based rPFS and OS following addition of 177Lu-PSMA-617 to the standard-of-care (SOC) versus SOC alone. In the phase II TheraP study, 177Lu-PSMA-617 was associated with improved intermediate endpoints, including PSA response, when compared with cabazitaxel for patients with mCRPC who had received docetaxel, with no difference in OS.
PSMAfore is a phase III study that was designed to compare 177Lu-PSMA-617 with a change of ARPI in taxane-naive patients with mCRPC who had progressed on ARPI as their most recent therapy, and were considered candidates for a change of ARPI. The study was conducted at 74 sites across Europe and North America. Taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who had progressed once on a previous ARPI were randomly allocated 1:1 to open-label, intravenous 177Lu-PSMA-617 at a dosage of 7.4 GBq (200 mCi) ± 10% once every 6 weeks for six cycles, or a change of ARPI to abiraterone or enzalutamide, administered orally on a continuous basis per product labelling. Crossover from ARPI change to 177Lu-PSMA-617 was allowed after centrally confirmed radiographic progression.
The primary endpoint was rPFS, defined as the time from randomisation until radiographic progression or death, assessed in the intention-to-treat population. Safety was a secondary endpoint. This study is ongoing. In this primary report of the study, the study team presents primary (first data cut-off) and updated (third data cut-off) analyses of rPFS; all other data are based on the third data cut-off.
Overall among 585 patients screened, 468 met all eligibility criteria and were randomly allocated between 15 June 2021 and 7 October 2022 to receive 177Lu-PSMA-617 (234 patients) or ARPI change (234 patients). Baseline characteristics were mostly similar between groups; median number of 177Lu-PSMA-617 cycles was 6.0 (IQR 4.0–6.0). Among patients assigned to ARPI change, 134 (57%) crossed over to receive 177Lu-PSMA-617.
In the primary analysis with a median time from randomisation to first data cut-off of 7.26 months (IQR 3.38–10.55), the median rPFS was 9.30 months (95% confidence interval [CI] 6.77–not estimable) in the 177Lu-PSMA-617 group versus 5.55 months (4.04–5.95) in the ARPI change group (hazard ratio [HR] 0.41, 95% CI 0.29–0.56; p < 0.0001).
In the updated analysis at time of the third data cut-off with a median time from randomisation to third data cut-off of 24.11 months (IQR 20.24–27.40), median rPFS was 11.60 months (95% CI 9.30–14.19) in the 177Lu-PSMA-617 group versus 5.59 months (4.21–5.95) in the ARPI change group (HR 0.49, 95% CI 0.39–0.61).
Other patient-relevant and clinically important endpoints also favoured 177Lu-PSMA-617 over ARPI change, including time to symptomatic skeletal events, time to worsening in HRQoL, pain and radiographic and biochemical PSA response rates, as well as investigator-assessed PFS and second-PFS on the next line of therapy.
The incidence of grade 3–5 adverse events was lower in the 177Lu-PSMA-617 group with at least one event occurring in 81 of 227 patients (36%) and four grade 5 (2%) but none treatment related than in the ARPI change group, 112 of 232 patients (48%) and five grade 5 (2%) of which one was treatment related.
The authors commented whether or not the high rate of crossover confounded the OS analysis will be explored at the time of the final analysis. The latest results support 177Lu-PSMA-617 as a treatment option for patients with mCRPC who have initially progressed on an ARPI and who are being considered for a change of ARPI as their next therapy.
In an accompanied comment in The Lancet, Drs. Joaquin Mateo and Amado J. Zurita wrote that 177Lu-PSMA-617 is the first approved prostate cancer therapy that follows the theranostics paradigm of drug development. Additional research will help to optimise the delivery of this theranostic approach, which depends on PSMA expression by the tumour. 177Lu-PSMA-617 is already reshaping the landscape of prostate cancer treatment, and the PSMAfore study underscores the potential of this treatment to benefit some patients in the pre-chemotherapy setting.
The study was funded by Novartis.
References
- Morris MJ, Castellano D, Herrmann K, et al. for the PSMAfore investigators. 177Lu-PSMA-617 versus a change of androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castration-resistant prostate cancer (PSMAfore): a phase 3, randomised, controlled trial. The Lancet; Published online 15 September 2024. DOI: https://doi.org/10.1016/S0140-6736(24)01653-2
- 1599P – Fizazi K, Morris MJ, Shore ND, et al.Symptomatic skeletal events, health-related quality of life and pain in a phase III study of [177Lu]Lu-PSMA-617 in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer: Third interim analysis of PSMAfore. Annals of Oncology 2024;35(Suppl 2):S964-S965.
- Mateo J, Zurita AJ. 177Lu-PSMA-617 for metastatic prostate cancer: aiming for the right spot. The Lancet; Published online 15 September 2024. DOI: https://doi.org/10.1016/S0140-6736(24)01919-6