SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 299,010 new cases of prostate cancer will be diagnosed in 2024 and 35,250 men will die of the disease.
The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Androgen Deprivation Therapies have included bilateral orchiectomy or Gonadotropin Releasing Hormone (GnRH) analogues, with or without first generation Androgen Receptor (AR) inhibitors such as CASODEX® (Bicalutamide), NILANDRON® (Nilutamide) and EULEXIN® (Flutamide) or with second-generation Androgen-Receptor Pathway Inhibitors (ARPI), which include ZYTIGA® (Abiraterone), XTANDI® (Enzalutamide) and ERLEADA® (Apalutamide). Approximately 10-20% of patients with advanced Prostate cancer will progress to Castration Resistant Prostate Cancer (CRPC) within five years during ADT, and over 80% of these patients will have metastatic disease at the time of CRPC diagnosis. The estimated mean survival of patients with CRPC is 9-36 months, and there is therefore an unmet need for new effective therapies. Patients who progress on Androgen Deprivation Therapy are often switched to second line hormonal treatments that block testosterone with a different mechanism of action, and upon further progression, offered taxane based chemotherapy.
Prostate-Specific Membrane Antigen (PSMA) is a Type II cell membrane glycoprotein that is selectively expressed in prostate cells, with high levels of expression in prostatic adenocarcinoma. PSMA is a therefore an excellent target for molecular imaging and therapeutics, due to its high specificity for prostate cancer. Lu-177–PSMA-617 (PLUVICTO®) is a radiopharmaceutical that targets PSMA. It is comprised of Lutetium-177, a cytotoxic radionuclide, linked to the ligand PSMA-617, a small molecule designed to bind with high affinity to PSMA. Radioligand therapy with Lu-177–PSMA-617 targets PSMA and releases its payload of lethal beta radiation into the prostate cancer cell.
The FDA in March 2022, approved Lu-177–PSMA-617 for the treatment of adult patients with Prostate-Specific Membrane Antigen (PSMA)-positive metastatic Castration-Resistant Prostate Cancer (mCRPC), who had been treated with Androgen-Receptor Pathway Inhibitors such as Enzalutamide or Abiraterone acetate and 1 or 2 taxane based chemotherapy regimens. This approval was based on the VISION Phase III study.
PSMAfore is a Phase III trial conducted to assess the benefit of Lu-177–PSMA-617 in patients with metastatic Castration-Resistant Prostate Cancer who had progressed on Androgen-Receptor Pathway Inhibitors, but had not received taxane based chemotherapy, with the hope of making this promising therapy available to more patients earlier in the course of their treatment journey. This study enrolled 468 patients with taxane-naive metastatic CRPC who had PSMA-positive disease on gallium-68–PSMA-11 PET/CT, and were candidates for an Androgen-Receptor Pathway Inhibitor change after one progression on prior Androgen-Receptor Pathway Inhibitor. These patients were randomized to receive either Lu-177–PSMA-617 or a change in Androgen-Receptor Pathway Inhibitor therapy (Abiraterone or Enzalutamide). The Primary endpoint was radiographic Progression Free Survival (rPFS). Secondary endpoints included Overall Survival, Prostate-Specific Antigen (PSA) declines of 50% or more from baseline-known as a PSA50 response, Quality of Life measures, and Safety profiles.
At the primary analysis conducted at 7.3 months, patients treated with Lu-177–PSMA-617 demonstrated a median rPFS of 9.3 months compared to 5.55 months in the Androgen-Receptor Pathway Inhibitor change group, showing a statistically significant and clinically meaningful benefit (HR=0.41; 95% confidence interval [CI] = 0.29-0.56). The positive outcomes persisted at the second interim analysis at 15.9 months, where Lu-177–PSMA-617 continued to show superiority in rPFS, PSA50 response rates (57.6% versus 20.4%), Objective Response Rates (50.7% versus 14.9%), and time to PSA progression (10.55 months versus 4.24 months). Moreover, the safety profile of Lu-177–PSMA-617 was manageable and consistent with previous observations from the VISION trial, with fewer Grade or more adverse events compared to the Androgen-Receptor Pathway Inhibitor change group. Common treatment-related adverse events included dry mouth and myelosuppression.
It was concluded that Lu-177–PSMA-617 represents a promising advancement in the armamentarium against advanced prostate cancer, and Lu-177–PSMA-617 has the potential to redefine treatment paradigms for patients with advanced prostate cancer, particularly in the pretaxane setting. The findings from the PSMAfore study suggest that Lu-177–PSMA-617 could provide a viable therapeutic option earlier in the disease course, potentially delaying or obviating the need for more toxic chemotherapy regimens.
Phase 3 trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). Sartor O, Herrmann K, Castellano D, et al. Presented at the Society of Nuclear Medicine and Molecular Imaging. June 9, 2024; Toronto, ON, Canada.
