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177Lu-PSMA-617 represents an acceptable option for patients with metastatic castration-resistant prostate cancer who are progressing after docetaxel, as it has been shown to provide similar overall survival benefit to that of cabazitaxel, with a stronger progression-free survival benefit and fewer toxicities
177Lu-PSMA-617 (LuPSMA; lutetium Lu 177 vipivotide tetraxetan; Pluvicto) represents an acceptable option for patients with metastatic castration-resistant prostate cancer (mCRPC) who are progressing after docetaxel, as it has been shown to provide similar overall survival (OS) benefit to that of cabazitaxel (Jevtana), with a stronger progression-free survival (PFS) benefit and fewer toxicities.1
Data from the TheraP trial (NCT03392428), which were presented during the 2022 ASCO Annual Meeting, showed that at 36 months of follow-up, there was no statistically significant or clinically meaningful difference in OS between the LuPSMA and cabazitaxel arms. The restricted mean survival time (RMST) in the investigative arm was 19.1 months (95% CI, 16.9-21.4) vs 19.6 months (95% CI, 17.4-21.8) in the control arm (HR, 0.97; 95% CI, 0.70-1.4; P = .99).
However, LuPSMA was found to significantly improve progression-free survival (PFS) over cabazitaxel, with a RMST of 7.1 months (95% CI, 5.9-8.4) and 5.0 months (95% CI, 4.2-5.8), respectively, translating to a 38% reduction in the risk of disease progression or death (HR, 0.62; 95% CI, 0.45-0.85; P = .0028).
“The TheraP data support the choice of LuPSMA over cabazitaxel for patients with prostate-specific membrane antigen–positive mCRPC after docetaxel and androgen receptor pathway inhibition, on the basis of its higher prostate-specific antigen [PSA] response rate, greater PFS benefit, quality-of-life benefits, favorable safety profile and dosing schedule, and similar survival outcomes,” Michael S. Hofman, MBBS (Hons), FRACP, FAANMS, director of the Prostate Cancer Theranostics and Imaging Centre of Excellence at the Peter MacCallum Cancer Centre, said in a presentation on the data.
TheraP, the first randomized controlled trial of LuPSMA, enrolled patients with mCRPC following docetaxel treatment, who had a rising PSA and a PSA of at least 20 ng/mL. To be eligible for enrollment, patients were required to have an ECOG performance status of 0 to 2. Patients underwent PET imaging with 68Ga-PSMA-11 and needed to have high prostate-specific membrane antigen (PSMA) expression. Patients could not have FDG-positive/PSMA-negative sites of disease.
A total of 291 patients were screened for the study, and 200 were deemed eligible for inclusion. These patients were randomized 1:1 to receive treatment with either LuPSMA, given at 8.5 GBq every 6 weeks for a maximum of 6 cycles (n = 99), or cabazitaxel, given at 20 mg/m2 every 3 weeks for a maximum of 10 cycles (n = 101).
Eighty patients were excluded after PSMA/FDG-PET (51 patients had standardized uptake value maximum < 20, 29 were discordant); follow-up was available in 61 patients (76%). In the cabazitaxel arm, 15 men withdrew from the trial after randomization.
Previous data from the trial showed that a PSA reduction of 50% or more from baseline occurred more frequently in those within the LuPSMA arm vs those in the cabazitaxel arm, at 66% (95% CI, 56%-75%) vs 37% (95% CI, 27%-46%), respectively, translating to a difference of 29% (95% CI, 16%-42%; P < .0001), meeting the primary end point.2 Moreover, fewer patients on the investigative arm experienced grade 3 or 4 adverse effects (AEs), at 33% and 53%, respectively.
At a median follow-up of 36 months, 70 of 101 patients receiving cabazitaxel, 77 of 99 patients receiving LuPSMA, and 55 of 61 patients excluded after PSMA/FDG-PET had died. In his presentation, Hofman also discussed post-protocol treatments. Of those randomized to LuPSMA, 32% went on to receive cabazitaxel and 5% received additional LuPSMA. In the cabazitaxel arm, 21% of patients received additional cabazitaxel and 20% received LuPSMA.
“There was a pinching of the curve around the median, and then there was separation, so that by 12 months, there was significantly less progression in the LuPSMA arm,” Hofman said. “We noted this in the prior analysis, and this means that the treatment effect is not constant with respect to time. Because of this, our biostatistians elected to use RMST in an updated statistical analysis plan for OS, and [that was] applied to the PFS.”
The hazard ratios were similar for radiographic PFS and PSA-PFS, at 0.65 and 0.60, respectively in the per-protocol sensitivity analysis.
OS was also evaluated in the patients who were excluded due to screening failure; 61 of 80 patients consented to follow-up. The next line of treatment for these patients was cabazitaxel (48%), enzalutamide (Xtandi; 7%), LuPSMA (5%), carboplatin (5%), other (5%), and mitoxantrone (2%). RMST was 18.8 months (95% CI, 16.8-20.8) in the randomized patients vs 11.0 months in the patients who failed screening (95% CI, 9.0-13.1).
Hofman explained that the strengths of the study included its prospective, randomized, multicenter design, the fact that it had 3 years of follow-up, and that it had an active control arm. Limitations included the fact that post-protocol crossover limit the ability of the investigators to observe OS difference.
In addition, “TheraP was never powered for overall survival, and this is also significant with regards to withdrawals in the cabazitaxel arm in patients seeking to have lutetium therapy, which did not occur in the LuPSMA arm,” Hofman noted.
“The clinical implications are that LuPSMA has similar OS to cabazitaxel, a proven life-prolonging therapy, but with fewer AEs and better patient-reported outcomes. But we should be clear that LuPSMA shows greater activity, and that is not just confined to PSA response rates, because we see it with radiographic PFS and RECIST,” Hofman concluded.
No additional safety signals were reported with longer-term follow-up.
In March 2022, the FDA approved 177Lu-PSMA-617 for the treatment of adult patients with PSMA-positive mCRPC who have previously received other anticancer therapies, such as androgen receptor pathway inhibition and taxane-based chemotherapy.3