Improved survival is found in mCRPC after PSMA-targeted therapy

Badar M. Mian, MD

Despite maintaining castrate levels of testosterone through the use of androgen deprivation therapy and antiandrogens, some men with metastatic prostate cancer will develop castration-resistant prostate cancer (CRPC). Metastatic CRPC (mCRPC) remains an incurable disease state with relatively short survival. Recent advances in the treatment of mCRPC have included cell cycle checkpoint inhibitors and drugs targeting cancers with genomic alterations (BRCA1 or BRCA2).

A targeted therapeutic approach to mCRPC was studied in a phase 3 clinical trial (VISION, NCT03511664) to determine the efficacy and safety of delivering lutetium-177 (¹⁷⁷Lu) to prostate-specific membrane antigen (PSMA)-expressing mCRPC cells. The trial was presented at the 2021 ASCO annual meeting and results were also published in the New England Journal of Medicine.^{1 177}Lu-PSMA-617 delivers beta-particle radiation preferentially to PSMA-positive cells and the surrounding microenvironment. PSMA expression increases with increasing stages of prostate cancer and is associated with poor prognostic indicators. mCRPC lesions in most patients are PSMA-positive, and increased expression has been independently associated with reduced survival.

The VISION trial included patients who had experienced disease progression to mCRPC after receiving 1 or more approved androgen-receptor–pathway inhibitors and with 1 or more taxane-based chemotherapy regimens. PSMA positivity on the basis of gallium-68 (68Ga)-labeled PSMA-11 (68Ga-PSMA-11) PET-CT imaging at baseline was required for confirmation of radionuclide binding. To qualify as PSMA-positive mCRPC, at least 1 PSMA-positive metastatic lesion was required, without any PSMA-negative lesions.

The trial was conducted at 84 sites (52 in North America and 32 in Europe) between June 4, 2018, and October 23, 2019. Of the 1003 patients who underwent scanning, 831 (82.9%) met the eligibility criteria for PSMA positivity on PET scan. They were randomly assigned to receive either ¹⁷⁷Lu-PSMA-617 plus standard of care (551 men) or standard of care alone (280 men). Patients were randomized in a 2:1 ratio to receive either ¹⁷⁷Lu-PSMA-617 plus standard of care (study group) or standard of care (control group) alone. Standard of care included androgen suppressive therapies to maintain castration level testosterone, but without any concurrent cytotoxic chemotherapy, systemic radioisotopes, immunotherapy, etc. The study group received intravenous infusions of ¹⁷⁷Lu-PSMA-617 (dose of 7.4 GBq (200 mCi)) once every 6 weeks for 4 cycles. In patients with evidence of response, 2 additional cycles (up to 6 cycles in total) were allowed at the discretion of the treating physician.

Follow-up imaging with CT scan or MRI and bone scans were scheduled every 8 weeks for 24 weeks and then every 12 weeks. The median follow-up was 20.3 months in the study group and 19.8 months in the control group. The trial was designed to evaluate 2 co-primary end points, imaging-based progression-free survival (PFS), and overall survival (OS). Secondary end points included objective response and disease control, safety profile of ¹⁷⁷Lu-PSMA-617 and health-related quality-of-life, pain, and biomarker outcomes.

Among all 831 patients who had undergone randomization, improved median OS was noted in the ¹⁷⁷Lu-PSMA-617 treatment group when compared with the control group, 15.3 months vs 11.3 months, respectively (hazard ratio [HR] for death, 0.62; P < .001). In the group of 581 patients in the analysis set, the median imaging-based PFS was 8.7 months in the treatment group, as compared with 3.4 months in the control group (HR for progression or death, 0.40; P < .001).

For the 581 patients in the analysis set, the median time to the first symptomatic skeletal event or death was 11.5 months in the treatment group and 6.8 months in the control group (HR, 0.50; P < .001). Among the 248 patients who had measurable target lesions on PSMA PET scan, a complete response was noted in 9.2% men in the treatment group and none in the control group. A partial response was noted in 41.8% in treatment group and 3% in the control group. Similarly, confirmed decreases in the prostate-specific antigen level of at least 50% and 80% from baseline were noted at a higher level in the treatment group, and the time to worsening of quality of life and pain scores favored the treatment group.

Targeted therapies, including radioligand therapies such as ¹⁷⁷Lu–PSMA-617, have the promise to affect only the cancer cells while sparing normal tissues, especially when selecting candidates using molecular imaging to confirm radionuclide binding. However, adverse events (AEs) still occurred in a higher proportion of men treated with the targeted therapy, compared with the controls. Grade 3 or higher AEs were noted in 52.7% of men in the treatment group and 38.0% in the control group. Fatigue, dry mouth, and nausea were the most common AEs in the treatment group. Significantly higher rate of anemia, thrombocytopenia, and lymphopenia were noted in the treatment group, and 12% required discontinuation of treatment with ¹⁷⁷Lu-PSMA-617.

Although the OS increase by a median of 4.0 months may appear a modest improvement, it should be noted these patients were heavily pretreated using androgen deprivation as well as antiandrogen and taxane chemotherapy. The use of ¹⁷⁷Lu-PSMA-617 significantly extended both the imaging-based survival and overall survival. Further, the time to symptomatic skeletal events, worsening of health-related quality of life and pain were all delayed following treatment with this radioligand targeted therapy. These benefits, along with low incidence of severe AEs, suggest that the addition of ¹⁷⁷Lu-PSMA-617 to standard of care for mCRPC appears to be well tolerated, safe, and effective.

Reference

1. Sartor O, de Bono J, Chi KN, et al. Lutetium-177–PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. Published online June 23, 2021. doi:10.1056/NEJMoa2107322