Study shows 177Lu-PSMA-617 is noninferior to cabazitaxel in post-chemo mCRPC

The latest update from the phase 2 TheraP trial (NCT03392428) showed that ¹⁷⁷Lu-PSMA-617 (Pluvicto) led to comparable overall survival results with a potential quality of life benefit versus cabazitaxel (Jevtana) in patients with with metastatic castration-resistant prostate cancer who progressed after docetaxel.¹

“In this updated analysis, we show that improvements in these surrogate outcomes did not translate into improved, although the study was not powered for this outcome,” wrote the study authors. “Nevertheless, given fewer grade 3–4 [AEs] and improved patient-reported outcomes with ¹⁷⁷Lu-PSMA-617, it is reasonable to conclude that quality of life during treatment was better with 177Lu-PSMA-617 than cabazitaxel. Treatment with ¹⁷⁷Lu-PSMA-617 also requires fewer visits and injections than cabazitaxel.”

An analysis of overall survival (OS) at a median follow up of 35.7 months (31.1-39.2) showed that 78% of patients in the experimental arm and 69% of patients in the control arm had died. The restricted mean survival time of the ¹⁷⁷Lu-PSMA-617 arm was 19.1 months (95% CI; 16.9-21.4) vs 19.6 months (95% CI; 17.4-21.8; P = 0.77) in the cabazitaxel arm. Median OS was 16.4 months (95% CI; 13.7 to 19.4) in the experimental arm and19.4 months (14.0-21.7) in the control arm (HR 0.97; 95% CI, 0.70-1·.35; P = 0.99).

Despite there being no statistically significant differences in OS between the 2 patient cohorts, when compared with cabazitaxel, ¹⁷⁷Lu-PSMA-617 produced a higher prostate-specific antigen (PSA) response rate (66% vs 37%), a higher objective response rate (ORR) per RECIST v 1.1 criteria (49% vs 24%), longer progression-free survival (PFS; HR 0.63; 95% CI 0.46-0.86), fewer grade 3 and 4 adverse events (AEs; 33% vs53%), and improved patient-reported outcomes in the initial analysis of the TheraP trial.²

“In this updated analysis, we show that improvements in these surrogate outcomes did not translate into improved [OS], although the study was not powered for this outcome,” wrote the study authors. “Nevertheless, given fewer grade 3–4 [AEs] and improved patient-reported outcomes with ¹⁷⁷Lu-PSMA-617, it is reasonable to conclude that quality of life during treatment was better with 177Lu-PSMA-617 than cabazitaxel. Treatment with ¹⁷⁷Lu-PSMA-617 also requires fewer visits and injections than cabazitaxel.”

Investigators of this open-label, randomized phase 2 trial randomly assigned a total of 200 participants 1:1 to receive either cabazitaxel at 20 mg/m² intravenously every 3 weeks for up to 10 cycles or ¹⁷⁷Lu-PSMA-617 intravenously every 6 weeks for a maximum of 6 cycles, starting at 8.5 GBq and decreasing by 0.5 GBq each cycle.

Overall, 78% of patients in both arms had over 20 metastases. A majority of these metastases were bone metastases in the experimental arm and control arm (91% vs 89%), with visceral metastases (7% vs 13%) and lymph node disease (7% vs 9%) also being prevalent. Previous treatments in each respective arm included enzalutamide (Xtandi) only (49% vs 57%), abiraterone acetate (Zytiga) only (21% vs 24%), and both agents combined (21% vs 9%). All patients were previously treated with docetaxel, according to eligibility criteria.

Previous analyses of this study looked into the primary endpoint of prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline.³ The study showed that PSA responses were more frequent among patients in the 177Lu-PSMA-617 arm vs the cabazitaxel group (66% vs 37% P <.0001; 66% vs 44% by treatment received; P = 0.0016). Investigators observed no deaths related to 177Lu-PSMA-617.

“A strength of TheraP is that it used cabazitaxel, an active treatment that prolongs survival in patients with metastatic castration-resistant prostate cancer, and was deemed the next appropriate standard treatment option for patients recruited to TheraP,” said the study authors. “TheraP provides data that supports the notion that ¹⁷⁷Lu-PSMA-617 and cabazitaxel are viable options for the treatment of metastatic castration-resistant prostate cancer.”

References

1. Hofman MS, Emmett L, Sandhu S, et al. Overall survival with [177Lu]Lu-PSMA-617 versus cabazitaxel in metastatic castration-resistant prostate cancer (TheraP): secondary outcomes of a randomised, open-label, phase 2 trial. Lancet Oncol. Published online November 30, 2023. doi:10.1016/s1470-2045(23)00529-6
2. Hofman MS, Violet J, Hicks RJ, et al. [177Lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (LuPSMA trial): a single-centre, single-arm, phase 2 study. Lancet Oncol. 2018;19:825–833. doi:10.1016/S1470-2045(18)30198-0.
3. Hofman MS, Emmett L, Sandhu S, et al. [177Lu]Lu-PSMA-617 versus cabazitaxel in patients with metastatic castration-resistant prostate cancer (TheraP): a randomised, open-label, phase 2 trial. Lancet. 2021;397(10276):797-804. doi:10.1016/s0140-6736(21)00237-3