Targeted radioligand therapy ups survival in previously-treated mCRPC

Adding the lutetium-labelled PSMA*-617 (¹⁷⁷Lu PSMA-617) targeted radioligand therapy to standard of care (SOC) led to significant extension of radiographic progression-free survival (rPFS) and overall survival (OS) compared with SOC alone in patients with metastatic castration-resistant prostate cancer (mCRPC) who had progressed after treatment with chemotherapy and androgen inhibitors, according to the VISION trial presented at ASCO 2021.

“Despite recent therapeutic advances, mCRPC remains invariably fatal,” the researchers noted.

PSMA, being highly expressed in prostate cancer including metastatic lesions — while its presence on normal tissue is relatively limited — makes it an excellent molecular target for imaging and therapy in prostate cancer, the researchers pointed out.  

¹⁷⁷Lu PSMA-617 is an investigational targeted radioligand therapy that specifically delivers ß-particle radiation to PSMA-expressing cells and adjacent microenvironment.  

“This novel targeted radiotherapy could fill a significant need for patients with mCRPC that has progressed despite chemotherapy and targeted anti-androgen therapy. The success of this treatment highlights the importance of investigating alternatives to traditional types of cancer therapies,” said ASCO President Professor Lori J. Pierce from the University of Michigan in Ann Arbor, Michigan, US.

The phase III, international, open-label VISION study enrolled 831 patients with PSMA-positive mCRPC screened by PET imaging who had previously been treated with ≥1 androgen receptor pathway inhibitor and 1–2 taxane-based regimens. The patients were randomized 2:1 to receive ¹⁷⁷Lu PSMA-617 (7.4 GBq Q6W) on top of SOC or SOC alone. SOC was determined by investigator and excluded cytotoxic chemotherapy and radium-223. [ASCO 2021, abstract LBA4]

After a median follow-up of 20.9 months, the addition of ¹⁷⁷Lu PSMA-617 significantly improved rPFS compared with SOC alone (median, 8.7 vs 3.4 months; hazard ratio [HR], 0.40; one-sided p<0.001) —thus meeting the primary endpoint.

The alternate primary endpoint of OS was also met, with a median OS of 15.3 months in the ¹⁷⁷Lu PSMA-617 group compared with 11.3 months in the SOC alone group (HR, 0.62; one-sided p<0.001).

Both rPFS and OS showed generally consistent findings across prespecified subgroups.    

In addition, all key secondary outcomes also reached statistical significance between the two groups, in favour of ¹⁷⁷Lu PSMA-617 addition — including objective response rate (29.8 percent vs 1.7 percent), disease control rate (89.0 percent vs 66.7 percent), and time to first symptomatic skeletal event (median, 11.5 vs 6.8 months; HR, 0.50).

“The findings suggest that ¹⁷⁷Lu-PSMA-617 warrants consideration as a new standard of care in this patient population, pending regulatory review and approval,” said lead author Dr Michael J. Morris of Memorial Sloan Kettering Cancer Center in New York, New York, US.

While high-grade treatment-emergent adverse events occurred more frequently in the ¹⁷⁷Lu-PSMA-617 arm vs the SOC alone arm (52.7 percent vs 38.0 percent), Morris said ¹⁷⁷Lu-PSMA-617 was ”safe and well tolerated, with no new safety signals.”

Grade 3–5 adverse events that were more common in the ¹⁷⁷Lu-PSMA-617 arm included bone marrow suppression (23.4 percent vs 6.8 percent), fatigue (7.0 percent vs 2.4 percent), renal effects (3.4 percent vs 2.9 percent), and nausea and vomiting (1.5 percent vs 0.5 percent).

The grade 3–5 bone marrow suppression events that were considered clinically relevant, according to Morris, were high-grade anaemia (12.9 percent vs 4.9 percent) and thrombocytopenia (7.9 percent vs 1.0 percent).

*PSMA: Prostate-specific membrane antigen