Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer

prostate cancer: prostate cancerThe treatment landscape for metastatic castration-resistant prostate cancer (mCRPC) continues to evolve; however, patients who progress on multiple lines of therapy have limited treatment options and the 5-year survival rate is less than 30 percent (JCO Glob Oncol 2021; doi: 10.1200/GO.20.00511). Consequently, there is a critical need for additional precision medicine treatment options. To progress the field, research has shown that prostate-specific membrane antigen (PSMA) is highly expressed in mCRPC, making it a promising diagnostic and therapeutic target for radioligand therapy (Front Oncol 2021; https://doi.org/10.3389/fonc.2021.630589). Recently, the FDA approved lutetium (177Lu) vipivotide tetraxetan (177Lu-PSMA-617) for the treatment of adult patients with PSMA-positive mCRPC who have been treated with other anticancer treatments (androgen receptor (AR) pathway inhibition and taxane-based chemotherapy). 177Lu-PSMA-617 is a radioligand therapy that delivers beta-particle radiation electively to PSMA-positive cells and the surrounding microenvironment while sparing most normal tissues in patients. The decision to approve 177Lu-PSMA-617 was supported by findings of the international, prospective, open-label Phase III VISION trial (NCT03511664), which was published in the New England Journal of Medicine (2021; doi: 10.1056/NEJMoa2107322). In the study, the researchers aimed to assess the efficacy of 177Lu-PSMA-617 plus standard of care (SoC) therapies that could safely be combined to provide physicians with a broad permitted range of concomitant treatment options. The study enrolled patients with CRPC who had at least one metastatic lesion on baseline computed tomography, magnetic resonance imaging, or bone scan imaging. Patients were required to have received at least one AR pathway inhibitor and one or two prior taxane-based chemotherapy regimens, as well as be selected for PSMA positivity on the basis of PSMA positron-emission tomography (PET) imaging. Additionally, patients needed to have an ECOG performance status ranging from 0 to 2, a life expectancy of at least 6 months, and acceptable organ and bone marrow function. Eligible participants were randomized 2:1 to receive the radioligand therapy at a dose of 7.4 GBq (200 mCi) administered by IV infusion once every 6 weeks for 4 cycles plus best SoC (BSoC) (investigational arm; n=551) or BSoC alone (control arm; n=280) in men with progressive, PSMA-positive mCRPC. Two additional cycles of the radioligand therapy could be given in those with evidence of response, per investigator discretion. Baseline characteristics of the patients were balanced between the groups. Participants continued to receive standard treatment, with or without the radioligand therapy, until disease progression, intolerable toxicity, lack of clinical benefit, or a prohibited treatment was agreed to be necessary. The alternate primary endpoints included imaging-based progression-free survival (PFS) and overall survival (OS). Key secondary endpoints included objective response, disease control, and time to first symptomatic skeletal event. Other endpoints were safety, health-related quality of life, pain, and biomarker outcomes such as PSA response. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment. The median follow-up was 20.9 months; the median imaging-based PFS in the investigative arm was 8.7 months versus 3.4 months in the control arm (HR: 0.40; 95% CI, 0.29-0.57; P<.001) and the median OS in the investigative arm was 15.3 versus 11.3 months in the control arm (HR, 0.62; 95% CI, 0.52 to 0.74; P<0.001). Furthermore, 9.2 percent of patients in the investigative arm (n=184) achieved a complete response versus 0 percent of those in the control arm (n=64). Partial responses were reported in 41.8 percent and 3.0 percent of those on the investigative and control arms, respectively. Moreover, more patients in the investigative arm had confirmed reductions in the PSA level of at least 50 percent and 80 percent from baseline compared to those on the control arm. In addition, about one-third (30%) of patients with evaluable disease at baseline demonstrated an overall response in the investigative arm versus 2 percent in the SoC-alone arm. Other secondary efficacy outcomes also favored the addition of 177Lu-PSMA-617 to SoC. The most common adverse events (all grades) in the investigative arm included fatigue (43%), dry mouth (39%), nausea (35%), anemia (low red blood cell counts) (32%), decreased appetite (21%), and constipation (20%). The most common laboratory abnormalities that deteriorated from baseline in ≥30 percent of patients who received the radionuclide therapy included decreased lymphocytes, hemoglobin, leukocytes, platelets, calcium, and sodium. The safety follow-up duration in VISION was not sufficient to capture late radiation-associated toxicities. Oncology Times reached out to first author, Oliver Sartor, MD, to discuss the study, the recent FDA approval of 177Lu-PSMA-617, and progression of the field of precision medicine. Sartor is the C.E. & Bernadine Laborde Professor of Cancer Research, Medical Director of the Tulane Cancer Center, and Associate Dean for Oncology at Tulane School of Medicine. Oncology Times: What are some of current treatment challenges in metastatic castration-resistant prostate cancer? Sartor: “The current treatment challenges in mCRPC are immense. First and foremost, the disease is fatal. Though prolonged responses are seen on occasion, inevitably progression occurs. Despite the progress, which is substantial, there are any opportunities for improvement in outlet therapeutic approaches.” Oncology Times: Can you elaborate on the differences between a phenotypic precision medicine approach versus a genotypic precision medicine approach? Sartor: “Genotyping precision medicine is the use of targeted medication, which takes advantage of an underlying genomics defect in a cell to exert its effect. Phenotypic precision medicine also entails use of a targeted medication, but in this case the underlying target is not typically the result of a genomic alteration. Instead, the underlying target is expressed in (or on) a cell in a manner that reflects the underlying cell's pathophysiology.” Oncology Times: How is 177Lu-PSMA-617 a step forward in the evolution of precision medicine for prostate cancer? Sartor: “Without a doubt, lutetium (177Lu) vipivotide tetraxetan is a step forward in phenotypic precision medicine. In this case, molecularly targeted radiation is achieved by the binding of the drug to a cell surface marker called PSMA. The binding molecule, PSMA-617, carries an isotope lutetium-177. After binding of the drug to the PSMA, the cancerous cell and the surrounding microenvironment is showered with radiation. Lutetium (177Lu) vipivotide tetraxetan prolonged survival in a prospective randomized Phase lll trial and is now approved by the FDA for treatment of selected advanced metastatic castrate-resistant prostate cancer.” Oncology Times: What is the mechanism of action of177Lu-PSMA-617 after administration into the bloodstream? Can it be used as an independent marker for risk stratification? Sartor: “After circulating in the bloodstream, 177Lu-PSMA-617 eventually binds to the PSMA expressed on the surface of cells, and as noted before, radiates the region surrounding the area where it deposits. 177Lu-PSMA-617 binding is not typically used for this stratification, but the expression of Pearson may be detected with the use of PET imaging and those images can be used for risk stratification.” Dibash Kumar Das is a contributing writer.