177Lu-PSMA-617 significantly improves rPFS in earlier mCRPC setting

In patients with PSMA–positive metastatic castration-resistant prostate cancer (mCRPC) who progressed on a second-generation androgen-receptor pathway inhibitor (ARPI), ¹⁷⁷Lu-PSMA-617 (LuPSMA; lutetium Lu 177 vipivotide tetraxetan) significantly improved radiographic progression-free survival (rPFS) compared to switching to a different ARPI, according to findings from the phase 3 PSMAfore study.¹

Novartis plans to share the study data at a future medical meeting and start discussions with the FDA next year about an indication for ¹⁷⁷Lu-PSMA-617 in this setting.

The PSMA-targeted radioligand therapy was previously shown in the phase 3 VISION trial to improve overall survival (OS) when added to standard of care (SOC) versus SOC alone in patients with PSMA-positive mCRPC who had progressed on an ARPI and taxane-based chemotherapy. According to Novartis, the developer of ¹⁷⁷Lu-PSMA-617, the PSMAfore study is the first clinical trial of a PSMA-targeted radioligand therapy to demonstrate a clinically meaningful benefit in the pre–taxane-based chemotherapy mCRPC setting.

“With the announcement of these positive topline phase 3 results, Pluvicto becomes the first PSMA-targeted radioligand therapy to demonstrate significant and clinically meaningful benefits for people living with this type of prostate cancer who have not received taxane-based chemotherapy,” Shreeram Aradhye, MD, president, global drug development and chief medical officer, Novartis, stated in a press release.¹ “We look forward to discussing the data with healthcare authorities in order to bring this innovative new early treatment option to many more prostate cancer patients sooner after their diagnosis.”

Overall, the open-label, multi-center, phase 3 PSMAfore study enrolled 469 patients with PSMA-positive mCRPC who progressed only once after treatment with a second-generation ARPI. Patients were randomized in a 1:1 ratio to ¹⁷⁷Lu-PSMA-617 or a change in ARPI. The primary end point is rPFS. The data for the key secondary end point of OS are not yet mature. There were no new safety signals with ¹⁷⁷Lu-PSMA-617 compared with established clinical trial research with the treatment. Novartis plans to share the study data at a future medical meeting and start discussions with the FDA next year about an indication for ¹⁷⁷Lu-PSMA-617 in this setting.

Current approval of ¹⁷⁷Lu-PSMA-617

¹⁷⁷Lu-PSMA-617 is approved by the FDA for the treatment of patients with PSMA-positive mCRPC in the post androgen receptor pathway inhibition, post taxane-based chemotherapy setting.²

The approval of LuPSMA was based on findings from the VISION trial, in which adding LuPSMA to SOC led to a nearly 40% reduction in the risk of death versus SOC alone in patients with progressive PSMA-positive mCRPC.³ The findings, which were presented during the 2021 ASCO Annual Meeting, showed that at a median follow-up of 20.9 months, the addition of LuPSMA improved the median OS by 4 months over SOC alone (HR, 0.62). Adding the targeted radioligand therapy also led to a 5.3-month improvement in median rPFS translating to a 60% reduction in the risk of progression or death (HR, 0.40).

Overall, the open-label VISION trial (NCT03511664) included 831 patients (1179 initially screened) with progressive PSMA-positive mCRPC who received at least 1 novel androgen axis drug (eg, enzalutamide [Xtandi] or abiraterone acetate [Zytiga]) and were previously treated with 1 to 2 taxane regimens.

Patients were randomized in a 2:1 ratio to LuPSMA (7.4 GBq every 6 weeks x 6 cycles; n = 551) plus SOC or SOC alone (n = 280). Individual investigators determined the SOC; however, radium-223 (Xofigo) and cytotoxic chemotherapy were not allowed. The coprimary end points of the trial were OS and rPFS.

The median OS was 15.3 months in the LuPSMA arm versus 11.3 months in the SOC alone arm, translating to a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.52-0.74; P <.001).The rPFS was 8.7 versus 3.4 months, respectively (HR, 0.40; 99.2% CI, 0.29-0.57; P <.001).

The safety analysis included 529 patients in the LuPSMA cohort and 205 patients in the control group. The investigators considered LuPSMA treatment to be well tolerated. The most common adverse events (AEs) across all grades occurring in the LuPSMA arm were fatigue (49.1% vs 29.3% in the control arm), bone marrow suppression (47.4% vs 17.6%, respectively), dry mouth (39.3% vs 1%), nausea/vomiting (39.3% vs 17.1%), kidney effects (8.7% vs 5.9%), second primary malignancies (2.1% vs 1%), and intracranial bleeding (1.3% vs 1.5%).

High-grade treatment-emergent AEs occurred in 52.7% of patients receiving LuPSMA compared with 38% of patients treated with SOC alone. The most common grade 3-5 AEs reported in the LuPSMA arm were bone marrow suppression (23.4% vs 6.8% in the control arm), fatigue (7% vs 2.4%, respectively), kidney effects (3.4% vs 2.9%), and nausea/vomiting (1.5% vs 0.5%).

References

1. Novartis Pluvicto™ shows statistically significant and clinically meaningful radiographic progression-free survival benefit in patients with PSMA–positive metastatic castration-resistant prostate cancer. Published online and accessed December 5, 2022. https://bit.ly/3utNH3z

2. Novartis Pluvicto™ approved by FDA as first targeted radioligand therapy for treatment of progressive, PSMA positive metastatic castration-resistant prostate cancer. March 23, 2022. https://www.novartis.com/news/media-releases/novartis-pluvictotm-approved-fda-first-targeted-radioligand-therapy-treatment-progressive-psma-positive-metastatic-castration-resistant-prostate-cancer

3. Morris MJ, De Bono JS, Chi KN, et al. Phase 3 study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol 39, 2021 (suppl 15; abstr LBA4).