Can theranostics improve outcomes in high-risk localized prostate cancer?

Standard treatment is insufficient for some patients with high-risk localized prostate cancer, and the emerging field of theranostics provides a potential opportunity to improve outcomes, Karen Elizabeth Hoffman, MD, MHSc, MPH, explained in a presentation at the SUO 23rd Annual Meeting.¹

“Anywhere from 20% to 50% of patients experience post-prostatectomy biochemical recurrence within 5 years of surgery,” explained Hoffman, an associate professor in the Department of Radiation Oncology at The University of Texas MD Anderson Cancer Center in Houston. “If you look at contemporary trials, metastasis-free survival [MFS] after external beam radiation and androgen-deprivation therapy (ADT) is about 85% at 5 years,” Hoffman added.

“Radiation delivered by theranostics has the potential to address micrometastatic disease in high-risk patients and thereby improve cancer control," said Elizabeth Hoffman, MD, MHSc, MPH.

Thus, she said there is an unmet need for some of these high-risk patients that can be filled by theranostics, a process whereby one radioactive drug is used for imaging/diagnosis, and a second radioactive drug is used to deliver therapy.

Hoffman said research has already shown how radiotherapy can address microscopic disease in patients with high-risk prostate cancer. She pointed to results from the POP-RT trial, which showed that in patients with high-risk localized prostate cancer, prophylactic whole-pelvic nodal radiotherapy improved MFS, biochemical failure-free survival, and disease-free survival (DFS) versus prostate-only radiotherapy (PORT).

Overall, the study included 224 patients, with 114 and 110 patients randomized to PORT and whole-pelvic radiotherapy (WPRT), respectively. The distant MFS rate at 5 years was 95.9% with WPRT vs 89.2% with PORT (HR, 0.35; P = .01).²

Building on this research, Hoffman said, “Radiation delivered by theranostics has the potential to address micrometastatic disease in high-risk patients and thereby improve cancer control.”

The key now, she explained, is to determine how to integrate theranostics with the current standard treatments of surgery, radiotherapy, and ADT.

Neoadjuvant approach

Hoffman said that 1 approach being explored is the use of theranostics as neoadjuvant treatment prior to radical prostatectomy. Specifically, the single-arm LuTectomy trial is exploring the feasibility of using the PSMA-targeted radiopharmaceutical ¹⁷⁷Lu-PSMA-617 (LuPSMA; lutetium Lu-177 vipivotide tetraxetan; Pluvicto) in the neoadjuvant setting.

The study enrollment goal is 20 patients, with the first 10 patients receiving 1 cycle of LuPSMA followed by radical prostatectomy and pelvic nodal dissection. The second 10 patients will receive 2 cycles of LuPSMA before surgery.

Initial results for the first 10 patients were shared during the 2022 European Association of Urology Congress. Overall, 6 (60%) of the 10 patients had a partial PSMA response, 3 patients had stable disease, and 1 patient had disease progression. “There was a pathologic treatment effect in 8 of 10 cancers after a single treatment with LuPSMA,” added Hoffman.

The treatment was safe, with no adverse events greater than grade 2. Additionally, for 9 out of 10 patients, surgery difficulty was as expected, with only 1 patient experiencing a surgery that was “slightly more difficult.”

Hoffman said the single-dose of neoadjuvant LuPSMA appears safe and feasible and she now anticipates future results showing whether administering 2 cycles of neoadjuvant LuPSMA increases disease response.

Other approaches

A second approach Hoffman described was the delivery of a theranostic concurrently with ADT. She said that based on preclinical models, “It is postulated that delivery of ADT with LuPSMA may enhance cancer killing,” based on the idea that, “testosterone suppression may increase PSMA expression.” Accordingly, ongoing studies are exploring the impact of ADT on PSMA expression and radiation dose delivered to the tumor.

Researchers are also exploring the potential of using theranostics along with external beam radiation therapy. Hoffman said the 2 treatment approaches may be complementary: “EBRT is spatially based while theranostics is biologically based,” and “EBRT treats gross disease and theranostics can be used for micrometastatic disease.”

Accordingly, 2 studies are exploring radiotherapy with LuPSMA:

• Lunar Study: 177-Lutetium-PSMA Before Stereotactic Body Radiotherapy for the Treatment of Oligorecurrent Prostate Cancer, The LUNAR Study (LUNAR; NCT05496959)
• EBRT + Lu-PSMA for N1M0 Prostate Cancer (PROQURE-1; NCT05162573)

Which type of theranostic is best?

Hoffman said that as the use of theranostics in the high-risk localized setting is increasingly explored, the type of theranostic used will become a key focus. She noted that radionuclide therapy targeting PSMA with alpha-emitting 225Ac-PSMA-617 may have some advantages over radionuclide therapy targeting PSMA with beta-emitting 177Lu-PSMA-617.

“Small volume micrometastasis may be most efficiently treated with the alpha emitter because [it has] higher LET [Linear Energy Transfer], which provides more effective cell kill, as well as shorter range, which provides more local deposition of dose.”

In her concluding remarks, Hoffman said, “Additional studies are needed to determine how to optimally integrate theranostics with our standard local therapies."

References

1. Hoffman KE. Theranostics in High-Risk Localized Prostate Cancer. Presented at: 2022 SUO Annual Meeting. November 30 – December 2, 2022; San Diego, CA.

2. Murthy V, Maitre P, Kannan S, et al. Prostate-Only Versus Whole-Pelvic Radiation Therapy in High-Risk and Very High-Risk Prostate Cancer (POP-RT): Outcomes From Phase III Randomized Controlled Trial. J Clin Oncol. 2021;39(11):1234-1242. doi: 10.1200/JCO.20.03282.