Treatment of metastatic castration-resistant prostate cancer is complex and depends in part on prior therapy. Yet guidelines on management differ among professional organizations and countries, including recommendations on the use of therapeutic radiopharmaceuticals. These theranostic agents, designed to target disease-specific proteins or antigens expressed in a tumor or host organ for metastases, can be an effective treatment option for many patients.

Most men with advanced prostate cancer eventually develop castration-resistant prostate cancer (CRPC), and nearly all present with or develop metastatic disease (mCRPC). Bone metastases occur in up to 90% of men with mCRPC, resulting in bone pain, fracture, spinal cord compression, and reduced quality of life.1 Treatment of mCRPC is complex, often involving androgen-deprivation therapy (ADT) and a novel androgen receptor (AR) pathway–targeting agent, and depends in part on prior therapy (Figure 1).2 Yet guidelines on mCRPC management differ among professional organizations and countries, including recommendations on the use of therapeutic radiopharmaceuticals.2-6 These theranostic agents, designed to target disease-specific proteins or antigens expressed in a tumor or host organ for metastases, can be an effective treatment option for many patients.7

Figure 1. Treatment Options for Metastatic Castration-Resistant Prostate Cancer

AR = androgen receptor; dMMR = deficient mismatch repair; HRR = homologous recombination repair; mCRPC = metastatic castration-resistant prostate cancer; MSI-H = microsatellite instability–high; PARP = poly (ADP-ribose) polymerase; PSMA = prostate-specific membrane antigen; TMB = tumor mutational burden.

Approved Agents

Two radiopharmaceuticals, radium-223 dichloride (Ra-223) and lutetium-177–labeled PSMA-617 (LuPSMA; lutetium Lu 177 vipivotide tetraxetan), are now approved by the U.S. Food and Drug Administration (FDA) for the treatment of mCRPC, and both are included in National Comprehensive Cancer Network (NCCN) clinical practice guidelines (Table 1).2 Ra-223, a targeted alpha emitter, is approved for the treatment of patients with CRPC, symptomatic bone metastases, and no known visceral metastatic disease.8 LuPSMA is a beta emitter approved for patients with prostate-specific membrane antigen (PSMA)-positive mCRPC who have received an AR pathway inhibitor and taxane-based chemotherapy. In addition to the aforementioned differences in mechanism of action, these agents also differ with respect to half-life and emission length in tissue (Table 1).

Table 1. Therapeutic Radiopharmaceuticals Approved for the Treatment of mCRPC

AR = androgen receptor; mCRPC = metastatic castration-resistant prostate cancer; FDA = U.S. Food and Drug Administration; PSMA = prostate-specific membrane antigen.

Approval of Ra-223 was based on the phase III ALSYMPCA trial in which men with progressive, symptomatic mCRPC and no visceral metastases were randomly assigned to receive Ra-223 or placebo. Ra-223 treatment was associated with significantly improved median overall survival (14.9 vs 11.3 months), longer time to first skeletal-related event (15.6 vs 9.8 months), and improved quality of life (25% vs 16%) compared with placebo.9 Subgroup analysis revealed that Ra-223 significantly prolonged overall survival irrespective of previous docetaxel use, indicating its benefit when used prior to as well as after chemotherapy.10 Overall survival and skeletal-related event benefits were also seen in a trial of Ra-223 in Japanese patients with symptomatic mCRPC.11 Results from a real-world study of patients with mCRPC treated with Ra-223 indicated a median overall survival of 12.9 months, supporting the efficacy seen in the ALSYMPCA trial.12 Ra-223 therapy also appears to be safe and effective in elderly patients with CRPC and symptomatic metastases.13

LuPSMA approval was based on results of the phase III VISION trial in which men with PSMA-positive mCRPC previously treated with an AR pathway inhibitor and taxane-based therapy received LuPSMA plus standard of care or standard of care alone. Median progression-free survival (8.7 vs 3.4 months) and median overall survival (11.3 vs 5.3 months) were significantly improved with LuPSMA therapy compared with the control arm.14 Supporting these results, a meta-analysis showed that patients treated with LuPSMA had a significantly greater response compared with control patients based on ≥ 50% decrease in prostate-specific antigen (PSA).15 Because LuPSMA is approved only for individuals with PSMA-positive tumors, patient selection and reimbursement require determination of tumor PSMA expression using a gallium PSMA positron-emission tomography scan. In the VISION trial, 87% of patients demonstrated PSMA avidity on screening PSMA scans. This is important, noted Neal Shore, MD, FACS, Chief Medical Officer, Urology/Surgical Oncology, GenesisCare US in Myrtle Beach, South Carolina, “because 13% of patients will not show that avidity and therefore will not qualify for LuPSMA.” Its efficacy in the real-world mCRPC population therefore would be expected to be lower compared with the VISION trial, which selected for PSMA-positive patients, and this could present challenges for coverage and reimbursement. In a randomized phase II trial (TheraP), men with PSMA-positive mCRPC received either LuPSMA or cabazitaxel. Although LuPSMA treatment resulted in a higher PSA response and lower toxicity compared with cabazitaxel, overall survival was similar.16

In contrast with LuPSMA, which is approved for use only following treatment with an AR pathway inhibitor and taxane-based chemotherapy, Ra-223 may be used regardless of prior use of taxane or AR pathway–targeted therapy and independent of PSMA status, with no requirement for prior treatment. Ra-223 can thus be used in various settings, either as monotherapy or in combination with other agents, and may be administered following or sequentially with AR pathway–targeted agents.12 Ra-223 should only be used in patients with bone metastases before onset of visceral metastases. Treatment schedules for these radiopharmaceuticals also differ: Ra-223 is administered intravenously every 4 weeks for up to 6 doses, while LuPSMA is given intravenously every 6 weeks for a total of 6 treatments.8,17

Administration of Radiopharmaceuticals for mCRPC

Facilities and Licensure

Both radiopharmaceuticals must be administered in an appropriately licensed facility, such as a nuclear medicine or radiotherapy department equipped to administer and monitor these agents. Administering physicians need the appropriate licensures and training to administer radiopharmaceuticals, and facilities must have the right physical plan to ensure patient safety.

Safety Precautions

Since LuPSMA emits gamma radiation, additional precautions are required for safe and effective administration and to minimize potential radiation exposure to medical personnel, treatment rooms, and patients’ family members and close contacts.17 According to Alicia Morgans, MD, MPH, a genitourinary medical oncologist at Dana-Farber Cancer Institute in Boston, “While there are few restrictions for Ra-223 in terms of being around loved ones in the days following treatment , patients receiving LuPSMA have more restrictions and limitations in their ability to be around other people for several days, and those safety precautions should be clearly communicated.”

Administration and Monitoring

Because Ra-223 targets only bone metastases and may not be associated with changes in biomarkers, regular imaging of the abdomen, pelvis, and chest is recommended for detection of metastases at nonbone sites.3 One advantage of LuPSMA is that it can be given not only for bone-dominant disease, but also for patients with nodal and visceral metastases of significance. Both agents can cause significant myelosuppression, requiring regular hematologic evaluation. Additionally, treatment with LuPSMA can result in renal toxicity, so kidney function laboratory tests (eg, serum creatinine , calculated creatinine clearance) should be performed before and during treatment.

Number of Doses

Radiopharmaceuticals for mCRPC typically do not require a large number of cycles for a response, but completion of the full course is recommended. Several studies have demonstrated that completing planned Ra-223 therapy may translate into higher treatment intensity and improved survival. Patients who receive fewer Ra-223 treatments (1–4 cycles) tend to have a shorter overall survival compared with those who receive the complete course (5–6 cycles).18-20 One study of LuPSMA for mCRPC indicated that in patients receiving up to eight cycles of therapy, any decrease in PSA levels after the first cycle was a significant predictor of survival; nearly one-third of patients who did not respond to the first dose of LuPSMA did have a PSA response following additional cycles.21

Concomitant Medications

Although not specifically indicated in the prescribing information, the NCCN Clinical Practice Guidelines in Oncology for prostate cancer recommend concomitant use of denosumab or zoledronic acid with Ra-223 as prophylaxis for fractures.2 (The majority of patients receiving ADT for mCRPC are already receiving such bone-protecting agents, however.) A reduction in fractures was noted in the ALSYMPCA trial of Ra-223 when bone-protecting agents were used.9 Similarly, while the fracture risk was increased when Ra-223 was given concomitantly with abiraterone plus prednisone/prednisolone in the phase III ERA 223 trial in men with asymptomatic/minimally symptomatic mCRPC, this risk was reduced by use of osteoprotective drugs.22 In light of the increased risk of skeletal-related events, concurrent use of Ra-223 with abiraterone acetate is not recommended, nor should Ra-223 be used in combination with docetaxel or any other systemic therapy except ADT.

Broader Use of Ra-223 in mCRPC

While ALSYMPCA and other trials demonstrated the clinical benefit of Ra-223 in symptomatic mCRPC, it may also have potential when used earlier in the disease course, prior to onset of severe symptoms. In a study of Ra-223 in men with asymptomatic mCRPC and bone metastases, asymptomatic patients were better able to complete planned Ra-223 therapy and had significantly better overall survival, time to disease progression, and time to first symptomatic skeletal-related event compared with symptomatic patients and also experienced less treatment-emergent adverse events (Figure 2).22 Earlier use of Ra-223 could therefore facilitate completion of treatment and allow sequencing with other therapies. The ongoing PEACE III trial is evaluating the combination of Ra-223 and enzalutamide in men with asymptomatic or mildly symptomatic mCRPC.

Figure 2. Estimated Kaplan-Meier Overall Survival for Symptomatic or Asymptomatic Patients With Metastatic Castration-Resistant Prostate Cancer Treated With Ra-223

CI = confidence interval; NR = not reached; Ra-223 = radium-223 dichloride.
From Heidenreich A, et al.20 This figure is licensed under the terms of the Creative Commons Attribution 4.0 International License.

Clinicians may want to consider earlier use of Ra-223 in the treatment pathway (before or after chemotherapy) since this could improve outcomes. In one study, first-line therapy with Ra-223 was associated with survival ≥ 2 years, and a retrospective analysis indicated improved median overall survival when Ra-223 was administered as second-line therapy compared with the third-line setting.12,23 Yet a study of real-world clinical practice patterns found that use of Ra-223 was greater in subsequent lines of therapy, indicating the potential for its earlier use.24 Interim analysis of the ongoing REASSURE trial suggests that fewer patients discontinue Ra-223 treatment when administered prior to rather than following chemotherapy.25 Interestingly, biomarker analysis of this study found that a decline in alkaline phosphatase in first 12 weeks of Ra-223 treatment was associated with improved overall survival, suggesting its potential as a surrogate biomarker of efficacy.26

Some prostate cancer experts believe that the definition of symptomatic disease should not be limited to just severe bone pain. Although most clinical trials of radiopharmaceuticals have used traditional efficacy endpoints such as survival and time to skeletal-related events, other clinical measures might also be considered. “Symptoms from metastatic CRPC can be things like fatigue or mild pain,” noted Dr. Morgans. “You don't have to have symptoms like severe back pain to qualify, and it doesn't just necessarily need to be bone pain.” A small study evaluated Ra-223 in men with symptomatic mCRPC, using pain palliation as the primary endpoint. Responders saw a 62% reduction in median worst pain at week 8, along with decreases in pain interference in general activity and a decline in worst fatigue.27 An integrated analysis of the effects of Ra-223 on patient-reported pain, analgesic use, and quality of life in men with symptomatic or asymptomatic extensively pretreated mCRPC found that the majority had reductions in pain, pain interference, and fatigue.28 Consideration of endpoints such as decreased pain and improved quality of life could therefore lead to greater clinical benefit with Ra-223. Dr. Shore agreed with this broader consideration of symptoms in men with mCRPC. “Over a decade of experience with Ra-223, we have learned that the construct of symptomatology can be very subjective,” he said. “There are other factors that are correlative to symptomatology such as fatigue, discomfort, possibly shortness of breath because of rib metastases preventing diaphragmatic excursion, and difficulty with sleep patterns because of discomfort of axial spine metastases. Yet for various reasons some patients are reluctant to talk about these symptoms with their providers.”

Broader use of Ra-223 could provide patients and physicians with additional therapeutic options for mCRPC. “The reason is to offer patients, in a timely way, a [drug with a] novel mechanism of action,” explained Dr. Shore. “Radium-223 represents a truly novel mechanism of action, on top of the six other novel mechanisms of action for our patients with CRPC. I try to optimize an efficient sequential delivery of the six novel mechanisms of action, which have demonstrated survival benefit as well as important secondary endpoint benefits for my patients with advanced prostate cancer.”

I try to optimize an efficient sequential delivery of the six novel mechanisms of action, which have demonstrated survival benefit as well as important secondary endpoint benefits for my patients with advanced prostate cancer. Neal Shore, MD, FACS

Safety

Both of these radiopharmaceuticals are generally well tolerated, including in elderly patients. The most common adverse effects observed in the ALSYMPCA trial of Ra-223 were myelosuppression, nausea, diarrhea, vomiting, and peripheral edema.9 In the LuPSMA VISION trial, fatigue, xerostomia, nausea, anemia, decreased appetite, and constipation were the most common toxicities.14 Although most adverse events with these agents are mild to moderate, myelosuppression (arising from radiation damage to healthy bone marrow) may require transfusions in some patients. LuPSMA therapy can have off-target effects: since PSMA is also expressed in the salivary glands and kidneys, it increases the risk of renal toxicity and xerostomia. Because the adverse effects of radiopharmaceuticals are typically less than those seen with chemotherapy, Ra-223 or LuPSMA could be an alternative treatment for some patients who are not fit enough for chemotherapy or prefer to avoid its toxicity.

Conclusion

Radiopharmaceuticals constitute an important and efficacious addition to the therapeutic armamentarium for mCRPC. Optimal use of these agents, though, requires a multidisciplinary approach, emphasized Dr. Morgans. “One of the most important things about radiopharmaceutical use and education for patients is that it takes a multidisciplinary team to collaborate in order to administer these most effectively and safely, address any complications, and counsel patients,” she remarked. “The evolving complexity of advanced care emphasizes the importance of engaging and collaborating with colleagues across specialties.” Dr. Shore agreed and stressed that decisions regarding use of radiopharmaceuticals should always involve the patient. “It's essential when having the shared decision-making discussion with patients regarding optimizing sequencing of an approved therapy to take into account not only tumor burden, tumor location, and comorbidities but also patient preference regarding parenteral vs an oral therapy or concerns about specific adverse events.”

One of the most important things about radiopharmaceutical use and education for patients is that it takes a multidisciplinary team to collaborate in order to administer these most effectively and safely, address any complications, and counsel patients. Alicia Morgans, MD, MPH

Combining radiopharmaceuticals with other agents might further increase their efficacy in mCRPC.29,30 Improvements in PSA levels were seen when Ra-223 was combined with enzalutamide or sipuleucel-T, and for LuPSMA with enzalutamide,31,32 although no clinical benefit was observed with Ra-223 plus atezolizumab or enzalutamide.33 Ongoing trials are exploring Ra-223 or LuPSMA in combination with AR pathway–targeted therapy, chemotherapy, poly (ADP-ribose) polymerase inhibitors, or other agents.

According to Dr. Shore, significant gains in knowledge and experience have been made since the initial approval of Ra-223, which has facilitated greater interaction among the multidisciplinary oncology team. “This will also help us with advancing treatment options for patients with mCRPC as the field of theranostics is further established for the prostate cancer patient’s journey,” he said.

Radiopharmaceuticals for Treatment of Metastatic Castration-Resistant Prostate Cancer
Radium-223 dichloride (Ra-223) is currently approved for the treatment of patients with castration-resistant prostate cancer (CRPC) and:
Choose 1
A
Bone or visceral metastases
B
Prostate-specific membrane antigen (PSMA)-positive disease
C
Symptomatic bone metastases and no known visceral metastatic disease
D
No bone metastases

Disclosure

Dr. Morgans has received honoraria from Genentech, Janssen, Sanofi, AstraZeneca, Astellas Scientific and Medical Affairs, Astellas Colombia, Janssen, Bayer, Clovis Oncology, Myovant Sciences, Advanced Accelerator Applications, Exelixis, and Merck; has served in a consulting or advisory role for AstraZeneca, Sanofi, Bayer, Astellas Pharma, Janssen, Advanced Accelerator Applications, Myovant Sciences, Blue Earth Diagnostics, Exelixis, Novartis, Myriad Genetics, Lantheus Medical Imaging, and Merck; has received research funding from Bayer, Seattle Genetics/Astellas, Genentech, AstraZeneca, Astellas Scientific and Medical Affairs, Dendreon, Sanofi, and Myovant Sciences; and has received travel, accommodations, or expenses from Sanofi.

Dr. Shore has served in a consulting or advisory role for AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb/Sanofi, CG Oncology, Clovis Oncology, Dendreon, Exact Imaging, Exact Sciences, FerGene, Ferring, Foundation Medicine, Genesis Cancer Care, Genzyme, InVitae, Janssen Scientific Affairs, MDxHealth, Medivation/Astellas, Merck, Myovant Sciences, Myriad Genetics, Nymox, Pacific Edge Biotechnology, PeerView, Pfizer, Phosphorus, Propella Therapeutics, Sanofi, Sesen Bio, Specialty Networks, Tolmar, and Urogen Pharma; has served on speakers bureaus for Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Dendreon, Foundation Medicine, Guardant Health, Janssen, Merck, and Pfizer; and has received research funding from AbbVie, Amgen, Astellas Pharma, AstraZeneca, Bayer, Boston Scientific, Bristol Myers Squibb/Pfizer, Clovis Oncology, Dendreon, Exact Imaging, Ferring, Foundation Medicine, InVitae, Janssen, MDxHealth, Merck, Myovant Sciences, Myriad Genetics, Nymox, Pfizer, Sanofi, Sesen Bio, and Tolmar.

References

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