Despite Early Trial Closure, 177LuPSMA-617 Demonstrates Safety and Improved PFS in mCRPC

Jeremie Calais, MD

Jeremie Calais, MD

In a preliminary analysis of a phase II trial, the radiolabeled small molecule, 177 lutetium prostate-specific membrane antigen-617 (¹⁷⁷LuPSMA-617), demonstrated a biochemical progression-free survival (BPFS) of 4 months in a cohort of 64 men with metastatic castrate-resistant prostate cancer (mCRPC). For 27 men who completed 4 cycles of therapy, a BPFS of 9 months was reported, according to investigators from the University of California Los Angeles, David Geffen School of Medicine.¹

Prostate-specific antigen (PSA) levels declined by ≥50% at any time (best response) in 38% of patients with mCRPC treated with¹⁷⁷LuPSMA-617. Further, after 2 cycles of therapy (12 weeks), PSA levels declined by ≥50% in 27% of patients.

The agent is currently not approved by the FDA, but researchers were able to obtain¹⁷⁷LuPSMA-617, which binds with high affinity to PSMA, for research purposes, according to lead investigator Jeremie Calais, MD, assistant clinical professor, Department of Nuclear Medicine, Ahmanson Translational Imaging Division, who presented his findings during the 2019 American Urologic Association meeting in Chicago, Illinois. The trial design also included a cost recovery mechanism, an FDA regulation that allows patients to pay for a nonapproved drug, which in this trial was $10,000 per cycle per patient.²

Men were screened for high levels of PSMA, which is overexpressed by prostate cancer cells and neovascular cells, by PET/CT scan. Prior to enrollment, patients had received androgen receptor inhibitor treatment and were either chemotherapy naïve or were post-chemotherapy.

The men received 4 cycles of¹⁷⁷LuPSMA-617 every 8 weeks and were randomized to receive either 6.0 GBq or 7.4 GBq of radionuclide treatment. Prior to trial approval, the FDA also requested that the researchers obtain kidney dosimetry readings at the first cycle, Calais said. Primary endpoints were safety and PSA response ≥50% decline from baseline by week 12, or after the second cycle. Secondary endpoints were progression-free survival (PFS) and radiographic PFS (rPFS). The trial (NCT03042312) opened in July 2017 and was originally powered for 200 patients to obtain a PSA response in ≥40% of patients, but “enrollment was closed by industry in July 2018 before reaching the targeted enrollment size,” said Calais.

The majority of patients (33%) had received 1 line of prior chemotherapy, with 30% receiving at least 2 lines of therapy. Eighty-three percent had undergone concomitant castration and 23% received a second-generation androgen receptor inhibitor, Calais said. The median PSA of all patients was 75 ng/ml at baseline. Forty-one patients (64%) received the 7.4 GBq dose and 23 patients (36%) received the lower dose.

Forty-five percent of patients completed the 4 cycles (n = 29), with 55% (n = 16) reporting a PSA response. In the overall cohort, 61% (n = 39) achieved a best PSA response of any PSA decline; 9 patients (14%) reported a ≥90% PSA from baseline. After 2 cycles, 15 patients (27%) reached ≥50% PSA decline from baseline.

Fifty-three patients (83%) discontinued the trial because of disease progression and 11 patients (17%) are still undergoing surveillance, Calais said.

“Similar to other PSMA molecules from Europe or Australia, we see 10% to 15% of patients who have an incredibly deep and durable response with a PSA response of more than 90%,” Calais said. “Of note, there was no difference between 6.0 GBq versus 7.4 GBq.” He noted that the primary endpoint was not met, “but that was based on 200 patients, not 64 patients.” The median kidney dose was 2.78 Gy/cycle (mean 2.9, range 0.9-5.9).

Mild adverse effects were reported, with the most common grade 1/2 events reported being xerostomia (70%), nausea (55%), constipation (37%), diarrhea (27%), and vomiting (18%). “We observed 4% of patients with grade 3 kidney failure and 2% of patients reported grade 4 thrombocytopenia,” Calais said. He noted that there was no difference in safety between the 2 treatment dosages.

Reviewing biochemical progression, after a median follow-up of 5 months across the entire patient population, the median PFS was 16 weeks withP= .905. In the cohort of 29 patients who received 4 cycles with a median follow-up of 10 months, the median PFS was 37 weeks withP= .430.

One good responder who received 3 cycles of¹⁷⁷LuPSMA-617 emphasized improved results from baseline, including a PSA level improvement of 38% (26 mg/nL vs 16 ng/nL), bone PSMA improvement of 91% (1405 ml vs 123 ml), and liver PSMA levels improvement of 100% (24 ml vs 0 ml).

In a nonresponder who also received 3 cycles of treatment, radiographic findings demonstrated deficits from baseline, including a PSA level decline of 624% (20 mg/nL vs 146 ng/nL) and bone PSMA decline of 341% (231 ml vs 1021 ml). “Interestingly, in the same patient, soft tissue lesions in the lymph node had a positive response with an improvement of 97% (40 ml vs 1 ml),” Calais said.

References:

1. Calais J. LBA-25: Late-Breaking Abstract: RESIST-PC Phase 2 trial: 177Lu-PSMA-617 Radionuclide Therapy for Metastatic Castrate-Resistant Prostate Cancer. Presented at: 2019 AUA Annual Meeting; May 3-6, 2019; Chicago, IL. Abstract LBA-25.www.eventscribe.com/2019/AUA2019/fsPopup.asp?Mode=presInfo&PresentationID=517984.
2. Charging for investigational drugs under an IND - questions and answers: guidance for industry. US Food and Drug Administration website. Published June 2016.www.fda.gov/regulatory-information/search-fda-guidance-documents/charging-investigational-drugs-under-ind-questions-and-answers. Accessed May 5, 2019.