177Lu-PNT2002 Significantly Improves rPFS Vs ARPI in Metastatic Castration-Resistant Prostate Cancer

Treatment with ¹⁷⁷Lu-PNT2002 resulted in a significant improvement in radiographic progression-free survival (rPFS) vs abiraterone acetate (Zytiga) or enzalutamide (Xtandi) in patients with metastatic castration-resistant prostate cancer (mCRPC) whose disease had progressed on an androgen receptor pathway inhibitor (ARPI), meeting the primary end point of the phase 3 SPLASH study (NCT04647526).¹

The prostate-specific membrane antigen (PSMA)–targeted small molecule radioligand, which comprises a glutamate-urea–based pharmacophore that is attached to a DOTAGA radiometal chelator via a linker, resulted in a median rPFS of 9.5 months by blinded independent central review vs 6.0 months with an APRI; this translated to a 29% reduction in the risk of radiographic progression or death (HR, 0.71; P = .0088).^1,2

At the time of the analysis, hazard ratio for overall survival (OS) was 1.11; however, data were immature, with only 46% of the protocol-specified target OS events reached.¹

In terms of safety, treatment-emergent adverse effects (TEAEs) by Common Terminology Criteria for Adverse Events occurred in 30.1% of those who received ¹⁷⁷Lu-PNT2002 vs 36.9% of those given an ARPI. Moreover, serious TEAEs were reported in 17.1% of those in the radioligand arm vs 23.1% of those in the control arm. TEAEs resulted in discontinuation for 1.9% and 6.2% of patients, respectively.

“There is an urgent unmet need for targeted treatment options for mCRPC patients, particularly for those whose cancer has progressed on ARPIs,” Kim Chi, MD, principal investigator, and medical oncologist at BC Cancer, stated in a press release. “The SPLASH study results demonstrate that 177Lu-PNT2002 is well tolerated and has the potential to play an important role in addressing those needs for patients with chemotherapy-naive mCRPC.”

The open-label study enrolled patients with progressive mCRPC based on at least 1 of the following per The Prostate Cancer Clinical Trials Working Group 3: serum or plasma prostate-specific antigen (PSA) progression, soft tissue progression, and bone progression.² They were required to be at least 18 years of age, an ECOG performance status of 0 or 1, and have previously received only 1 ARPI in the form of abiraterone, enzalutamide, darolutamide (Nubeqa), or apalutamide (Erleada) in the castration-sensitive or -resistant disease setting. They also had high PSMA expression based on quantitative assessment via PSMA PET.

If they previously received cytotoxic chemotherapy in the form of cabazitaxel or docetaxel for castration-resistant disease, they were excluded. Other exclusion criteria included having liver metastases that were larger than 1 cm, superscan on bone scan, central nervous system metastases, or any contraindications to the use of planned treatment with ARPIs.

In the dosimetry and safety run-in portion of the trial, patients underwent screening followed by treatment with ¹⁷⁷Lu-PNT2002 at 6.8 GB1 every 8 weeks for 4 cycles. Prior dosimetry results indicated that the average dose to red marrow was 0.034 Gy/GBq, which was lower than critical thresholds and suggests amenability for combination regimens. Lacrimal glands were the organ that received the largest absorbed doses of the therapy, followed by the kidneys, at 1.2 Gy/GBq and 0.73 Gy/GBq, respectively.

A total of 412 patients were randomly assigned in a 2:1 fashion to receive ¹⁷⁷Lu-PNT2002 at 6.8 GBq every 8 weeks for 4 cycles or an ARPI control in the form of abiraterone or enzalutamide.^1,2 Notably, patients on the control arm were permitted to cross over to the radioligand arm upon progression.

In addition to rPFS serving as the trial’s primary end points, secondary end points included objective response rate, duration of response, OS, PSA response, and biochemical PFS.³ Investigators are also examining safety and tolerability.

Preliminary safety and efficacy data from the dosimetry lead-in sub-study of SPLASH were shared at the 2022 ESMO Congress.²

In the total eligible patients (n = 27), the median age was 72.0 years (range, 57-86), with 74.1% of patients at least 65 years. Most patients were White (85.2%), and slightly half were from the United States (55.6%). The median baseline PSA was 22 (range, 0.3-701.0). Regarding ECOG performance status, 59.3% had a status of 0 and 40.7% had a status of 1.

Most patients did not previously receive a taxane for hormone-sensitive disease. About half (51.9%) had prior exposure to a bisphosphonate. All patients received opioids for cancer-associated pain. All participants had progressed on a previous ARPI, which included enzalutamide (44.4%), abiraterone (44.4%), apalutamide (7.4%), and darolutamide (3.7%). Metastatic status on previous ARPI therapy was M0 or M1 in 40.7% and 59.3% of patients, respectively.

At a median follow-up of 9.2 months, the median rPFS was 11.5 months. The Kaplan Meier–estimated 12-month rPFS rate was 44%. At a median follow-up of 11.7 months, the median OS had not yet been reached. In evaluable patients (n = 10), the radiographic objective response rate was 60%; this comprised a 20% complete response rate and a 40% partial response rate. Thirty percent of patients achieved stable disease, and 10% experienced disease progression. Moreover, 42.3% of patients experienced a PSA decline of at least 50%.

In terms of safety, TEAEs occurred in 92.6% of patients; in 51.9% of patients, these effects were treatment related. Any serious AEs (SAEs) were reported in 22.2% of patients; 3.7% of SAEs were treatment related. TEAEs led to dose delays or discontinuations of ¹⁷⁷Lu-PNT2002 for 11.1% and 3.7% of patients, respectively.

One patient experienced a TEAE that resulted in death in the form of intravascular coagulation likely because of an underlying malignancy; this was not determined to be related to study drug per investigator assessment.

The most common treatment-related AEs that occurred in more than 10% of patients included dry mouth (grade 1, 25.9%; grade 2, 0%; grade 3, 0%; grade 4/5, 0%), fatigue (11.1%; 11.1%; 0%; 0%), nausea (11.1%; 7.4%; 0%; 0%), and anemia (3.7%; 3.7%; 7.4%; 0%). Additional treatment-related toxicities of interest included thrombocytopenia (3.7%; 0%; 3.7%; 0%), neutropenia (0%; 3.7%; 3.7%; 0%), and acute kidney injury (0%; 0%; 3.7%; 0%). Laboratory abnormalities included decreased lymphocyte count (3.7%; 0%; 0%; 0%), neutrophil count (0%; 3.7%; 0%; 0%), and red blood cell count (3.7%; 0%; 0%; 0%).

Full data from the SPLASH study will be shared at a future medical conference.1 Additional follow-up findings are expected in 2024 before the possible submission of a new drug application, according to Lantheus Holdings, Inc.

References

1. Lantheus and POINT Biopharma announce positive topline results from pivotal SPLASH trial in metastatic castration-resistance prostate cancer. News release. Lantheus Holdings, Inc. December 18, 2023. Accessed December 19, 2023. https://lantheusholdings.gcs-web.com/news-releases/news-release-details/lantheus-and-point-biopharma-announce-positive-topline-results
2. Hansen AR, Probst S, Tutrone RF, et al. 1400P Efficacy and safety of 177Lu-PNT2002 prostate-specific membrane antigen (PSMA) therapy in metastatic castration-resistant prostate cancer (mCRPC): initial results from SPLASH. Ann Oncol. 2022;33(suppl 7):S1185. doi:10.1016/j.annonc.2022.07.1886
3. Study evaluating mCRPC treatment using PSMA [Lu-177]-PNT2002 therapy after second-line hormonal treatment (SPLASH). ClinicalTrials.gov. Updated November 2, 2023. Accessed December 19, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04647526