FDA Grants Breakthrough Therapy Designation to 177Lu-PSMA-617 for mCRPC

The FDA has granted breakthrough therapy designation to ¹⁷⁷Lu-PSMA-617, an investigational radioligand therapy for the treatment of metastatic castration-resistant prostate cancer (mCRPC), according to a press release by Novartis.

The breakthrough therapy designation is based on results of the randomized, parallel assignment phase 3 VISION trial (NCT03511664), designed to enroll 831 participants and an estimated completion date of June 2022. The primary end points of the study are overall survival (OS) and radiographic progression-free survival (rPFS). Secondary outcomes include number of participants with treatment-emergent adverse events (TEAEs), overall response rate (ORR), disease control rate (DCR), duration of response (DoR), time to first symptomatic skeletal event, progression-free survival (PFS), biochemical response, prostate-specific antigen 80 response, quality of life, function assessment of cancer therapy, and brief pain inventory short form.

During the study, patients were randomized 1:1 to receive either ¹⁷⁷Lu-PSMA-617 intravenously every 6 weeks for a maximum of 6 cycles or best supportive care or best standard of care (SOC) alone. In the experimental arm, best supportive care or best SOC may also be used.

In order to participate, patients must be18 years of age or older, have an EGOC score of 0 to 2, have a life expectancy greater than 6 months, have confirmed prostate cancer, have been previously treated with at least 1 but no more than 2 taxane regimens, have 1 or more metastatic lesion, and have adequate organ function. Patients who have received an systemic anti-cancer therapy within 28 days prior to randomization, an investigational agents within 28 days prior to randomization, known hypersensitivity to any components of the study therapy, concurrent cytotoxic chemotherapy, transfusion for the sole purpose of making the patient eligible for inclusion, or symptomatic cord compression are not eligible to participate.

The addition of ¹⁷⁷Lu-PSMA-617 led to a nearly 40% reduction in the risk of death compared to SOC alone, according to results presented at the 2021 American Society of Clinical Oncology (ASCO) Annual Meeting. At a median follow-up of 20.9 months, the addition of the agent lead to a median OS improvement of 4 months over SOC alone. Additional targeted radioligand therapy lead to a 5.3-month improvement in rPFS, equating to a 60% reduction in the risk of progression or death (HR, 0.40). 

The median OS in the experimental arm was 15.3 months compared to 11.3 months in the SOC alone arm. The rPFS for the experimental arm was also higher at 8.7 months compared to 3.4 months in the SOC alone arm (HR, 0.40; 99.2% CI, 0.29-0.57; P <.001). The ORR rate for the experimental arm was 29.8% versus 1.7% in the control arm. The DCR was 89% for those in the experimental arm versus 66.7% for those in the control arm.

The safety analysis was made up of 529 patients from the experimental arm and 205 patients in the control coup. The most common adverse event (AE) across all grades was fatigue. All-grade fatigue occurred at a rate of 49.1% in the experimental arm versus 29.3% in the control arm. All-grade bone marrow suppression occurred in 47.4% in the experimental arm versus 17.6% in the control arm. Dry mouth (39.3% versus 1%), nausea/vomiting (39.3% versus 17.1%), kidney effects (8.7% versus 5.9%), second primary malignancies (2.1% versus 1%) and intracranial bleeding (1.3% versus 1.5%) were also observed.

High-grade TEAEs occurred in 52.7% of the patients in the experimental arm versus 38% of patients in the control arm. The most common grade 3-5 AEs reported were bone marrow suppression, fatigue, kidney effects, and nausea/vomiting.

_REFERENCE:

_{Novartis receives FDA breakthrough therapy designation for investigational 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC). News release. Novartis. June 16, 2021. Accessed June 17, 2021. https://bit.ly/3vC39Jb}