Authors' objectives: To assess the clinical efficacy, safety, and cost-effectiveness of 177Lu-PSMA-617 treatment of mCRPC with of implementing this treatment in Norway, in a health technology assessment (HTA). Important aspects linked to radiation safety, organisational implications and patient perspectives on 177Lu-PSMA-617 is also included in this work. Prostate cancer is the most common cancer type among Norwegian men. In 10-20% of these patients, the cancer will advance to metastatic, castration resistant prostate cancer (mCRPC). As mCRPC is incurable, the treatment options are limited to palliative therapy, using radiation and chemotherapy to manage symptoms and prolong life. Radioligand therapy (RLT) is increasingly being used for treating various malignancies. RLT for mCRPC uses the radionuclide lutetium-177 labelled with a binding ligand for prostatespecific membrane antigen (PSMA). 177Lu-PSMA-617 was approved in both USA and Europe in 2022. The product is called PluvictoTM (Novartis), and the drug name is formally called “lutetium (177Lu) vipivotide tetraxetan”. PluvictoTM is indicated for use in patients with progressive PSMA-positive mCRPC who previously have been treated with hormone therapy and taxane-based chemotherapy and is meant to be a supplement to life prolonging treatment.

Authors' results and conclusions: We included three RCTs that compared the effect of 177Lu-PSMA-617, either alone or in combination with standard of care therapy, to different comparators, i.e., docetaxel (Satapathy 2021), cabazitaxel (TheraP: Hofman 2021), or standard of care therapy (VISION: Sartor 2021). The study populations included 40 (Satapathy 2021), 200 (TheraP: Hofman 2021), and 831 (VISION: Sartor 2021) participants, respectively. The studies also varied with respect to the participants’ previous treatments, from chemotherapy-naïve patients (Satapathy 2021), previous treatment with docetaxel and cabazitaxel being the next possible treatment (TheraP: Hofman 2021), to previous treatment with one approved anti-androgen therapy and 1-2 taxane-based chemotherapy regimens (VISION: Sartor 2021). Due to the limited number of studies, as well as the above-mentioned variation between the studies, we did not perform a metaanalysis, and their results are therefore not directly comparable. Data on overall survival was only presented in the VISION study, which showed that treatment with 177Lu-PSMA-617 plus standard of care therapy prolonged survival with four months when compared with standard of care therapy alone (median 15.3 months versus median 11.3 months), and this result was statistically significant; HR 0.62 (0.52 to 0.74) (GRADE: high). For progression-free survival, treatment with 177Lu-PSMA-617 plus standard of care therapy1 prolonged survival with 5.5 months when compared with standard of care therapy1 alone (median 8.7 months versus median 3.4 months), and this result was statistically significant; HR 0.40 (0.31 to 0.51) (GRADE: high). When compared with cabazitaxel, treatment with 177Lu-PSMA-617 overall prolonged progression-free survival, and this result was also statistically significant; HR 0.63 (0.46 to 0.86) (GRADE: low). However, this difference was not evident in the median progression-free survival time of 5.1 months in the 177Lu-PSMA-617 group versus 5.1 months in the cabazitaxel group.2 When compared with docetaxel, treatment with 177Lu-PSMA-617 had little or no effect on progression-free survival; HR 0.90 (0.46 to 1.77) (GRADE: very low). In terms of safety, treatment with 177Lu-PSMA-617 plus standard of care therapy increased the risk of severe adverse events ≥grade 3 when compared with standard of care therapy alone, and this result was statistically significant; RR 1.39 (1.14 to 1.69) (GRADE: moderate). When compared with cabazitaxel, treatment with 177Lu-PSMA-617 reduced the risk of severe adverse events ≥grade 3, but this result was not statistically significant; RR 0.73 (0.18 to 1.04) (GRADE: very low). When compared with docetaxel, treatment with 177Lu-PSMA-617 reduced the risk of severe adverse events ≥grade 3, but this result was not statistically significant; RR 0.60 (0.27 to 1.34) (GRADE: very low). The most common adverse events associated with 177Lu-PSMA-617 treatment were fatigue, dry eyes and mouth, and pain. The overall incidence of more serious adverse events such as nephrotoxicity, was low. The results of the cost-utility analysis in the base case scenario show that treatment with 177Lu-PSMA-617 plus standard of care therapy patients with mCRPC is associated with higher QALY-gain (incremental QALYs: 0.44) and higher costs (incremental costs: NOK XXXXXX) when compared to standard of care therapy alone. The resulting incremental cost-effectiveness ratio (ICER) is equal to NOK XX XXXXX per QALY. These results are most sensitive to changes in the parameters of survival functions as well as the price of 177Lu-PSMA-617. The calculated absolute shortfall for patients with mCRPC is equal to 11.67 qualityadjusted life-years, which implies that these patients loose on average 11.67 good years of life (defined as QALYs) compared to men of their age in the general population. Results of the budget impact analysis show that the incremental annual total cost of introducing 177Lu-PSMA-617 plus standard of care therapy for patients with mCRPC will reach NOK XX XXXXX over five years Treatment with 177Lu-PSMA-617 plus standard of care therapy prolongs overall and progression-free survival more than standard of care therapy alone but has a higher risk of severe adverse events ≥grade 3. However, 177Lu-PSMA-617 treatment has shown mostly mild adverse events, and long-term radiation-induced malignancies can be disregarded due to short life expectancy for this population. For patients, the main expectation regarding 177Lu-PSMA-617 treatment is first and foremost as a new option for life prolonging treatment for mCRPC. In terms of health economics, we assumed that the 177Lu-PSMA-617 would take place in an outpatient setting. The cost-utility analysis indicates that treatment with 177Lu-PSMA-617 is more effective, but also more costly than standard of care therapy alone. Implementation of 177Lu-PSMA-617 treatment in Norway will likely affect the current organisation and allocation of resources that needs to be further explored.

Authors' methods: Effiacy and safety: We identified relevant publications from randomised controlled trials (RCTs) through a systematic search. Our selection criteria included men over 18 years diagnosed with mCRPC, and treatment with the radionuclide lutetium-177 labelled with the specific ligand PSMA-617. We had no limitations as to the possible comparators. The main efficacy outcome was survival, i.e., overall survival and progression free survival, and safety outcome was severe adverse events ≥grade 3. The included studies were critically appraised using the Cochrane Risk of Bias tool. We assessed the certainty of evidence for all outcomes using the GRADE approach (Grading of Recommendations Assessment, Development and Evaluation), expressing the certainty as high, moderate, low, or very low, depending on the level of confidence we have in the effect estimates. The results are mainly presented as hazard ratios (HR) and risk ratios (RR) with 95% confidence intervals (CI). Health economics: In the health economic evaluation, we performed a cost-utility analysis (CUA) comparing 177Lu-PSMA-617 plus standard of care therapy with standard of care therapy alone as treatment options in mCRPC. A partitioned survival analysis was developed and analysed in TreeAge Pro Healthcare® 2023. The efficacy input in the model was based on the survival and safety data from the VISION trial (Sartor 2021). Incremental costeffectiveness rate (ICER) was estimated from a modified Norwegian health care perspective, incorporating all pertinent costs and health outcomes expressed in 2023 Norwegian kroner (NOK) and quality-adjusted life-years (QALYs). Both costs and effects were discounted at an annual rate of 4%. Probabilistic sensitivity analyses (ProbPSA), as well as a series of one-way sensitivity analyses were conducted to handle uncertainties in the model parameters. In line with the Government White Paper on priority setting (Meld. St. 34 2015-2016), we estimated the absolute shortfall for patients with mCRPC to quantify the severity criterion. Additionally, the budget impact of introducing 177LuPSMA-617 in combination with standard of care as a treatment option for mCRPC patients in Norway, was estimated.

Project Status: Completed

URL for project: https://www.fhi.no/en/cristin-projects/ongoing/health-technology-assessment-of-177lu--psma-617-treatment-for-metastatic-ca/

Year Published: 2023

URL for published report: https://www.fhi.no/en/publ/2023/177Lu-PSMA-617-for-the-treatment-of-metastatic-castration-resistant-prostate-cancer/

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Norway

Organisation Name: Norwegian Institute of Public Health

Contact Address: P.O. Box 222 Skoyen, N-0123, Oslo