TheraP Points To Metastatic CRPC Response To Radiolabelled PSMA-Target Agent

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The first randomised study of a lutetium-177 [177Lu]-labelled small molecule targeting prostate-specific membrane antigen (PSMA) suggests that the treatment offers improved prostate-specific antigen (PSA) response and fewer adverse events (AEs) compared with cabazitaxel treatment for metastatic castration-resistant prostate cancer (CRPC). 

The findings for [177Lu]Lu-PSMA-617 were presented at the 2021 Genitourinary Cancers Symposium by Michael Hofman, from the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia, and simultaneously published in The Lancet.  

“The side-effect profile and patient reported outcomes favour [1⁷⁷Lu]Lu-PSMA-617 and this treatment might be a particularly useful option in men for whom cabazitaxel is not suitable”, the investigators say. 

But they emphasise that “[n]o benefit in overall survival has been shown” for the treatment and they therefore await the results for the phase III VISION trial comparing [177Lu]Lu-PSMA-617 to the standard of care or best supportive care.

The phase II study was conducted at 11 Australian centers with 200 patients who were deemed suitable for cabazitaxel as their next treatment and had positron emission tomography (PET) findings indicating PSMA-positive disease and no metastatic sites that were positive for the PET marker FDG but negative for PSMA.

Overall, 98 of the 99 men began their randomly assigned treatment of up to six cycles of [177Lu]Lu-PSMA-617 given at a dose of 6.0–8.5 GBq every 6 weeks, as did 85 of the 101 patients instead assigned to receive up to 10 cycles of cabazitaxel 20 mg/m2 every 3 weeks.

The primary endpoint of PSA response, defined as at 50% or greater reduction from baseline, was significantly higher with [177Lu]Lu-PSMA-617 than cabazitaxel in both the intention-to-treat analysis (66 vs 37%) and prespecified sensitivity analysis by treatment received (66 vs 44%).

In addition, [177Lu]Lu-PSMA-617 treatment was associated with delayed progression compared with cabazitaxel therapy, with a significant hazard ratio (HR) of 0.63, including radiographic progression-free survival (PFS, HR=0.64) and PSA progression-free survival (HR=0.60).

At 12 months, 19% of patients given [177Lu]Lu-PSMA-617 achieved PFS compared with 3% of their cabazitaxel-treated counterparts, although the median duration of PFS in both groups was 5.1 months.

Among men with RECIST-measurable disease at baseline, an objective response was recorded for 49% of the [177Lu]Lu-PSMA-617 arm and 24% of the cabazitaxel arm, with a significant relative risk of 2.12 in favour of the radiolabelled small molecule therapy.

Grade 3–4 AEs were reported by 33% of patients given [177Lu]Lu-PSMA-617 and 53% of those given cabazitaxel; [177Lu]Lu-PSMA-617 was associated with a higher rate of thrombocytopenia at this grade than cabazitaxel (11 vs 0%) but fewer episodes of grade 3–4 neutropenia (4 vs 13%) and febrile neutropenia (0 vs 8%).

Toxicity led to discontinuation of [177Lu]Lu-PSMA-617 in 1% of men and cabazitaxel in 4%, and there were no study drug-related deaths.

Among the 90 men with a McGill-Melzack care for present pain intensity (PPI) of 2 or greater, pain response was reported for 60% of those given [177Lu]Lu-PSMA-617 versus 43% of those receiving cabazitaxel. Although this difference did not reach statistical significance, PPI-progression-free survival did significantly favour [177Lu]Lu-PSMA-617 use, with a HR of 0.72, the researchers say.

In addition, Michael Hofman and co-authors say that patient-reported outcomes indicated “clinical meaningful improvements in quality of life and symptoms” for use of [177Lu]Lu-PSMA-617 versus cabazitaxel with regard to diarrhoea, fatigue, social functioning and insomnia, as well as a significant reduction in frequency of troublesome symptoms such as diarrhoea, urinary symptoms and feeling dizzy or lightheaded.

Thomas Hope, from the University of California San Francisco, USA, and Jeremie Calais, from the University of California Los Angeles, write in a linked comment that the “most important strength of the TheraP trial” was the use of cabazitaxel, a control with proven efficacy.

They highlight that radiographic PFS curves for the treatment arms were similar for the first 6 months, before [177Lu]Lu-PSMA-617 overtook the control agent, indicating two interesting findings.

“First, PSMA-targeted radiopharmaceutical therapy treatment is cumulative, unlike chemotherapy. Tumour cells receive doses of radioactivity every 6 weeks, and therefore the treatment effect might not be shown immediately”, the commentators write.

“Second, a subpopulation of patients exist who have a prolonged benefit from PSMA-targeted radiopharmaceutical therapy, pushing out the tail of the PSMA-targeted radiopharmaceutical therapy progression-free survival curves.”

Thomas Hope and Jeremie Calais conclude: “As we await the planned overall survival analysis from TheraP, researchers in nuclear medicine are hoping that PSMA-targeted radiopharmaceutical therapy will bring the promise that was not achieved with radium-223 for patients with metastatic castration-resistant prostate cancer, and instead replicate the benefit of somatostatin receptor-targeted radiopharmaceutical therapy for patients with neuroendocrine tumours.” 

References 

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; Advance online publication 11 February 2021. https://doi.org/10.1016/S0140-6736(21)00237-3  

Hope TA, Calais J. PSMA-targeted radiopharmaceutical therapy in patients with metastatic castration-resistant prostate cancer. Lancet; Advance online publication 11 February 2021. https://doi.org/10.1016/S0140-6736(21)00349-4