177Lu-PSMA-617 for treatment of metastatic castration resistant prostate cancer: a health technology assessment
Health technology assessment|
In this health technology assessment, we included three randomised controlled trials that compared the effect of 177Lu-PSMA-617, either alone or in combination with standard of care therapy (SoC), to docetaxel, cabazitaxel, or SoC alone.
In the PDF file, prices are redacted for reasons of confidentiality for the manufacturer. In the text below, the hidden figures appear as X.
177Lu-PSMA-617 is a new radioligand therapy that is being used in treating metastatic castration resistant prostate cancer. It consists of the radionuclide lutetium-177 labelled with the ligand PSMA-617 for specific binding to prostate-specific membrane antigen (PSMA) typically expressed by prostate cancer cells.
In this health technology assessment, we included three randomised controlled trials that compared the effect of 177Lu-PSMA-617, either alone or in combination with standard of care therapy (SoC), to docetaxel, cabazitaxel, or SoC alone. The main efficacy outcome was survival, i.e., overall survival (OS), as well as progression-free survival (PFS). Safety outcome was severe adverse events ≥grade 3 (SAE). The results are presented as hazard ratio (HR) and risk ratio (RR), with an assessment of our confidence in the results (GRADE).
177Lu-PSMA-617 + SoC versus SoC alone (total n=831)
- OS: HR 0.62 (0.52 to 0.74) (GRADE: high)
- PFS: HR 0.40 (0.31 to 0.51) (GRADE: high)
- SAE: RR 1.39 (1.14 to 1.69) (GRADE: moderate)
177Lu-PSMA-617 versus cabazitaxel (total n=200)
- PFS: HR 0.63 (0.46 to 0.86) (GRADE: low)
- SAE: RR 0.73 (0.18 to 1.04) (GRADE: very low)
177Lu-PSMA-617 versus docetaxel (total n=40)
- PFS: HR 0.90 (0.46 to 1.77) (GRADE: very low)
- SAE: RR 0.60 (0.27 to 1.34) (GRADE: very low)
Treatment with 177Lu-PSMA-617 plus SoC therapy prolonged overall and progression-free survival with median four and five months, respectively, compared with SoC alone, but increased the risk of severe adverse events ≥grade 3 in patients previously treated with hormone therapy and taxane-based chemotherapy. We have high and moderate confidence in these results. 177Lu-PSMA-617 prolonged progression-free survival and reduced the risk of severe adverse events ≥3 more than cabazitaxel in patients previously treated with docetaxel. However, we have low and very low confidence in these results. There is seemingly no difference in progression-free survival when comparing 177Lu-PSMA-617 with docetaxel in patients who were treatment-naïve, but 177Lu-PSMA-617 reduced the risk of severe adverse events ≥3 more than docetaxel. However, we have very low confidence in these results. The most common adverse events associated with 177Lu-PSMA-617 were fatigue, dry eyes and mouth, and pain. The incidence of more serious adverse events such as nephrotoxicity, was low.
Patients’ expectation towards 177Lu-PSMA-617 is first and foremost as a new option for life prolonging treatment for mCRPC. An implementation of 177Lu-PSMA-617 in Norway will likely affect the current organisation and allocation of resources. Furthermore, implementation must ensure that the treatment is managed in line with the Norwegian radiation protection legislation.
Our cost-effectiveness analysis shows that treatment with 177Lu-PSMA-617 together with SoC is more effective, but also more costly than SoC alone in mCRPC patients who previously have been treated with anti-androgen therapy and taxane-based chemotherapy. The incremental cost-effectiveness ratio (ICER) was NOK X per quality adjusted life year (QALY). The absolute shortfall for patients with mCRPC is equal to 11.67 QALYs.
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 prostate-specific 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.
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.
Efficacy 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).
We included three RCTs that compared the effect of 177Lu-PSMA-617, either alone or in combination with standard of care therapy0F, to different comparators, i.e., docetaxel (Satapathy 2021), cabazitaxel (TheraP: Hofman 2021), or standard of care therapy1 (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 meta-analysis, 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 therapy1 prolonged survival with four months when compared with standard of care therapy1 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.1F 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 therapy1 increased the risk of severe adverse events ≥grade 3 when compared with standard of care therapy1 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.
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 cost-effectiveness 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 177Lu-PSMA-617 in combination with standard of care as a treatment option for mCRPC patients in Norway, was estimated.
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 X) when compared to standard of care therapy alone. The resulting incremental cost-effectiveness ratio (ICER) is equal to NOK X 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 quality-adjusted 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 X over five years.
Radiation safety and legislation
Implementation of 177Lu-PSMA-617 as a treatment option in Norway is associated with radiation safety aspects. The requirements in Norwegian radiation protection legislation must be implemented to reduce the risk of unintended exposure of staff, public and environment. Aspects about radiation protection will also have organisational or health economic consequences. Implementation of 177Lu-PSMA-617 is associated with an increase in patients treated with radiopharmaceuticals. This will therefore challenge amongst others waste management, capacity of patient room, dosimetry and personnel resources. 177Lu-PSMA-617 treatment may be associated with some radiation toxicity to the organs at risk. However, the risk for long-term radiation effects, like radiation-induced malignancy, is neglectable for this patient group, due to the short life expectancy.
177Lu-PSMA-617 will be a much-anticipated supplement to the existing treatment of mCRPC in Norway. With an estimated 400-500 new mCRPC patients per year, an average of 4.46 treatments with 177Lu-PSMA-617 per patient per year, will lead to about 2 200 treatments in total per year. As such, the health-services need capacity for this patient load in terms of the treatment itself, but also treatment-related measures, including imaging, haematology, and radiation hygiene. Furthermore, necessary resources will also include staffing, equipment, and facilities in line with radiation safety requirements. Resource requirements are likely to depend on whether the 177Lu-PSMA-617 treatment is provided in a centralised model (only university hospitals) or a decentralised model (university hospitals as well as local hospitals). Expert representatives have advocated for the treatment to be given in an outpatient setting. If the 177Lu-PSMA-617 treatment is to be implemented for mCRPC in Norway, experts should be consulted to consider the organisational matters more in depth.
The patient group eligible for 177Lu-PSMA-617 treatment are men with a relatively large spread in age, in different life situations, with diverse backgrounds, and with various preferences for how they want their life to be. Expectations related to the 177Lu-PSMA-617 treatment may vary among patients. Overall, there is a high expectation of 177Lu-PSMA-617, as a new option for life prolonging treatment for mCRPC when other treatments have not worked. Patients also expect that the proposed treatment will reduce the metastatic disease, thereby relieving pain and lessen the use of pain medications. By reducing the symptom burden and symptom treating medication, the treatment may have a positive impact on the patients’ quality of life and result in better function and less use of municipal services.
The work in this HTA have been executed in a systematic manner and in accordance with our project plan. However, our report is limited in having included only three RCTs; VISION (Sartor 2021), TheraP (Hofman 2021), and Satapathy 2021. The VISION study was the only study to report results on overall survival. We are aware that the TheraP study also have reported data on overall survival, but as these results were published in a conference abstract, we chose to exclude it from our HTA.
The three included studies differed in terms of study populations. First, the inclusion criteria varied between the included studies, causing the study participants to be in different stages of their mCRPC treatment plan. Second, the studies were conducted in various countries, causing the study populations to differ in terms of race and ethnicities, which may (in part) influence morbidity and mortality of prostate cancer. As such, the results from the studies with predominantly Caucasian patient population, i.e., VISION and TheraP, will likely be most relevant to a Norwegian setting. Third, the three studies were also powered differently according to their main outcomes, with the VISION study being the only study with sufficient power for assessing overall survival. Although treatment with 177Lu-PSMA-617 in combination with standard of care therapy showed greater risk of severe adverse events ≥3 compared with standard of care therapy alone, the most common adverse events related to 177Lu-PSMA-617 are mostly mild. Furthermore, long-term effects such as radiation-induced malignancies probably have little relevance as the patient population has a short life expectancy.
While cabazitaxel is considered the most relevant treatment alternative for patients with mCRPC in the Norwegian clinical practice, due to unavailability of good quality complete data that directly compare 177Lu-PSMA-617 with cabazitaxel, we chose to base efficacy input in our cost-effectiveness analysis on the VISION trial. This was the only study we regarded as high certainty evidence for main outcomes that shaped our model, with data available for both the overall and progression-free survival. We assumed an outpatient setting for treatment with 177Lu-PSMA-617 in our analyses. Willingness to pay for additional quality-adjusted life-year is not officially defined in Norway, we therefore abstained from concluding about cost-effectiveness, as well as from performing a net benefits analysis.
In the decision-making process, the sections on clinical effect and health economics should be considered together in order to evaluate the treatment under consideration in terms of the three criteria (benefits, resource use and severity) applicable in priority setting in the Norwegian health care system. The clinical efficacy and safety section of this report provides the necessary information for establishing the clinical benefit of treatments in terms of gains in overall and progression-free survival, and safety considerations. The health economic evaluation section combines that information in the health economic model with resource use in treatments, to determine incremental costs in relation to health gains measured in terms of QALYs, as well as severity, measured as absolute shortfall.
Treatment with 177Lu-PSMA-617 plus standard of care therapy1 prolongs overall and progression-free survival more than standard of care therapy1 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.
 The standard of care therapy in the VISION study was not permitted to include the use of any cytotoxic chemotherapeutic agent (e.g., taxanes), systemic radioisotopes (e.g., radium-223), immunotherapy, or drugs that were considered investigational at the start of the study (e.g., olaparib).
 The progression-free survival at 12 months however, was 12% in the 177Lu-PSMA-617 group and 3% in the cabazitaxel group (TheraP: Hofman 2021)