Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer

Is there more on the horizon for the treatment of patients with metastatic prostate cancer? According to research recently published in the New England Journal of Medicine, there is still more to come.¹

The study was conducted by the VISION investigators of Tulane University through a collaboration supported by Endocyte, a Novartis company. Prostate cancer and, specifically, metastatic castration-resistant prostate cancer (mCRPC) continues to be the second leading cause of cancer death in the United States. The current standard treatment protocols for patients with M1 CRPC include use of androgen receptor blockers, such as abiraterone, enzalutamide, docetaxel (if not previously used), and, in certain circumstances, Sipuleucel-T and radium-223 for patients with symptomatic bone metastasis.²

Recently, there has been an emphasis on genomic testing for patients and curation of a treatment plan based on the ideals of precision medicine. Radioligand therapies have been utilized, and specifically has been considered, owing to its ability to target cancerous cells while sparing normal prostatic tissue, as well as its radionuclide binding that can be visualized on imaging.³

The authors quoted several recent reports that argue that prostate-specific membrane antigen (PSMA) is highly expressed in prostate cancer cells and is an independent biomarker for poor prognosis.⁴  In most patients with mCRPC, there is a high expression of PSMA at the site of metastasis, which is inversely correlated with reduced survival.⁵ This is what led previous researchers to consider the utility of ¹⁷⁷Lu-PSMA-617, a radioligand-based therapy that delivers β-particle radiation directly to PSMA-avid cells. The study quotes several early-phase trials that have shown the effectiveness of ¹⁷⁷Lu-PSMA-617 to improve biochemical and radiographic responses while minimizing pain and treatment-related toxicity.

The VISION Study on ¹⁷⁷Lu-PSMA-617

In this context, the VISION investigators conducted their prospective, randomized, international phase 3 trial investigating the efficacy and safety of ¹⁷⁷Lu-PSMA-617. The study population was patients previously treated for mCRPC who also displayed PSMA-positive disease on PSMA positron-emission tomography (PSMA-PET) imaging.

Patients were included in the study on the basis of their mCRPC status; they were required to have 1 or more sites of metastasis on imaging with disease progression on at least 1 androgen receptor blockade medication and a taxane-containing regimen. In addition, patients were required to have at least 1 PSMA-positive metastatic lesion and no PSMA-negative lesions. PSMA positivity was according to the study protocol.

Patients were randomized to receive either ¹⁷⁷Lu-PSMA-617 plus standard of care (SOC) treatment, as defined in the study protocol, or SOC alone. Patients were given ¹⁷⁷Lu-PSMA-617 intravenously every 6 weeks for 4 cycles with the option to continue for 2 additional cycles in patients who responded initially. Imaging for assessments were performed every 8 weeks for 24 weeks and then every 12 weeks thereafter.

Endpoints of the study focused on progression-free survival (PFS) and overall survival (OS). Additionally, the study evaluated safety, health-related quality of life, pain, and impact on prostate-specific antigen (PSA).

Nearly 1200 patients were evaluated and, after screening for eligibility, 831 patients were included. A total of 551 patients were assigned to the ¹⁷⁷Lu-PSMA-617 plus permitted SOC protocol and 280 were assigned to the SOC-only arm. However, because 56% of patients in the control arm discontinued the trial, and in communication with the Food and Drug Administration (FDA), the study was rerandomized to have 581 patients assigned to the treatment arm, and 196 were assigned to the control arm.

When evaluating for the primary endpoints, of the patients who received ¹⁷⁷Lu-PSMA-617, median time to PFS, as seen on imaging, was 8.7 months compared with 3.4 months in the control group. Median OS for the treatment arm was 15.3 months versus 11.3 months in the control arm. Median follow-up time was approximately 20 months for both arms.

Results

After careful sensitivity analysis, the results were found to be similar before and after the study readjusted its randomization scheme. In the ¹⁷⁷Lu-PSMA-617 arm, the first sign of evidence of symptomatic skeletal involvement or death was at 11.5 months, compared to 6.8 months in the control arm. Using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, of the 248 patients with measurable target lesions, 9.2% of patients in the ¹⁷⁷Lu-PSMA-617 arm had a complete response compared to no patients in the control arm. A partial response was seen in 41.8% in the ¹⁷⁷Lu-PSMA-617 arm, compared with 3% in the control arm.

In terms of drug safety, there was a higher incidence of grade 3 adverse events (AEs) in the ¹⁷⁷Lu-PSMA-617 arm compared with the control arm. Common AEs included:

• Fatigue
• Dry mouth
• Nausea
• Anemia
• Back pain
• Arthralgia
• Decreased appetite
• Constipation
• Vomiting
• Thrombocytopenia
• Lymphopenia
• Leukopenia

For AEs of grade 3 or more, the most common included fatigue, anemia, thrombocytopenia, and lymphopenia.

What VISION Means for mCRPC Patients

The authors started their discussion by noting that the phase 3 VISION trial offers evidence that using the PSMA-targeted radioligand ¹⁷⁷Lu-PSMA-617 prolonged OS and delayed disease progression when added to the SOC treatment in patients with PSMA-expressing mCRPC. Although there was an increased incidence of AEs seen in the ¹⁷⁷Lu-PSMA-617 arm compared with the control arm (98.1% vs 92.9%), and higher rates of grade 3 AEs (52.7% vs 38%), these AEs resulted in low rates of dose reduction (5.7%), interruption of treatment (16.1%), and discontinuation (11.9%) of ¹⁷⁷Lu-PSMA-617.

These findings are consistent with previous studies. The patient population included individuals who were no longer responding to androgen-receptor pathway inhibitors, and almost all the patients had been introduced previously to taxane-containing therapies such as docetaxel.

The authors note that there are current phase 3 trials investigating the utility of using ¹⁷⁷Lu-PSMA-617 earlier in the prostate cancer treatment paradigm. Limitations of the VISION study included the lack of a double-blind design or a placebo arm. Notwithstanding these limitations, however, the trial gives strong evidence that the addition of ¹⁷⁷Lu-PSMA-617 to SOC treatment for select mCRPC patients with progressive disease and metastatic sites consistent with PSMA-positive imaging, improves the imaging-based PFS and OS while being well-tolerated and having a relatively low toxic effect.

David Ambinder, MD is a urology resident at New York Medical College / Westchester Medical Center. His interests include surgical education, GU oncology and advancements in technology in urology. A significant portion of his research has been focused on litigation in urology. 

References

1. Sartor O, de Bono J, Chi KN, et al; for the VISION Investigators. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi: 1056/NEJMoa2107322
2. National Comprehensive Cancer Center®. NCCN Framework for Resource Stratification of NCCN Guidelines (NCCN Framework™: Core Resources): Prostate Cancer. Version 2.2021. August 25, 2021; page PROS-16. https://www.nccn.org/professionals/physician_gls/pdf/prostate_core.pdf. Accessed April 24, 2022.
3. Rowe SP, Gorin MA, Pomper MG. Imaging of prostate-specific membrane antigen with small-molecule PET radiotracers: from the bench to advanced clinical applications. Annu Rev Med. 2019;70:461-477. doi: 1146/annurev-med-062117-073027
4. Hupe MC, Philippi C, Roth D, et al. Expression of prostate-specific membrane antigen (PSMA) on biopsies is an independent risk stratifier of prostate cancer patients at time of initial diagnosis. Front Oncol. 2018;8:623. doi: 3389/fonc.2018.00623
5. Vlachostergios PJ, Niaz MJ, Sun M, et al. Prostate-specific membrane antigen uptake and survival in metastatic castration-resistant prostate cancer. Front Oncol. 2021;11:630589. doi: 3389/fonc.2021.630589