Examining 177Lu-PSMA-617 as a Treatment for Metastatic Castration-resistant Prostate Cancer

The National Cancer Institute¹ estimates that approximately 3.2 million people were living with prostate cancer in the United States in 2018. While a serious disease, outcomes for patients with prostate cancer are usually not fatal and have improved in recent decades. According to the American Cancer Society,² the 5-year survival rate for prostate cancer increased from 83% between 1987 and 1989 to 98% between 2010 and 2016. Prostate cancer survival at 10 years is also 98%.

Unfortunately, not all prostate cancers are treatable. The 5-year survival rate drops to 30% for patients with distant-stage prostate cancer. Metastatic castration-resistant prostate cancer (mCRPC), a form of advanced prostate cancer characterized by a nonresponse to androgen deprivation therapy (ADT), is especially challenging to treat and has an estimated median range of survival of 15-36 months³ depending on disease burden.

While mCRPC is still considered an incurable disease, new treatments⁴ have been developed and approved by the US Food and Drug Administration (FDA) that demonstrate an improvement in overall survival for patients. These treatments include the autologous cellular immunotherapy Provenge (sipuleucel-T), adrenal inhibitor Zytiga (abiraterone acetate), anti-androgen medication Xtandi (enzalutamide), and the antimicrotubular antineoplastic agent Jevtana (cabazitaxel)—all improve overall survival by several months. In 2020, FDA^5-6 approved two new therapies—the poly ADP ribose polymerase (PARP) inhibitors Lynparza (olaparib) and Rubraca (rucaparib)—for the treatment of patients with mCRPC and who have a germline and/or somatic-associated form of the disease.

Radiopharmaceuticals have also been employed as therapies for mCRPC. Strontium-89 chloride, samarium-153, and radium-223 dichloride are radiopharmaceuticals used to treat mCRPC that has spread to the bone. Recently, a new radiopharmaceutical that targets prostate-specific membrane antigen (PSMA) has entered the scene: ¹⁷⁷Lu-PSMA-617. The radioligand therapy works⁷ by attaching a small molecule, PSMA-617, to PSMA proteins that are highly expressed in prostate cancer cells while the gamma and beta emitter lutetium-177 targets radiation to those cells. One potential advantage to ¹⁷⁷Lu-PSMA-617 is the ability to use PSMA-directed imaging to identify PSMA expression sites and allow for personalized treatment.

In Germany, a retrospective multicenter trial⁸ was performed in 2015 that showed a 40% overall biochemical response rate in 145 patients after the first therapy cycle of ¹⁷⁷Lu-PSMA-617. A review of 17 studies where patients with mCRPC received ¹⁷⁷Lu-PSMA-617, published⁹ in the open access journal Cureus, indicated “a majority of patients responded to therapy, and in the prospective studies, survival was found to be upwards of one year.”

In 2017, ABX Biochemical Compounds, a German-based company with the intellectual property rights to PSMA-617, granted Endocyte the right to develop PSMA-617. Endocyte launched the phase 3 VISION trial (NCT03511664) in 2018 before it was announced that Novartis would acquire¹⁰ Endocyte later that year. (Advanced Accelerator Applications, a subsidiary of Novartis, has also licensed¹¹ the PSMA-compound PSMA-SR6 from Johns Hopkins University.)

In this literature review, we explore the data from the phase 3 VISION trial recently presented¹² at the 2021 virtual annual meeting of the American Society of Clinical Oncology and published in the New England Journal of Medicine.

Results from VISION

In the phase 3 VISION trial, 831 patients with mCRPC from 84 clinical sites who had been treated with an androgen-receptor–pathway inhibitor and 1-2 taxane-containing regimens were randomized to receive ¹⁷⁷Lu-PSMA-617 after PSMA screening in addition to standard of care or receive standard of care alone. Among the 1003 participants who initially underwent Ga-PSMA-11 PET–CT scanning before randomization, 95.1% had a PSMA-positive metastatic lesion and 8.7% had a PSMA-negative metastatic lesion, the researchers said.

While the definition of standard of care differed by investigation site, the trial excluded the use of cytotoxic chemotherapy, systemic radioisotopes like radium-223, hemi-body radiotherapy, and investigational drugs but allowed novel androgen axis drugs like abiraterone or enzalutamide. Participants in the ¹⁷⁷Lu-PSMA-617 group underwent a regimen of 7.4 GBq of ¹⁷⁷Lu-PSMA-617 every 6 weeks over 4 treatment cycles, and they could receive another 2 treatment cycles if they responded to therapy.

The alternate primary outcomes for the study were overall survival and radiographic progression-free survival (PFS) until death or up to 32 months. The trial also investigated a dozen secondary outcome measures, including treatment-related adverse events, overall response rate, disease control rate, duration of response, time to first skeletal event, PFS, biochemical response, prostate-specific antigen (PSA) 80 response, duration of PSA response, European Quality of Life (EuroQoL) -5 Domain 5 Level Scale (EQ-5D-5L), Functional Assessment of Cancer Therapy - Prostate (FACT-P) Questionnaire, and Brief Pain Inventory-short Form (PBI-SF).

There were 581 patients with data available for analysis. The results showed patients who received ¹⁷⁷Lu-PSMA-617 had a median imaging-based PFS of 8.7 months compared to patients who received standard of care and had a median imaging-based PFS of 3.4 months (hazard ratio for progression or death, 0.40; 95% confidence interval, 0.29-0.57; P<.001). In the 831 patients who were randomized in the trial, the median overall survival was 15.3 months for those who received ¹⁷⁷Lu-PSMA-617 compared with 11.3 months for those who received standard of care (HR; 0.62; 95% CI, 0.52-0.74; P<.001). Among patients who received ¹⁷⁷Lu-PSMA-617, the median follow-up was 20.3 months compared with 19.8 months for patients who received standard of care.

Regarding secondary outcomes in the analysis set of 581 patients, symptomatic skeletal event or death occurred at median 11.5 months for patients receiving ¹⁷⁷Lu-PSMA-617 compared with median 6.8 months for patients receiving standard of care (HR, 0.50; 95% CI, 0.40-0.62; P<.001). Patients in the ¹⁷⁷Lu-PSMA-617 group had a complete response in 9.2% of cases where there were measurable target lesions according to response evaluation criteria in solid tumors (RECIST), while no patients in the group receiving standard of care had a complete response. There was a partial response in 41.8% of patients receiving ¹⁷⁷Lu-PSMA-617 and 3% of patients receiving standard of care.

While more patients in the ¹⁷⁷Lu-PSMA-617 group experienced adverse events than the group that received standard of care alone (98.1% vs 82.9%), most were mild, with the most common adverse events experienced including fatigue (43.1%), dry mouth (38.8%), and nausea (35.3%). The researchers also noted that 5.7% of patients in the ¹⁷⁷Lu-PSMA-617 group reduced their dose, 16.1% interrupted their treatment, and 11.9% discontinued treatment due to an adverse event.

Limitations of the trial included the design—which did not include a placebo, was not double blinded, and moved imaging progression-free survival to an alternative primary outcome through a protocol amendment. Adverse events were also only counted to 30 days after the last treatment with standard of care or ¹⁷⁷Lu-PSMA-617, the researchers noted.

“Among patients in the ¹⁷⁷Lu-PSMA-617 group who continued to receive standard care after their last cycle of the radioligand therapy, adverse events during the treatment period were therefore assessed for longer than 30 days after the last dose of ¹⁷⁷Lu-PSMA-617,” the authors said. “Nevertheless, the 30-day post-dose period for such adverse events may have led to an underestimation of toxicity, given the 7-day half-life of ¹⁷⁷Lu-PSMA-617. The incidence of toxic effects may also have been overestimated relative to the control group because patients in the ¹⁷⁷Lu-PSMA-617 group had a longer treatment time than those in the control group.”

Future of ¹⁷⁷Lu-PSMA-617

“Patients suffering from metastatic CRPC who have progressed through contemporary hormonal treatments and chemotherapy have few meaningful therapeutic options,” Michael J Morris, MD, chair of the VISION trial’s Scientific Committee and Prostate Cancer Section Head of the Genitourinary Oncology Service, Division of Solid Tumor Oncology at Memorial Sloan Kettering Cancer Center, stated in a press release¹³ announcing the trial’s results. “The study demonstrated that ¹⁷⁷Lu-PSMA-617 improves disease progression and prolongs survival, which are key measures of clinical benefit in the mCRPC population.

On June 16, 2021, ¹⁷⁷Lu-PSMA-617 was granted¹⁴ a Breakthrough Therapy designation by the FDA for treatment of patients with mCRPC. Based on results from the VISION trial, Novartis said it planned on submitting data to US and European Union regulatory authorities in the second half of 2021.

Novartis has also launched two additional trials evaluating ¹⁷⁷Lu-PSMA-617 in patients with prostate cancer: the phase 3 PSMAfore study (NCT04689828) examining patients with mCRPC who have progressed from ADT but have not been treated with a taxane-containing regimen, and the phase 3 PSMAddition trial (NCT04720157) of patients with metastatic hormone-sensitive prostate cancer. 

References:

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