Radioligand Therapy Boosts Survival in mCRPC

Richard L. Wahl, MD

THE PROSTATE SPECIFIC MEMBRANE antigen (PSMA)-targeting therapy, lutetium Lu 177 vipivotide tetraxetan (Pluvicto; formerly ¹⁷⁷Lu-PSMA617), was approved by the FDA for patients with metastatic castration-resistant prostate cancer (mCRPC) in March.¹

Investigators explored the efficacy of radioligand therapy lutetium Lu 177 vipivotide tetraxetan in combination with standard care options including treatments such as hormonal therapies radiation therapy, or glucocorticoid at any dose, in the phase 3 VISION trial (NCT03511664). Overall survival (OS) data supported the approval. The median OS among the 551 patients who received the combination was 15.3 months (95% CI, 14.2-16.9) vs 11.3 (95% CI, 9.8-13.5) among the 280 patients who received standard care alone (HR, 0.62; 95% CI, 0.52-0.74; P < .001).²

“[PSMA-targeting] drugs are starting to become increasingly applied in patients who have not had good responses to the more standard therapies,” Richard L. Wahl, MD, said in an interview with OncologyLive^®. “I think [lutetium Lu 177 vipivotide tetraxetan] will become a relatively standard part of the care of patients with advanced prostate cancer. [This drug] targets the PSMA protein on the surface of prostate cancer [tumors]. Most metastatic prostate cancers have an abundance of PSMA on their surface and when the lutetium 177 label molecule is injected, it will home in to those tumors and deliver radiation selectively to the tumor [rather than the] normal tissue.” Wahl is the Elizabeth E. Mallinckrodt Professor of Radiology, chair of the Department of Radiology, and director of the Mallinckrodt Institute of Radiology at the Washington University School of Medicine in St Louis, Missouri.

Response was evaluated among those who had measurable disease at baseline. The overall response rate was 30% (95% CI, 25%-35%) vs 2% (95% CI, 0%-2%) among patients who received the combination (n = 319) vs those who received standard care (n = 120), respectively.² The complete response rate and partial response rate with lutetium Lu 177 vipivotide tetraxetan and standard care were 6% and 24%, respectively. These rates were 0% and 2%, respectively, with standard care alone.²

The OS analysis was performed in the intention-to-treat population, which included all patients who had undergone randomization. The coprimary end point, imaging-based progression-free survival (PFS), was assessed in the population enrolled following a protocol amendment that required enhanced education measures at trial locations to address high withdrawal rates.³

Among the 385 patients who received the combination the median imagebased PFS was 8.7 months vs 3.4 months with standard care alone (n = 196; HR, 0.40; 99.2% CI, 0.29-0.57; P < .001).³ A key secondary end point analyzed in this patient population was time to first symptomatic skeletal event. The median time to event onset was 11.5 months in the investigative arm vs 6.8 months in the control arm (HR, 0.50; 95% CI, 0.40-0.62; P < .001).³

Adverse effects (AEs) were more prevalent in the lutetium Lu 177 vipivotide tetraxetan arm than the control arm; however, Wahl noted that the treatment was well tolerated. “[One] exciting thing about the therapy was how well tolerated it was,” Wahl said. “The adverse effect profile was quite manageable. [There was a] modest reduction in appetite that was not uncommon and some drops in red blood cell count and white cell count occurred.”

The most common all-grade AEs with the radiotherapy were fatigue (43.1%), dry mouth (38.8%), nausea (35.3%), and anemia (31.8%). Among patients in the control arm the most common all-grade AEs were fatigue (22.9%), nausea (16.6%), back pain (14.6%), and decreased appetite (14.6%).

“One thing [to note with lutetium Lu 177 vipivotide tetraxetan] is that it accumulates in the salivary glands, so some patients could [experience] dry mouth,” Wahl said. He also noted that there were few contraindications for this therapy among this patient population.

Integrating PSMA Radiotherapy into Practice

In addition to approving lutetium Lu 177 vipivotide tetraxetan, the FDA also approved gallium Ga 68 gozetotide (Locametz), a diagnostic agent administered during a PET scan.¹ “The PSMA-PET scan, a nuclear medicine procedure, is [used] to see if a small, safe tracer dose of the PSMA targeting agent will accumulate in tumors,” Wahl said. “If the tumors accumulate PSMA to a sufficient extent, then patients will be candidates for [lutetium Lu 177 vipivotide tetraxetan].”

Payment barriers regarding testing to identify eligible patients, and regarding the agent itself, represent one hurdle to integrating this agent into practice. “The scans that are done for this [patient population] are important and necessary to identify individuals who have the PSMA target,” Wahl said. “But one of the challenges we’re facing in nuclear medicine is the availability of funding from Medicare to pay for these scans. When these scans are introduced, there’s a passthrough period of 2 to 3 years when Medicare will pay the cost.” Wahl noted that after 3 years, if therapy is administered in the outpatient setting, reimbursement only covers a generic, nontargeted diagnostic agent. “One of the concerns is that the availability of the diagnostic agents may become limited if they weren’t paid for appropriately and that might limit access for patients to these innovative therapies. That’s something we want to avoid.” In terms of the longevity of nuclear therapy, Wahl said agents such as lutetium Lu 177 vipivotide tetraxetan “will make a real difference and change the way that prostate cancer is treated.”

He added that one area that could be explored is moving the therapy into earlier settings. Ongoing trials of the agent include the phase 3 PSMAfore (NCT04689828), a trial evaluating lutetium Lu 177 vipivotide tetraxetan plus best supportive care vs androgen receptor–directed therapy (ARDT) in patients with mCRPC who previously received an alternate ARDT and who are naïve to taxane-based therapy. The investigational agent is also being compared with standard therapy among patients with metastatic hormone-sensitive prostate cancer in the phase 3 PSMAddition trial (NCT04720157).

Of note, Novartis, the developer of lutetium Lu 177 vipivotide tetraxetan, temporarily suspended production of the agent in May and halted enrollment to ongoing clinical trials to address “potential quality issues in the production process.”

In the news release, Novartis stated that they have set a target goal of 6 weeks to the return to manufacturing of their radiopharmaceuticals, which also includes the approved agent lutetium Lu 177 dotatate (Lutathera).⁴

References

1. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA. March 23, 2022. Accessed May 20, 2022. bit.ly/3Mxr3yX
2. Pluvicto. Prescribing information. Advanced Accelerator Applications USA, Inc; 2022. Accessed May 20, 2022. bit.ly/3wCjPCV
3. Sartor O, de bono J, Chi KN, et al; VISION Investigators. Lutetium-177–PSMA-617 for metastatic castration- resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/NEJMoa2107322
4. Novartis provides update on production of radioligand therapy medicines. News release. Novartis. May 5, 2022. Accessed May 20, 2022. bit.ly/3luNTuZ