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Feature: Lu-177-PSMA-617 for the Treatment of Metastatic Castration-resistant Prostate Cancer

Bryan Fitzgerald, PharmD, BCOP
Oncology Clinical Pharmacy Specialist
University of Rochester Medical Center
Rochester, NY

Prostate cancer is the most common cancer diagnosed in males in the United States, with an estimated 268,490 new cases diagnosed and 34,500 deaths in 2022.1-2 In general, most men diagnosed do not die from their prostate cancer, with favorable 5-year relative survival rates of 96.8%.1-2 However, presentation ranges from localized disease to widespread metastatic disease, with prognoses and treatment considerations varying considerably.

Treatment for advanced and metastatic prostate cancer includes the use of androgen deprivation therapy (ADT) to achieve castrate levels of testosterone of less than 50 ng/dL. Patients with metastatic disease which progresses despite these castrate levels of testosterone are classified as having metastatic castration-resistant prostate cancer (mCRPC). Generalizing prognosis for patients with mCRPC can be difficult, as this population is heterogeneous and various disease characteristics and risk factors may contribute to the overall survival picture.

For the treatment of mCRPC, the National Comprehensive Cancer Network (NCCN) preferentially recommends abiraterone, enzalutamide, and docetaxel, in no specific order.3 After exposure to novel hormonal therapy (NHT, e.g. abiraterone or enzalutamide), the NCCN recommends treatment with docetaxel. Conversely, after prior docetaxel therapy, treatment with abiraterone or enzalutamide are recommended.

After progression on both NHT and docetaxel, treatment options for mCRPC are somewhat limited. Current recommendations include agents such as cabazitaxel, radium-223, poly ADP-ribose polymerase (PARP) inhibitors (olaparib, rucaparib), and pembrolizumab; however, many of these agents are recommended only for select patients with treatment criteria that are not applicable to the entire mCRPC population.3 Radium-223 is indicated for mCRPC patients with symptomatic bone-only metastases; therefore, any patient with visceral metastases would not be considered a candidate for this agent. PARP inhibitors play a role in treatment if tumor cells harbor DNA repair pathway mutations (i.e. BRCA mutation), which may only be present in up to 30% of patients.4 Pembrolizumab is only recommended for patients with particular markers of genomic instability.3 Only cabazitaxel has an indication for all patients with mCRPC whose disease progressed on docetaxel, without specific disease-related constraints.

Lutetium-177 vipivotide tetraxetan (Lu-177-PSMA-617) is the most recent novel agent approved for the treatment of mCRPC, approved by the US Food and Drug Administration in March 2022. It is indicated for the treatment of patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who have received novel hormonal therapy and taxane-based chemotherapy.5 By offering a new treatment option for these patients, the approval of Lu-177-PSMA-617 potentially changes the treatment landscape for mCRPC.

Prostate-specific membrane antigen (PSMA), also called glutamate carboxypeptidase II, is a transmembrane protein present on the cell surfaces in various tissue types, including the prostate, salivary glands, proximal renal tubules, and small intestine.6 Specifically, PSMA expression is 100 to 1000 times greater on prostate cancer cells than normal prostate cells.7 Clinically, PSMA overexpression has been associated as a poor prognostic factor in patients with prostate cancer.8

Because of its high levels of expression on prostate cancer cells, PSMA has been investigated as a tumor-specific target. Currently, PSMA is the target for two radioactive diagnostic agents utilized for prostate cancer imaging via PSMA PET, gallium-68 (Ga-68) PSMA-11 and fluorine-18 (F-18) piflufolastat PSMA.3 Compared with conventional imaging, PSMA PET has the benefit of providing increased sensitivity and specificity of detecting micrometastatic disease and has considerably changed the imaging landscape of prostate cancer.3 Lu-177-PSMA-617 is a radiopharmaceutical consisting of PSMA-617, a PSMA-binding ligand, conjugated with radioactive lutetium-177 (Lu-177). Upon binding to PSMA on the surface of prostate cancer cells, the radioligand-receptor complex is internalized, allowing direct, targeted delivery of the radioligand.8 Specifically, Lu-177-PSMA-617 emits beta-radiation within the PSMA-positive cells along with the surrounding microenvironment, resulting in DNA damage and cell death.8-9

The efficacy and safety of Lu-177-PSMA-617 was shown in the VISION trial, an open-label, international, phase 3 trial in patients with previously-treated mCRPC.9 To enroll in the trial, patients had to have proven mCRPC with disease progression after treatment with at least one taxane (docetaxel or cabazitaxel) and at least oneandrogen receptor pathway inhibitor (abiraterone or enzalutamide). Additionally, patients had to have at least one PSMA-positive metastatic lesion with no dominant PSMA-negative lesion(s) determined with gallium-68-PSMA-11 imaging.

In a 2:1 fashion, patients were randomized to receive Lu-177-PSMA-617 plus standard care or standard care alone. Standard care agents included abiraterone, enzalutamide, bisphosphonates, denosumab, radiation therapy, or glucocorticoids. Patients could not concurrently receive radium-223, immunotherapy, cytotoxic chemotherapy, or investigational drugs. The authors report that the use of these agents were prohibited because their safety in combination with Lu-177-PSMA-617 has not been demonstrated. Although 831 patients were initially randomized, only 581 patients were included in the analysis group (385 in the investigational arm and 196 in the control arm) after “enhanced trial-site education measures were implemented.” Lu-177-PSMA-617 was administered intravenously at a dose of 7.4 GBq (200 mCi) every six weeks for four cycles, but could be given for a total of six cycles at physician discretion. Patients continued treatment until disease progression on imaging was documented, unacceptable toxicities occurred, a perceived lack of clinical benefit, or initiation of a prohibited treatment agent.

The two primary outcomes were imaging-based progression-free survival (PFS) and overall survival (OS). Imaging-based PFS was defined as time from randomization to disease progression (as determined by independent central review) or death. OS was defined as time from randomization to death. Secondary outcomes included objective response rate (ORR), disease control, time to first symptomatic skeletal event or death, safety, health-related quality of life, pain, and PSA response.

With a median follow-up of 20.3 months in the Lu-177-PSMA-617 group and 19.8 months in the control group, patients receiving Lu-177-PSMA-617 had a significantly longer median imaging-based PFS of 8.7 months vs 3.4 months (HR 0.40; 99.2% CI 0.29 – 0.57; p < 0.001). Median OS was also longer in the Lu-177-PSMA-617 group: 15.3 months vs 11.3 months (HR 0.62, 95% CI 0.52 – 0.74; p < 0.001). Secondary outcomes favored Lu-177-PSMA-617, with an extended time to symptomatic skeletal events, longer time to pain progression, and decreased PSA levels.

In the VISION trial, the most common adverse events of Lu-177-PSMA-617 included fatigue (43%), dry mouth (39%), nausea (35%), and anemia (32%). Patients in the Lu-177-PSMA-617 group had a higher incidence of grade 3 or higher events, 53% vs 38%. Of note, 12% of patients discontinued Lu-177-PSMA-617 due to adverse events and 16% of patients had an adverse event leading to a dose interruption.9

Based on the results of the VISION trial, Lu-177-PSMA-617 is a preferred, category 1 recommendation in the NCCN guidelines for mCRPC patients with PSMA-positive disease after receipt of novel hormonal therapy and docetaxel.3 The NCCN recommendation keeps the same definition of PSMA-positivity as the inclusion criteria of the VISION trial as determined by Ga-68 PSMA-11 imaging.3,9 However, the NCCN also considers F-18 pilflufolastat PSMA imaging equivalent to Ga-68 PSMA-11 imaging to determine PSMA-positivity and eligibility for Lu-177-PSMA-617, which does differ from the FDA approval.3,5 This distinction by NCCN allows for a more generalized and wider applicability for determining PSMA status in potential candidates for Lu-177-PSMA-617.

Regarding toxicities, patients should be aware of common toxicities of fatigue, dry mouth, and nausea, along with the risks of myelosuppression and nephrotoxicity. Several of these toxicities correlate with PSMA expression on other tissues, which can offer some level of predictability with the toxicity profile. Baseline serum creatinine and complete blood count (CBC) are recommended along with continued monitoring throughouttreatment with Lu-177-PSMA-617, although no specified frequency is recommended.10

Because Lu-177-PSMA-617 emits beta radiation, precautions must be taken to minimize exposure to others. Prescribing information for Lu-177-PSMA-617 recommends limiting close contact with others (within 3 feet) for at least 2 days, with more conservative recommendations of 7 days around pregnant individuals and children.10 Furthermore, patients are recommended to sleep in separate bedrooms from others for 3 days, from children for 7 days, and from pregnant individuals for 15 days. Patients should limit sexual activity for 7 days. These precautions should be taken after every dose of Lu-177-PSMA-617, and patients should be aware of these precautions before initiating treatment.

Clinical Implications and Future Directions
Not only does the advent of the PSMA-targeted radiopharmaceutical Lu-177-PSMA-617 offer a novel treatment mechanism to fight mCRPC, but it offers patients a new treatment option with proven survival benefits in a previously limited treatment landscape. Of the screened patients in the VISION trial, 86.6% of them met eligibility for the trial based on PSMA status, which suggests many mCRPC patients may qualify for treatment with Lu-177-PSMA-617.9 Based on PSMA status alone, Lu-177-PSMA-617 can be widely applicable to many patients with mCRPC after receipt of novel hormonal therapy and docetaxel, unlike several of the other treatment options in this space.

Although the majority of patients with mCRPC may express PSMA to qualify for Lu-177-PSMA-617, there are other patient factors to take into consideration. Patients had to have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1 to be eligible for enrollment in the VISION trial.9 Additionally, patients must have received taxane-based chemotherapy to receive Lu-177-PSMA-617 in the VISION trial, and that eligibility criterion carried over to its labelled indication and place in therapy in the NCCN guidelines. Not all patients may qualify for docetaxel based on performance status or comorbidities and therefore may not qualify for Lu-177-PSMA-617.

As previously mentioned, cabazitaxel is a recommended treatment option for mCRPC patients after receiving docetaxel. The VISION trial did not compare Lu-177-PSMA-617 against cabazitaxel and therefore the clinical question remains of which agent should come first in mCRPC treatment, cabazitaxel or Lu-177-PSMA-617. To help provide some clinical guidance, the results of the TheraP trial may be applicable. TheraP was a phase 2 trial conducted in Australia which randomized mCRPC patients to receive Lu-177-PSMA-617 or cabazitaxel.11 The primary endpoint was PSA response, of which Lu-177-PSMA-617 was shown to have a higher PSA response than cabazitaxel. Additionally, Lu-177-PSMA-617 showed fewer grade 3 or 4 adverse events compared to cabazitaxel. An update to the TheraP trial presented at the 2022 American Society of Clinical Oncology Annual Meeting reported that overall survival rates, a secondary outcome of the trial, were similar between Lu-177-PSMA-617 and cabazitaxel after a median follow-up of 36 months.12 Although further studies are needed, these results may offer some guidance for clinicians deciding between Lu-177-PSMA-617 and cabazitaxel for a patient with mCRPC after docetaxel. 

Clinicians should consider the limitations of Lu-177-PSMA-617 and its applicability to patients affected by disparities in care. In particular, patients of African ancestry are known to be at a higher risk of being diagnosed with prostate cancer than other male groups.13, 14 Not only that, but compared to other males, males with African ancestry are more than twice as likely to die from prostate cancer, more likely to be diagnosed at a younger age, and more likely to be diagnosed with advanced prostate cancer.14 Unfortunately, patients of African ancestry are not well represented in most prostate clinical trials. Specifically in the VISION trial, 7% of participants were listed as African-American or black, which is an underrepresentation of the general population of patients with prostate cancer.9 Additionally, underserved patients may find the logistical implications of Lu-177-PSMA-617 to be more difficult or unobtainable – the multidisciplinary coordination, the travel to a tertiary medical center to receive treatment, as well as the recommendations to avoid close contact with other household members after treatment. In a patient population who may be of the greatest need for a new, life-prolonging treatment, these unique challenges and limitations should be more heavily considered when developing new therapeutic agents.

Future trials are underway investigating the use of Lu-177-PSMA-617 in different settings of metastatic prostate cancer treatment and in combination with other agents. The EVOLUTION trial (NCT05150236) is investigating the addition of ipilimumab and nivolumab to Lu-177-PSMA-617 for the treatment of mCRPC.15 The PSMAfore trial (NCT04689828) will compare Lu-177-PSMA-617 to NHT in the second-line, docetaxel-naïve mCRPC setting after progression on first-line NHT.16 For the treatment of metastatic castration-sensitive prostate cancer, the PSMAddition trial (NCT04720157) is investigating the addition of Lu-177-PSMA-617 to current treatments.17 Should these trials show positive results for Lu-177-PSMA-617, the use of this radiopharmaceutical could become more prevalent in the treatment of metastatic prostate cancer.

Based on the results of the VISION trial, Lu-177-PSMA-617 has demonstrated a proven survival benefit for a considerably large group of patients with mCRPC. Requiring a multidisciplinary approach to treatment with coordination between medical and radiation oncology, several factors must be considered with using Lu-177-PSMA-617, including toxicity awareness and monitoring, minimizing radiation exposure, and patient eligibility. Oncology pharmacists should understand the clinical impact of Lu-177-PSMA-617 in the mCRPC setting, as well as the opportunities for pharmacist involvement with monitoring, educating, and counseling these patients.


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