A novel radiopharmaceutical was more active than cabazitaxel against metastatic castration-resistant prostate cancer (mCRPC) and caused fewer grade 3/4 adverse events, according to results from the first and so for only comparator trial, known as THeraP.
Results of the phase 2 trial, which was conducted in 200 Australian men, were published online on February 11 in The Lancet.
The new product, a radiolabeled small molecule, lutetium-177 [¹⁷⁷Lu] Lu-PSMA-6170, is under development by Endocyte/Novartis. It binds to prostate-specific membrane antigen (PSMA) and delivers high doses of beta radiation.
The trial was conducted at 11 centers in Australia and was not blinded. Participants were men with mCRPC (median age, 72 years) who had experienced disease progression while receiving docetaxel and androgen receptor–directed therapy. They were eligible to receive cabazitaxel, which is generally considered the standard of care for this patient population.
To be eligible for the trial, men had to have metastases that expressed PSMA (detected after screening with two PET-CT scans). About one quarter of the men screened were not eligible to take part.
Participants were randomly assigned to receive cabazitaxel 20 mg/m2 intravenously every 3 weeks for up to ten cycles or Lu-PSMA 6.0–8.5 GBq intravenously every 6 weeks for up to six cycles. The mean path length of the beta particles with Lu-PSMA was short, at 0.7 mm, limiting damage to surrounding tissues.
The primary outcome was a reduction in prostate-specific antigen (PSA) level of at least 50% from baseline. On intention-to-treat analysis, this was achieved by 66% of the men in the Lu-PSMA group and by 37% of those who received cabazitaxel (P < .0001).
Median progression-free survival (PFS) was 5.1 months in both arms, but at 12 months, PFS was 19% with Lu-PSMA, vs 3% with cabazitaxel, translating to a significant delay in progression after 6 months of treatment (hazard ratio, 0.63; P = .0028).
There are no data on overall survival, but additional follow-up is planned. Several other trials in prostate cancer are underway.
This trial provides “strong evidence that [Lu-PSMA] is more active than cabazitaxel” and is “a potential alternative,” particularly when cabazitaxel is unsuitable, owing to the patient’s age or comorbidities, say the investigators, led by Michael Hofman, MBBS, professor of nuclear medicine at the Peter MacCallum Cancer Center, Melbourne, Australia.
Grade 3/4 thrombocytopenia was more common with the radiopharmaceutical than with cabazitaxel (11% vs 0%), but overall, grade 3/4 adverse events were less common (33% vs 53% with cabazitaxel). These events included neutropenia (4% vs 13%) and febrile neutropenia (0% ves 8%). Patient-reported pain, fatigue, social functioning, diarrhea, and insomnia also favored Lu-PSMA. No deaths were attributed to treatment in either arm.
Fifteen of the men assigned to receive cabazitaxel withdrew from the trial before receiving it, possibly opting for Lu-PSMA instead. The reduction in PSA level of greater than 50% held when these fifteen patients were excluded from the analysis (66% with Lu-PSMA, vs 44% with cabazitaxel; P = .0016).
A Cumulative Effect
The use of cabazitaxel as a comparator is the “most important strength of the TheraP trial…. Cabazitaxel is an effective therapy for patients who have already received docetaxel,” comment Thomas Hope, MD, associate professor of radiology at the University of California, San Francisco, and Jeremie Calais, MD, assistant professor of translational theranostics at the University of California, Los Angeles, in an accompanying editorial.
“Although TheraP is a smaller study than the studies in progress, it will be the only study to compare the efficacy of PSMA-targeted radiopharmaceutical therapy with a real competitor for a while,” they note.
Other ongoing trials “will not tell us the relative value of PSMA-targeted radiopharmaceutical therapy compared with that of an active therapy…. We encourage company sponsored trials to learn from the TheraP study and consider using a more active comparator,” they write.
The separation of PFS curves at 6 months “might be the most interesting aspect of this study,” the editorialists comment. Unlike chemotherapy, PSMA-targeted radiopharmaceutical therapy is cumulative, so “the treatment effect might not be shown immediately….
“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,” the editorialists comment.
In general, “we are in the infancy of radiopharmaceutical therapy,” they add.
Two PET Scans to Find Eligible Patients
One problem with this approach is that two PET scans are needed to ensure that the patients’ metastases express PSMA.
The two scans were undertaken with gallium-68 [⁶⁸Ga]Ga-PSMA-11 to assess PSMA expression and with 2-flourine-18[¹⁸F]fluoro-2-deoxy-D-glucose to delineate metastases. For patients to be eligible to participate in the trial, the two scans had to overlap; this ensured that all metastatic sites expressed PSMA.
The fact that more than a quarter of the patients who were screened did not qualify, mostly because of a mismatch, could be a problem, say the editorialists. In the United States, it’s unlikely that insurance companies will approve two PET scans for PSMA-targeted therapies once they hit the market, and the magnitude of benefit reported in TheraP is probably higher than would be seen from empiric treatment of all men with PSMA-positive disease, Hope and Calais say.
The study was funded by Prostate Cancer Foundation of Australia, Novartis, which is developing Lu-PSMA through its subsidiary Endocyte, and others. Hoffman has received personal fees from Janssen, Sanofi Genzyme, Mundipharma, Astellas, and Merck Sharp and Dohmer. Other investigators also have reported industry ties, including grants/personal fees from Novartis. Hope and Calais have company ties related to PSMA-targeted therapies.
M. Alexander Otto is a physician assistant with a master’s degree in medical science and a Newhouse journalism degree from Syracuse University. He is an award-winning medical journalist who worked for McClatchy and Bloomberg before joining Medscape, and also a MIT Knight Science Journalism fellow. Email: email@example.com.