Expanding 177Lutetium-PSMA-617 Use in the Community

Training at a larger academic center provides an opportunity to have firsthand access to ¹⁷⁷lutetium–prostate-specific membrane antigen-617 (177Lu-PSMA-617; Pluvicto), a groundbreaking treatment for patients with advanced metastatic castrate-resistant prostate cancer. Unfortunately, due to supply issues in 2022, there was a temporary halt in production, which put many patients’ lives at risk. Not being able to offer your patients the best potential treatment to extend their overall life and quality of life was difficult, to say the least. Providing this same level of care to patients in the community can be a challenge, as would finding an institution that would invest and develop this program as well. St Elizabeth Healthcare in Edgewood, Kentucky, offers ¹⁷⁷Lu-PSMA-617 treatments to patients within the Ohio, Indiana, and Kentucky tristate area. The number of patients with access is growing rapidly.

The novel theranostic ¹⁷⁷Lu-PSMA-617 is a targeted treatment for advanced metastatic castrate-resistant prostate cancer. The treatment utilizes a β particle type of radiation, which allows it to penetrate deeply but be less damaging to surrounding healthy tissue given that the ionizations they produce are more widely spaced. In prostate cancer, the agent binds to the PSMA receptor on the surface of the prostate cancer cells, which allows it to become internalized by the cell and leads directly to DNA damage.^1,2 This treatment is used in conjunction with the diagnostic test called the PSMA PET scan with gallium 68 gozetotide (Locametz). Both ¹⁷⁷Lu-PSMA-617 and gallium-68 gozetotide were approved by the FDA in March 2022 and have been shown to significantly improve prostate cancer survival rates, time to disease progression, and quality of life.³

There has been a growing amount of evidence showing the success of ¹⁷⁷Lu-PSMA-617 in the metastatic castrate- resistant setting, which led to its approval. The VISION study (NCT03511664) was a phase 3, randomized multicenter trial that compared the standard of care and 7.4 gigabecquerels ¹⁷⁷Lu-PSMA 617 every 6 weeks vs physician’s choice standard of care alone.⁴

Eligible patients needed to have been treated with at least 1 androgen receptor pathway inhibitor (ARPI) and 1 taxane and have PSMA positivity on a PET scan. PSMA PET positivity was loosely defined as uptake more than the liver parenchyma and specific exclusion criteria for PSMA-negative lesions as well. Primary end points were progression-free survival (PFS) and overall survival (OS). This was a heavily pretreated population of people, with 91% having bony metastasis, roughly 10% having visceral metastasis, 35% to 45% having 2 ARPIs, and up to 40% having had both docetaxel and cabazitaxel. Results showed that ¹⁷⁷Lu-PSMA-617 improved radiographic-PFS (rPFS) by roughly 5 months (8.7 months in the experimental group vs the standard of care, which was 3.4 months). OS in the experimental group was 15.3 months vs 11.3 months with the standard of care. Main adverse events included myelosuppression, fatigue, nausea, and dry mouth.4 Bone marrow reserve is 1 consideration when selecting patients given that many patients had at least a taxane and potentially cabazitaxel (Jevtana) along with 1 or 2 ARPIs and potential additional agents prior to receiving ¹⁷⁷Lu-PSMA 617. In the post hoc exploratory analysis, radiologic (rPFS) benefits with 177Lu-PSMA 617 were seen consistently, regardless of type of treatment used and number of lines for ARPI or chemotherapy.

PSMAfore Study

The PSMAfore study (NCT04689828) is a recent phase 3, multicenter clinical trial that is evaluating those with PSMA-positive metastatic castrate-resistant prostate cancer who have not been exposed to a taxane-containing regimen vs a change in ARPI.⁵ Patients in the APRI arm were allowed to cross over to the ¹⁷⁷Lu-PSMA-617 arm upon radiographic progression. A total of 469 patients were enrolled and the primary end point was rPFS and the secondary end point was OS. Interim trial results presented at the European Society for Medical Oncology Congress 2023 showed that the trial met its primary end point and showed a 59% reduction in risk of radiographic progression vs change in ARPI and improvement in rPFS (12 months in experimental arm vs 5.6 months). At the second interim analysis, there was no difference in OS but it was noted that 84% of the ARPI arm crossed over into the ¹⁷⁷Lu-PSMA-617 group.⁵ Longer follow-up is needed to determine the true impact in an earlier setting.

Novel ARPIs are in development and potential combinations with ¹⁷⁷Lu-PSMA-617 offer a new arsenal of potential options and only solidify ¹⁷⁷Lu-PSMA-617 in both earlier- and later-line settings. Given the explosion of new approvals involving PARP inhibitors in combination with ARPIs, there are other studies, such as the phase 1 LuPARP study (NCT03874884), which is testing the combination of ¹⁷⁷Lu-PSMA-617 with PARP inhibitors in an earlier setting as well. LuPARP has shown an impressive overall response rate of 78% in the study. The PSA50 response rates were actually higher in LuPARP (66%) than in the VISION study (46%).^6,7 The phase 2 ENZA-p study (NCT04419402) showed that the combination of ¹⁷⁷Lu-PSMA-617 plus enzalutamide (Xtandi) enhances PSA-PFS (13 months with combination therapy vs 7.8 months with enzalutamide alone (HR, 0.43; 95% CI, 0.290.63, P = .0001).8 This is one of the first true, randomized trials combining enzalutamide with ¹⁷⁷Lu-PSMA-617. In addition to different combination trials, there is ongoing research looking at alterations of ¹⁷⁷Lu-PSMA-617 with ¹⁷⁷Lu-PNT2002 and ¹⁷⁷Lu-PSMA-I&T (SPLASH study; NCT04647526 ),⁹ actinium-255, an α emitter, and PSMA antibody-drug conjugates. The real question that remains is: Where is the optimal sequence for this treatment and should it be in combination with others or not?

Best Practices

Putting together a radioligand program is no easy feat, especially within the community. As we began the process of evaluating the development of a radioligand program, it became clear that a process for administering ¹⁷⁷Lu-PSMA-617 would need to incorporate best practices and customized solutions in order to achieve success for our patients and our organization.¹⁰ Jason Rawe, director of radiation oncology at St Elizabeth Healthcare, played a pivotal role in the development of this new program focusing on clinical processes, policies, licensing, safety measures, staff training, preauthorization, billing, and patient education. Although some best practices were gleaned from our professional networks and other vendor-connected organizations, most of this development work had to be designed from the ground up considering the uniqueness of any organization’s characteristics. In order to understand the potential volume of patients, our team incorporated estimates in a variety of ways, including surveying our physicians, broad-based cancer incidence rates for focused disease sites/stages, comparable inference from facilities with similar settings, and a look back at PET scan and pharmacy orders. This analysis resulted in a range of estimates and helped us to triangulate an average range that we could use going forward to help estimate the need for resources.

Along the way, we heavily collaborated with our radiation oncology, pharmacy, and nuclear medicine departments as they would play an important role in the drug administration, follow-up, and adverse events management. One such item of consideration was the primary role of oversight for radiation surveillance and safety between our in-house physician staff and the nuclear medicine technicians who deliver the medication. The ultimate responsibility for doing pre- and postprocedure surveillance came down to our nuclear medicine department as it was determined that the professional who administers the treatment should be the one to ensure proper safety protocols were followed, even if that resource falls outside the department’s core staff. These unique situations highlight the need to collaborate and adapt across departments to ensure the best quality and most efficient process can be developed.

Olsi Gjyshi, MD, a radiation oncologist at St Elizabeth Healthcare, has had extensive experience with ¹⁷⁷Lu-PSMA-617.

“Managing ¹⁷⁷Lu-PSMA-617 can be quite a complex undertaking, involving multiple facilities and departments,” Gjyshi said.

Though lutetium-177 has a half-life of 6.6 days, its radioisotope, ^117mLu, which is usually found in trace amounts in samples, has a half-life of over 152 days. Despite representing a small proportion of the overall sample (< 0.3%), ^177mLu drives some of the waste storage requirements following administration of the treatment. As a result, the vials and tubing used for treatment delivery and any contaminated materials need to be stored in dedicated hot labs and specialized storage equipment for over 66 days (10 half-lives) in the nuclear medicine department before being resurveyed for radioactivity prior to being discarded through regular biohazard material containers once the material has reached background levels. In the unlikely event that there is continued detection of radioactivity past 66 days, which would suggest presence of the ^177mLu radioisotope, the items would need to be stored in dedicated containers for up to 5 years, which requires significant space considerations.^11,12

Overall, 177Lu-PSMA-617 will be changing the treatment landscape of metastatic prostate cancer in the castrate-sensitive and -resistant settings. As a result of this and the growing incidence of prostate cancer cases across the nation,¹³ more community oncology programs will need to incorporate ¹⁷⁷Lu-PSMA-617 within their practices earlier and offer this life-changing treatment.

This starts with assessing the true need for this type of treatment in one’s own community and identifying key resources, structural support systems, and safety concerns prior to bringing ¹⁷⁷Lu-PSMA-617 into one’s own institution. If one does not have access to ¹⁷⁷Lu-PSMA-617 at their own institution, I highly recommend establishing a connection with a major academic center with prostate cancer expertise and early referral of these patients to genitourinary oncologists. My goal in my own career and for community oncology as a whole is to offer academic level care right in our patient’s backyard. The majority of cancer care within the United States is provided by community oncologists and we need to shift our priorities to creating additional community oncology practices and specialized providers who can provide this expert level care within the communities they live and serve.

Matthew Kurian, MD, is a staff oncologist at St Elizabeth Healthcare in Edgewood, Kentucky, and an assistant professor of medicine at the University of Kentucky College of Medicine, Northern Kentucky Campus. Olsi Gjyshi, MD, is a staff radiation oncologist at St Elizabeth Healthcare. Jason Rawe is director, Radiation Oncology, at St Elizabeth Healthcare in Edgewood, Kentucky.

REFERENCES:

1. Patell K, Kurian M, Garcia JA, et al. Lutetium-177 PSMA for the treatment of metastatic castrate resistant prostate cancer: a systematic review. Expert Rev Anticancer Ther. 2023;23(7):731-744. doi:10.1080/14737140.2023.2213892

2. Hennrich U, Eder M. [177Lu]Lu-PSMA-617 (Pluvicto): the first FDA-approved radiotherapeutical for treatment of prostate cancer. Pharmaceuticals (Basel). 2022;15(10):1292. doi:10.3390/ph15101292

3. FDA approves Pluvicto for metastatic castration-resistant prostate cancer. FDA. March 23, 2022. Accessed March 25, 2024. https://tinyurl.com/5n8md3hz

4. Sartor O, de Bono J, Chi KN, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385(12):1091-1103. doi:10.1056/nejmoa2107322

5. Sartor O, Castellano Gauna DE, Herrmann K, et al. LBA13 phase III trial of [177Lu]Lu-PSMA-617 in taxane-naive patients with metastatic castration-resistant prostate cancer (PSMAfore). Ann Oncol. 2023;34(suppl 2):S1324-S1325. doi:10.1016/j.annonc.2023.10.085

6. ASCO Post staff. PSMAfore: Lutetium Lu-177 vipivotide tetraxetan in metastatic prostate cancer. ASCO Post. Updated November 13, 2023. Accessed March 25, 2024. https://tinyurl.com/bdcr6jf8

7. Sayyid R. LuPARP: phase 1 trial of 177Lu-PSMA-617 and olaparib in patients with metastatic castration resistant prostate cancer (mCRPC). UroToday. June 2023. Accessed March 25, 2024. https://tinyurl.com/58z958rk

8. Emmett L, Subramaniam S, Crumbaker M, et al. Enzalutamide and 177Lu-PSMA-617 in poor-risk, metastatic, castration-resistant prostate cancer (mCRPC): a randomised, phase II trial: ENZA-p (ANZUP 1901). Ann Oncol. 2023;34(suppl 2):S1281-S1282. doi:10.1016/S0923-7534(23) X0011-8

9. Study evaluating mCRPC treatment using PSMA [Lu-177]PNT2002 therapy after second-line hormonal treatment (SPLASH). ClinicalTrials.gov. Updated November 2, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT04647526

10. Lantheus and POINT Biopharma announce positive topline results from pivotal SPLASH trial in metastatic castration-resistance prostate cancer. News release. Lantheus Holdings. December 18, 2023. Accessed March 25, 2024. https://tinyurl.com/ydu6fk3u

11. Dash A, Pillai MR, Knapp FF Jr. Production of (177)Lu for targeted radionuclide therapy: available options. Nucl Med Mol Imaging. 2015;49(2):85-107. doi:10.1007/s13139014-0315-z

12. Prevot S, Dygaï-Cochet I, Riedinger JM, et al. Dealing with dry waste disposal issues associated with 177mLu impurities: a long-term challenge for nuclear medicine departments. EJNMMI Phys. 2023;10(1):3. doi:10.1186/s40658-023-00524-z

13. American Cancer Society releases latest cancer statistics, launches Initiative to address prostate cancer resurgence and disparities. News release. American Cancer Society. January 12, 2023. Accessed March 25, 2024. http:// pressroom.cancer.org/FactsandFigures23