The addition of 177Lu-PSMA-617 to standard of care prolongs the survival of patients with pretreated advanced metastatic castration-resistant prostate cancer

Results of the phase III VISION trial demonstrate that adding the PSMA-targeted radioligand therapy ¹⁷⁷Lu-PSMA-617 to a standard of care regimen for patients with metastatic castration resistant prostate cancer (mCRPC) who previously received an androgen receptor pathway inhibitor and chemotherapy significantly prolongs the survival and delays the development of radiographic disease progression.

Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains invariably fatal. Prostate-specific membrane antigen (PSMA) is an enzyme that is highly expressed in prostate cancer, including metastatic lesions. In contrast, expression on normal tissue is limited, making PSMA an excellent target for both PET-images and targeted systemic radiation treatment, which is known as radioligand therapy. PSMA-617 targets PSMA with a high affinity and delivers a payload of the β-particle emitting radioactive metal Lutetium-177 (¹⁷⁷Lu). When this drug binds to PSMA, the whole molecule is internalised by the tumour cells after which prostate cancer cells are exposed to a lethal dose of radiation and die.

The VISION study

The phase III VISION study enrolled PSMA-positive mCRPC patients who previously received at least one androgen receptor pathway inhibitor and one or two taxane-based treatment regimens. Patients were randomised (2:1) to ¹⁷⁷Lu-PSMA-617 (7.4 GBq every 6 weeks for 4 cycles) plus standard of care (SOC) vs. SOC alone. This SOC was investigator determined but excluded cytotoxic chemotherapy, immunotherapy, investigational drugs and radium-223. Responders with residual disease could have an extra two cycles of treatment. Prespecified alternate primary endpoints consisted of overall survival (OS) and radiographic progression-free survival (rPFS) using PCWG3 criteria by independent central review (ICR). The study would be positive if either or both primary endpoints were significant.

¹⁷⁷Lu-PSMA-617 delays disease progression and prolongs survival

Between June 4^th 2018 and October 23^rd 2019, 831 of 1,179 screened patients met all inclusion criteria and were randomised to receive ¹⁷⁷Lu-PSMA-617 + SOC (n=551) or SOC alone (n=280). ¹⁷⁷Lu-PSMA-617 + SOC was found to be associated with a 38% reduction in the risk of death (median 15.3 vs. 11.3 months, HR [95%CI]: 0.62 [0.52-0.74], one-sided p<0.001). This OS benefit was generally consistent across prespecified stratification factor subgroups, except for very small patient numbers, where wide confidence intervals were reported. In addition to this, also the risk of radiographic progression or death was reduced by 60%. In fact, adding ¹⁷⁷Lu-PSMA-617  prolonged the median rPFS from 3.4 months to 8.7 months (HR [99.2%CI]: 0.40[0.29-0.57], one-sided p<0.001). RECIST v1.1 responses also favoured the ¹⁷⁷Lu-PSMA-617 arm in patients with measurable disease, with a large difference in the proportion of patients with complete (9.2% vs. 0.0%) and partial (41.8% vs. 3.1%) radiographic responses. Patients in the combination arm stayed on treatment longer than those who received SOC only (7.82 vs. 2.07 months) and received more cycles of standard therapy (5 vs. 2).

Side effects were more common with ¹⁷⁷Lu-PSMA-617 (85.3% vs. 28.8%) but none were unexpected. Grade 3-5 bone marrow suppression was seen in 23.4% of patients in the ¹⁷⁷Lu-PSMA-617 arm, as compared to 6.8% of patients in the control arm, with high-grade thrombocytopenia in 7.9% and 1.0% of patients, respectively. Dry mouth occurred in 39.3% of the patients in the ¹⁷⁷Lu-PSMA-617 arm. None of these were high-grade. Also nausea and vomiting occurred in 39.3% of ¹⁷⁷Lu-PSMA-617 patients (vs. 17.1% with SOC alone), but this was only high-grade in 1.5% of patients. Finally, renal effects were reported in 8.7% of ¹⁷⁷Lu-PSMA-617 patients vs. 5.9% in the control arm.

Conclusion

Adding ¹⁷⁷Lu-PSMA-617 to SOC in patients with mCRPC whose cancer had already progressed after chemotherapy and androgen receptor pathway inhibitors prolonged life and delayed the time to radiographic progression. In addition, ¹⁷⁷Lu-PSMA-617 was well tolerated without new safety signals of concern. These findings warrant the adoption of ¹⁷⁷Lu-PSMA617 as a new treatment option in patients with mCRPC, pending approval. Ongoing trials are now investigating ¹⁷⁷Lu-PSMA617 in earlier stage prostate cancer.

Reference

Morris M, et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). Presented at ASCO 2021; Abstract LBA4.