Background
In spite of the rapid progress and many exciting advances in the treatment of metastatic castration-resistant prostate cancer over the past few years, the disease remains incurable with a median overall survival of 12-35 months.1-4
Radiopharmaceuticals are pharmaceutical agents which contain radioisotopes that emit radiation and may be used for diagnostic or treatment purposes. From a therapeutic perspective, radiopharmaceuticals are systemic radiotherapies, emitting alpha or beta radiation. Based on approvals to date, radiopharmaceuticals are indicated in patients with castrate resistant prostate cancer with symptomatic bone metastases. Historically, beta-particle emitting agents, including strontium-89 (Metastron), samarium-153 (Quadramet), phosphorus-32, and rhenium-186, were used as palliative therapies for patients with symptomatic bone disease5, with good efficacy for the relief of bone pain6. However, these agents did not significantly improve survival7. In contrast, the ALSYMPCA trial demonstrated an improvement in both overall survival and skeletal-related events for patients receiving the alpha-emitter radium-2234. Radium-223 functions as a calcium mimetic and selectively binds newly forming bone stroma in regions of high bone turnover in osteoblastic or sclerotic bone metastasis8. It then emits high-energy alpha particles with a very short range (less than 100 μm)9. This high-energy radiation induces a highly localized cytotoxic effect due to double-stranded DNA breakage.
In contrast to the localization of radium-223 to areas of high bone turnover due to its calcium mimetic properties, prostate-specific membrane antigen (PSMA)-based theranostics are targeted to regions of tumor cells on the basis of the PSMA protein, a type II transmembrane glycoprotein which functions as a zinc metalloenzyme found on prostatic epithelium. PSMA is highly expressed (100-1000 fold normal) in the vast majority of prostate cancer cells, including in patients with advanced disease, in those with castration-resistant disease, and in those with poorly differentiated disease. Further, PSMA has a high internalization rate into prostate cancer cells.
PSMA-based theranostics have, to date, utilized labelling to the beta-particle emitter Lutetium-117 (Lu-177). Lu-177 has favourable characteristics for theranostics as emitted beta-particles have limited tissue penetration (less than 2mm) which minimize injury to adjacent healthy tissue. Further, Lu-177 emits low-energy gamma rays which can be used to image the tumor in real time during treatment, with a relatively long half-life of 6.7 days resulting in a relatively prolonged treatment period following administration. While a number of 177Lu-labelled PSMA-targeted ligands have been developed, two are most commonly used: 177Lu-PSMA-617 and 177Lu-PSMA-I&T.
PSMA as a target for therapeutic intervention
A recent systematic review and meta-analysis published in European Urology has highlighted data for the use of Lu-177 in patients with metastatic castration-resistant prostate cancer10. The authors included a total of 24 studies with 1,192 patients who had received Lu-177 based therapy. The majority of these studies reported on 177Lu-PSMA-617 (20 studies) while 3 reported on 177Lu-PSMA-I&T, and 1 reported on both. In this heavily pre-treated population, 44% of patients (95% confidence interval 39-50%) had a PSA response of at least 50% among those receiving 177Lu-PSMA-617 with similar, though slightly lower numbers among those receiving 177Lu-PSMA-I&T (36%, 95% confidence interval 26-47%). Further, these authors found that treatment was well tolerated with very low rates of grade 3 or 4 toxicity, with the highest observed rates for anemia at 8% (95% confidence interval 5-12%). Using meta-regression, the authors demonstrated that patients who had more than one cycle of therapy were more likely to experience PSA declines of 50% or greater.
While the aforementioned systematic review highlighted 24 studies that have been performed examining the role of Lu-177 based theranostics, attention has focused on two key trials. The first of these, which is now published in the Lancet11, is the TheraP trial. This ANZUP/PCFA sponsored trial began in 2016 and represents a world-first study, being a phase III randomized controlled trial of a direct targeted radioligand. TheraP enrolled patients with metastatic castration-resistant prostate cancer who had previously received docetaxel and were eligible to receive cabazitaxel. Patients were required to have progressive disease with a rising PSA with absolute PSA of 20 ng/mL or higher. All patients underwent both Ga-68-PSMA-PET/CT and F-18-FDG-PET/CT prior to randomization. To be eligible for inclusion, patients must have had a high avidity lesion on PSMA PET/CT (SUV max >20 at any site) with measurable disease with SUV max of 10 or greater. Further, there could be no sites of disease which were FDG positive but PSMA negative.
Among 200 men at 11 sites in Australia who were eligible, randomization was performed in a 1:1 fashion to 177Lu-PSMA-617 or cabazitaxel. Randomization was stratified according to disease burden, prior use of enzalutamide or abiraterone, and study site.
The primary study outcome was PSA response and these data were initially reported at ASCO 2020. PSA response was operationalized looking at a response of at least 50% from baseline. Compared to those receiving cabazitaxel (37%, 95% confidence interval 27 to 46%), responses were significant higher among those who received Lu-PSMA (66%, 95% confidence interval 56 to 75%) with an absolute difference of 29% (95% confidence interval 16 to 42%, p<0.0001).
More recent data were presented at ASCO-GU 2021 examining secondary endpoints including PSA/radiologic PFS (PCWG3), pain response (≥2 point reduction on McGill-Melzack Present Pain Intensity scale, objective response rate (RECIST 1.1), adverse events (CTCAE), PROs (EORTC QLQ-C30) and overall survival. As of a data cut-off of July 20, 2020, median follow-up was 18.4 months. PFS was significantly longer in those assigned Lu-PSMA rather than cabazitaxel (rates at 1 year 19% [95% confidence interval 12-27%] vs 3% [1-9%], HR 0.63, 95% confidence interval 0.46-0.86; p = 0.003) based on 173 events. A similar benefit was seen whether PFS was examined radiographically (rPFS, HR 0.64, 95% confidence interval 0.46-0.88; p = 0.007; 160 events) or based on PSA (PSA-PFS, HR 0.60 95% confidence interval 0.44-0.83; p = 0.002; 172 events). Among men with measurable disease (n=78), objective response rates were significantly greater in the Lu-PSMA arm (49% vs 24%, RR 2.1, 95% confidence interval 1.1-4.1; p = 0.019). Similarly, among those with pain at baseline (n=90), pain responses occurred in 60% in the Lu-PSMA arm vs 43% for cabazitaxel (RR 1.42, 95% confidence interval 0.84-4.48; p = 0.10). Overall, patient-reported global health status was similar between arms (Lu-PSMA 64 [95% confidence interval 61-67] vs cabazitaxel 60 [57-64]), though significantly better function was noted for patients receiving Lu-PSMA with respect to fatigue, social functioning, insomnia, and diarrhea domains. No PRO domains were superior for cabazitaxel. The authors further assessed deterioration free survival, defined as the time to a 10 point or greater decline in EORTC QLQ-C30 global health related quality of life. Again, this favoured the Lu-PSMA treated group.
On March 23, 2021, Novartis reported that the phase III VISION trial assessing 177Lu-PSMA-617 compared to standard of care met both primary endpoints, significantly improving overall survival and radiographic progression-free survival among men with PSMA-positive metastatic castration-resistant prostate cancer. This study was subsequently published in the New England Journal of Medicine12. The VISION trial is an international, randomized, open-label phase III study evaluating 177Lu-PSMA-617 in men with PSMA-positive metastatic castration-resistant prostate cancer who had previously received treatment with next-generation androgen receptor signaling inhibition (abiraterone, enzalutamide, etc) and one or two prior lines of taxane chemotherapy. Additionally, patients must have had an ECOG performance status of 0-2 and a life expectancy of at least 6 months. Importantly, patients must have had PSMA-positive disease on the basis of a central review of 68Ga-PSMA-11 staging scans. PSMA positivity was defined as uptake greater in metastatic lesions than in the liver. Further, they could have no PSMA-negative metastatic lesions.
Following enrollment, patients were randomized in a 2:1 fashion to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks x 6 cycles) plus standard of care or standard of care alone. Standard of care treatments was at the discretion of the treating investigator; however, cytotoxic chemotherapy, immunotherapy, and radium-223 were explicitly excluded. Most patients received alternative androgen-directed therapies while others received palliative radiotherapy and glucocorticoids. The trial schema for VISION is as follows:
The trial assessed two alternate primary endpoints: radiographic progression-free survival using PCWG3 criteria by independent central review and overall survival. In addition to these two primary endpoints, they also assessed key secondary endpoints of objective response rate (RECIST v1.1), disease control rate, and time to first symptomatic skeletal event as well as other secondary endpoints including safety and tolerability, biomarkers including PSA, and health-related quality of life and pain.
Among 1,179 screened patients, the VISION trial enrolled 831 patients between June 4, 2018, and October 23, 2019, including 551 patients were allocated to 177Lu-PSMA-617 + standard of care and 280 were allocated to standard of care only. As expected in the randomization design, demographic characteristics and baseline features were well balanced between the two treatment groups. Further, pre-randomization treatment was well balanced. In both the radiographic progression free survival analysis set and among all randomized patients, between 45-50% of patients had received more than one androgen receptor pathway inhibitor and 41-48% of patients had received more than one taxane regime.
Over a median study follow-up of 20.9 months, treatment with 177Lu-PSMA-617+ standard of care significantly improved overall survival by a median of 4.0 months (median overall survival, 15.3 vs 11.3 months; HR, 0.62 [95% confidence interval 0.52, 0.74]; p < 0.001, one-sided), compared to standard of care alone, in the overall cohort of all randomized patients (n=831):
The second alternate primary endpoint showed that treatment with 177Lu-PSMA-617 + standard of care significantly improved radiographic progression free survival by a median 5.3 months (median radiographic progression free survival, 8.7 vs 3.4 months; HR, 0.40 [99.2% confidence interval: 0.29, 0.57]; p < 0.001, one-sided):
While a higher rate of high-grade (grade 3-5) treatment-emergent adverse events was observed with 177Lu-PSMA-617 (28.4% vs 3.9%), overall therapy was well tolerated. In terms of specific adverse events, treatment with 177Lu-PSMA-617 + standard of care was associated with increased rates of bone marrow suppression, xerostomia, and nausea and vomiting.
While both TheraP and VISION are assessing the role of 177-Lu-PSMA in mCRPC, there are notable differences. First, VISION is an industry sponsored trial with a much larger sample size (800 patients). Second, in VISION, a central production model is used with the agent subsequently shipped ready for clinical use. In contrast, in TheraP, lutetium is made on site. This allows some flexibility but required standardization and quality control in order to undertake the study. Moving forward, this on-site approach is expected to be much lower cost than centralized processing. Third, as mentioned above, in order to be included in TheraP, patients could not have sites of disease which were FDG positive but PSMA negative. This requirement led to the exclusion of approximately 30% of otherwise eligible men. In contrast, the VISION trial didn’t have this requirement. This narrowing of the selection criteria in TheraP will likely enrich for patients who are likely to respond, compared to VISION.
The SPLASH Trial
Second to 177Lu-PSMA-617, 177Lu-PSMA-I&T (also known as 177Lu-PNT2002) is the most commonly utilized theranostic agent in prostate cancer. To date, 177Lu-PNT2002 has been administered to more than 300 patients in administrative reports with PSA responses of 50% or greater in up to half of patients. However, unlike 177Lu-PSMA-617, it has not been used in phase III trials to date. The 177LU-PNT2002 PSMA therapy After Second line Hormonal treatment (SPLASH) trial (NCT04647526) will address this gap. SPLASH will prospectively evaluate the efficacy of 177Lu-PNT2002 for men with progressive metastatic castration-resistant prostate cancer after androgen receptor axis-targeted therapy.
The trial will enroll men at least 18 years of age who have documented progressive metastatic castration-resistant prostate cancer. Patients must have previously received only one androgen receptor axis-targeted therapy (in either the castration-sensitive prostate cancer or castration-resistant prostate cancer setting) but not have received chemotherapy for castration-resistant prostate cancer and unfit or unwilling to receive chemotherapy. To be eligible, all patients must undergo baseline imaging with either 68Ga-PSMA-11 or 18F-DCFPyL PSMA PET/CT and have evidence of “high PSMA expression” based on blinded independent central review. Patients must also have performance status of 0 or 1.
Patients are excluded for any prior cytotoxic chemotherapy for castration-resistant prostate cancer. However, those who received chemotherapy for hormone-sensitive disease is allowed, assuming that the last dose is at least 1 year prior to chemotherapy. Additionally, patients are excluded if they have liver metastases measuring 1cm or greater, a superscan on bone scan, CNS metastases, or contraindications to the use of planned androgen receptor antagonist therapy. Other exclusion criteria, in keeping with a standard approach in this disease space, are provided in the table that follows.
The initial portion of the study will involve a 25-patient dosimetry lead-in. In this phase, patients will receive up to four cycles of 177Lu-PNT2002 at 6.8 GBq every 8 weeks. Following initial safety and preliminary efficacy evaluation during the dosimetry portion of the study, it will continue to the randomization phase in which approximately 390 patients will be randomized in a 2:1 ratio to receive 177Lu-PNT2002 (Arm A) versus enzalutamide or abiraterone (with prednisone or dexamethasone) (Arm B). Unlike the VISION trial of 177Lu-PSMA-617 (which also focused later in the disease space), patients randomized to Arm B will be offered cross-over to 177Lu-PNT2002 treatment at the time of blinded independent central review-assessed radiologic progression.
The planned sample size of approximately 390 patients will allow for 90% power to test the alternative hypothesis of a hazard ratio ≤ 0.66 at an α of 0.025 for the primary endpoint of radiologic progression-free survival assessed by blinded independent central review using RECIST 1.1 (soft tissue) and PCWG3 (bone) criteria. In addition, a number of key secondary endpoints will be examined including objective response rate, duration of response, PSA response, biochemical progression free survival, overall survival, and safety and tolerability.
The SPLASH trial is sponsored by POINT biopharma, a relatively new clinical-stage global pharmaceutical company focusing on expanding radioligand therapy in the treatment of cancer through their development and commercialization. As their development pipeline focused on the treatment mechanism of action rather than disease indication, currently, POINT is developing radionuclide therapy for a variety of indications in prostate cancer and for patients with neuroendocrine tumors.
Moving forward, the optimal role for 177Lu-PSMA therapy remains to be better delineated. Ongoing questions include its role in combination therapy (with pembrolizumab, olaparib, docetaxel, enzalutamide, and other agents) and earlier in the disease process (including in those with de novo high-volume metastatic hormone naïve prostate cancer and with high-risk localized prostate cancer).
Published Date: August 2022