The Role of Theranostics in Prostate Cancer

Abstract

Theranostics in men with metastatic castration-resistant prostate cancer (mCRPC) has been developed to target bone and the tumor itself. Currently, bone-directed targeted alpha therapy with radium-223 (²²³Ra) is the only theranostic agent proven to prolong survival in men with mCRPC who have symptomatic bone metastases and no known visceral metastases. The clinical utility and therapeutic success of ²²³Ra has encouraged the development of other tumor-targeting theranostic agents in mCRPC, primarily targeting prostate-specific membrane antigen (PSMA) with radioligand therapy (RLT). There is increasing evidence of promising response rates and a low toxicity profile with ¹⁷⁷Lu-labeled PSMA RLT in patients with mCRPC. A phase III randomized study of ¹⁷⁷Lu-labeled PSMA RLT has completed accrual and is awaiting results as to whether the drug improves radiographic progression-free survival and overall survival in men with mCRPC receiving standard of care treatments. Additional early clinical trials are investigating the role of tumor-directed targeted alpha therapy with radiotracers such as ²²⁵Ac. In this article, we review the current status of theranostics in prostate cancer, discussing the challenges and opportunities of combination therapies with more conventional agents such as androgen receptor inhibitors, cytotoxic chemotherapy, and immunotherapy.

Introduction

Prostate cancer is the second most common cancer in men, with an incidence increasing globally by 40% over the last 14 years¹ and 1.3 million new cases diagnosed worldwide in 2018.² Globally, prostate cancer is the fifth-leading cause of cancer-related mortality.^1,3 However, evolving therapeutic approaches have altered the clinical course for men with metastatic prostate cancer with improvements in both survival and quality of life.

Typical first-line therapy for metastatic disease is a testosterone-reducing agent with androgen deprivation therapy (ADT), frequently combined with a novel androgen receptor (AR) axis inhibitor such as abiraterone or chemotherapy with docetaxel.^4–6 Most patients have an initial response to these regimens; however, the disease eventually progresses to metastatic castration-resistant prostate cancer (mCRPC). At this point, other strategies must be employed to improve survival, including cytotoxic chemotherapy, AR-directed therapies, therapeutic vaccine therapy, and, more recently, theranostic agents.^7–13

Theranostic agents target disease-specific structures (eg, proteins or antigens) expressed in a patient’s cancer or host organ for metastatic disease. These structures can be used as targets for ligands with specific radioisotopes for imaging and subsequently for therapy. These agents can not only be disease-specific but also can be varied to suit the desired sites of disease, namely in prostate cancer, tumor or bone.

Theranostic agents when used therapeutically can be combined with alpha- or beta-emitting radioisotopes. Beta emitters were initially used in the development of novel theranostic agents. They are longer range, low-energy agents (linear energy transfer [LET]: 0.3 keV/μm; tissue range: 2000–11,500 μm) that enhance cytotoxicity to tumor cells rather than delivering a lethal dose to a targeted single cancer cell due to their low LET,¹⁴ which results mainly in single-strand DNA breaks. However, due to their long tissue range, electrons can travel further to multiple cells and increase overall dose to tumor—the so-called crossfire effect—but can also potentially deliver dose to normal tissue. A newer approach in theranostics is to use short-range, high-energy alpha emitters (LET: 100keV/μm; tissue range: 20–80 μm), which are highly cytotoxic agents that travel over short distances. Upon travel into cell nuclei, they cause DNA damage,¹⁴ mainly as double-strand breaks. As a result, alpha radiation is thought to allow treatment of microscopic disease while sparing surrounding normal tissue.¹⁵

In this article, we provide an overview of the current and future molecular therapy strategies used for treatment of prostate cancer.

Bone-Targeting Strategies

Metastatic prostate cancer primarily occurs within bone. Normal bone structural integrity is maintained in a complex bone microenvironment by continuous balanced bone reabsorption by osteoclasts and bone formation by osteoblasts.¹⁶ Metastatic prostate cancer cells interact via signaling pathways with osteoblasts, osteocytes, osteoclasts, bone marrow stem cells, and hematopoietic cells within the bone microenvironment, disrupting normal tightly regulated osteoblastic and osteoclastic activity.^17,18 Growth factors released by prostate cancer cells in bone disrupt the balanced relationship between osteoblasts and osteoclasts, leading to proliferation of new disorganized woven bone. Osteoblasts also express growth factors (eg, vascular endothelial growth factor), which promote prostate cancer cell growth and survival.¹⁹ A bidirectional positive feedback loop between tumor cells and the bone microenvironment leads to characteristic osteoblastic bone metastasis formation.¹⁸ This cycle of dysregulated bone metabolism leads to pathological bone morphology and physiology, which in turn leads to bone pain, fractures, and increased mortality.^20,21

Beta-emitting bone-seeking radiopharmaceuticals, such as strontium-89-chloride (⁸⁹Sr) and samarium-153-EDTMP (¹⁵³Sm), have long been used as palliative agents in the setting of painful bone metastases, including prostate cancer, with reported improvement in pain and quality of life.²² However, to date, these agents have not been tested in formal comparative studies powered to demonstrate a clinical benefit.²² Nonetheless, preliminary data suggest that these agents might offer benefits relative to standard agents.^23,24

Radium-223 (²²³Ra) is a targeted alpha-particle therapy (TAT) approved by the US Food and Drug Administration (FDA) in 2013²⁵ and European Medicines Agency (EMA)²⁶ in 2018 for the treatment of patients with mCRPC and bone metastases following the ALSYMPCA (ALpharadin in SYMP-tomatic Prostate Cancer) trial.⁹ ALSYMPCA demonstrated that ²²³Ra (6 injections at 55 kBq/kg every 4 weeks) prolonged overall survival (OS) in men with mCRPC when added to standard anticancer therapies vs patients receiving best standard of care and placebo (median 14.9 vs 11.3 months receiving placebo; hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.58–0.83; P < 0.001). Patients in the ²²³Ra arm also demonstrated longer time to first symptomatic skeletal event (median 15.6 vs 9.8 months; HR 0.66, 95% CI 0.52–0.83; P < 0.001) than those in the placebo arm.^9,27 No benefit was conferred for increasing number of doses or administering higher doses of ²²³Ra.²⁸

Animal models of prostate cancer bone metastases treated with ²²³Ra have been difficult to develop due to the complexity of the metastatic cascade, including immunologic response and tumor heterogenitity²⁹ and were only recently developed in 2017,³⁰ post approval of ²²³Ra by the FDA. Thus, preclinical studies of bone metastasis models in other cancers were used for initial experiences in mCRPC, which demonstrated that ²²³Ra targets bone metastasis by replacing calcium in hydroxyapatite complexes in woven bone surrounding prostate cancer metastasis, leading to osteoblast-mediated new bone formation at sites of metastatic lesions.^{31,32 223}Ra decays to produce alpha particles with high LET, traveling over a short distance of ≤100 μm, which leads to localized cytotoxicity, likely inducing double-strand breakage of DNA in adjacent tumor cells, osteoblasts, and osteoclasts and disrupting the positive-feedback loops between these cells.³³

Preclinical studies have demonstrated that ²²³Ra causes inhibition of tumor growth, pathological bone reaction, and stabilization of the normal bone structure. In addition, as ²²³Ra causes irreparable damage of tumor cell DNA and cell death, the feedback loop is disrupted and becomes less reliant on active cell proliferation, possibly offering an advantage for killing tumors with a low proliferation rate or dormant micrometastases.³¹ Also, TAT may minimize damage of surrounding normal tissue when compared to beta-emitters or external beam radiotherapy due to the short distance travelled by high LET, comparable to 3–6 cell diameters. In mouse models, ²²³Ra deposited at the bone surface (not within the tumor) and skeletal accumulation was dependent on local blood vessel density, suggesting that local vascular supply is necessary for effective delivery of TAT.³⁴

It is thought that ²²³Ra may enhance immune system activity by inhibiting immunosuppression and altering cancer cells’ phenotypes, therefore making them susceptible to immune-mediated cell killing.³⁵ In vitro models in human prostate and breast cancer cell lines have shown that ²²³Ra enhances T cell-mediated lysis of tumor cells through antigen-specific CD8+ cytotoxic T lymphocytes and may augment immune responses via the stimulation of interferon genes pathway.³⁶

TAT is thought to be less prone to development of tumor resistance mechanisms, such as hypoxia, since it induces direct double-strand DNA damage, which is independent of oxygen. This is in comparison to oxygen-dependent activation of alternate signaling pathways used in AR-axis inhibitors and chemotherapy agents and oxygen-dependent DNA damage caused by external beam radiotherapy.

²²³Ra in Clinical Practice

The American and European guidelines regarding indications for treatment with ²²³Ra are conflicting. The National Comprehensive Cancer Network guidelines (2019) recommend treatment with ²²³Ra in men with mCRPC, symptomatic bone metastases, and no visceral metastases,³⁷ while the American Urological Association guidelines (2018) recommend ²²³Ra for patients with mCRPC and symptomatic bone metastases, good performance status, no previous docetaxel chemotherapy, and no known visceral disease.³⁸ The European Association of Urology guidelines (2020) recommend ²²³Ra as a potential life-prolonging treatment for men with mCRPC and progression on docetaxel chemotherapy.³⁹

²²³Ra was well tolerated during the ALSYMPCA trial and demonstrated a favorable short-term safety profile with improvements in quality-of-life measures and low rates of myelosuppression^9,40,41 as well as low cumulative incidence rates for hematologic and nonhematologic adverse events.⁴² The ALSYMPCA trial included follow-up of men with mCRPC and symptomatic bone metastases for up to 3 years from first injection of ²²³Ra to assess for association with possible induction of secondary malignancy, such as acute myelogenous leukemia, myelodysplastic syndrome, or new primary bone cancer.⁴² The 3-year follow-up did not find an association between ²²³Ra treatment and occurrence of second malignancies and there was a similar low incidence rate of nontreatment-related malignancies in both the ²²³Ra and placebo arms.⁴²

Long-term safety is being evaluated further through the ongoing Radium-223 alpha Emitter Agent in non-intervention Safety Study in mCRPC popUlation for long-teRm Evaluation (REASSURE) trial, a global, prospective, single-arm observational study of patients with mCRPC and bone metastases treated with ²²³Ra in routine clinical practice.⁴³ REASSURE is evaluating the long-term safety and occurrence of primary second malignancies during a 7-year follow-up period and to date, the rate and degree of severity of treatment-related adverse events seen in follow-up in both this trial⁴³ and the ALSYMPCA trial⁴² are not substantially different from those observed in the original ALSYMPCA trial.⁹ The primary safety concern raised by ²²³Ra concerns the use of the drug in combination with the novel AR-inhibitor abiraterone as a first-line therapy, which has been associated with increased risk of bone fractures; this is described in greater detail later in this review.^44,45

Currently, ²²³Ra is administered according to standard fixed doses based on patient weight. However, theranostic agents are unique in their ability to allow imaging in vivo of the uptake and retention of the agent, which enables calculation of absorbed radiation doses and radiation exposure in tumor and normal tissues, thus maximizing the antitumor effects of the therapy while sparing its effect on normal tissues⁴⁶ and potentially providing more personalized dosing.

²²³Ra decay produces a series of 6 products before becoming a stable lead molecule, with 28.3 MeV of emitted energy—95% comes from alpha emissions, 3.2% from beta particles, and <2% from gamma emissions. Gamma emissions, although low signal, allow the potential for quantitative imaging of ²²³Ra.^47,48 However, microscopic energy deposition within the bone matrix also presents challenges for internal dosimetry in the bone marrow and skeleton.⁴⁸

Small studies have demonstrated a correlation between absorbed dose and local lesion response to ²²³Ra. Pacilio et al showed a correlation between the uptake of ²²³Ra in a metastatic lesion and the scintigraphy agent technetium-99m-methylene diphosphonate (^99mTc MDP) in nine patients with mCRPC and bone metastases; thus, conventional bone scintigraphy might help to define lesion extent and response.^47,49

Several microdosimetric approaches are being developed, with potential application in clinical imaging and dosimetry.⁴⁶ With ²²³Ra, a trabecular marrow cavity model allows for calculation of the fraction of marrow volume receiving a cytotoxic absorbed dose, which may enable improved estimates of the dose of radiation delivered by radium and could potentially be applied to other TATs in the future.

Combination Therapies

Following the reassuring outcomes in terms of safety and tolerability in clinical practice, ²²³Ra has been proposed for use in combination with other agents, with many prospective trials ongoing.

First-line treatment for newly diagnosed metastatic disease typically employs ADT, to which the majority of patients have an initial response; however, with time the disease progresses to mCRPC but interestingly remains dependent on the AR-signaling pathway.⁵⁰ Novel hormonal agents (eg, abiraterone, a selective steroidal inhibitor of cytochrome P450 c17 (CYP17), a key enzyme for testosterone and estrogen biosynthesis,^51,52 and enzalutamide, a nonsteroidal antiandrogen) inhibit the AR axis system. Large randomized phase III clinical trials have demonstrated that these agents prolong the lives of men with mCRPC.^{10–12,37,53,54}

Due to different mechanisms of action and nonoverlapping safety profiles, combining ²²³Ra with abiraterone or enzalutamide was proposed. Preliminary data on combination strategies suggested that ²²³Ra could be safely combined with abiraterone or enzalutamide.^55–57 The subsequent phase III Evaluation of Radium-223 dichloride in combination with Abiraterone in castration-resistant prostate cancer (ERA-223) trial evaluated the efficacy and safety of adding ²²³Ra treatment or placebo to abiraterone plus prednisone or prednisolone in patients with asymptomatic or minimally symptomatic mCRPC,⁵⁸ with primary analysis revealing no statistically significant difference in OS between the groups (30.7 months [²²³Ra group] vs 33.3 months 1 [placebo group]; HR 1.195, 95% CI 0.950–1.505; P = 0.13).⁵⁸ However, patients in the ²²³Ra combination arm had an unexpected increased incidence of fractures (29% vs 11%). This study led the EMA in 2018 to contraindicate the combination use of ²²³Ra with abiraterone and prednisolone or prednisone.^44,45

Among other hypothesized etiologies, the increased risk of fractures in the combination ²²³Ra group may be due to concurrent steroid use, as potentially harmful effects of glucocorticoids and changes within the bone microenvironment have previously been demonstrated.⁵⁹ In the ERA-223 trial, concurrent use of bone health agents (BHAs), including bisphosphonates (zoledronic acid) and denosumab from baseline, was associated with a lower incidence of fractures in both the ²²³Ra and placebo groups (15% and 7%, respectively) compared with patients who did not receive BHAs (37% and 15%, respectively),⁵⁸ with similar findings seen in the ALSYMPCA trial, in which patients treated with ²²³Ra in combination with BHAs appeared to have a superior outcome to those who received ²²³Ra without BHAs in terms of symptomatic skeletal events.^9,27 Preliminary results from the ongoing randomized phase III PEACE trial comparing enzalutamide to combination enzalutamide and ²²³Ra in asymptomatic or mildly symptomatic mCRPC patients⁶⁰ (NCT02194842) have shown that enzalutamide in combination with ²²³Ra increases fracture risk by 33% but that the risk is almost completely eliminated by continuous administration of BHA, commencing at least 6 weeks before the first dose of ²²³Ra.⁶¹ Accrual is ongoing.

Another agent currently being studied in combination with ²²³Ra is docetaxel, an antimitotic chemotherapy agent. Docetaxel has been proven to improve survival when used in combination with ADT in newly diagnosed patients with metastatic castration-naïve disease.^4,5 Several factors support the combination of ²²³Ra with docetaxel, as chemotherapy has been shown to have a radiosensitizing effect through different mechanisms, such as reducing DNA repair, increasing vulnerability of hypoxic cells to cytotoxic agents, inhibiting pro-survival pathways, and reducing ability of tumor cells to repopulate during radiotherapy; these mechanisms result in an additive cytotoxic effect in combination with radiotherapy.^62,63

The potential benefits of combining radiopharmaceuticals with chemotherapy in patients with mCRPC have previously been demonstrated in clinical studies of chemotherapy in combination with palliative beta particle-emitting agents^64,65; however, no data currently exist on radiosensitizing effects when combining chemotherapy with TAT. The rationale for combining bone-targeted alpha therapy with chemotherapy is provided by the concept of simultaneous targeting of the tumor and bony compartment of the disease, with each agent independently prolonging survival and possibly augmenting the other via cross-sensitization.⁶⁶ A randomized phase I/II clinical trial showed that ²²³Ra (55 kBq/kg every 6 weeks, n = 36) plus docetaxel (60 mg/m² every 3 weeks) might enhance antitumor activity compared to docetaxel alone (75 mg/m² every 3 weeks, n = 17).⁶⁷ The ²²³Ra combination arm was well tolerated without greater adverse effects than in the docetaxel arm and demonstrated more durable suppression of prostate-specific antigen (PSA) and alkaline phosphatase.^67–69 On the basis of these encouraging results, a phase III trial of this treatment combination is currently recruiting patients (NCT03574571).⁷⁰ Additional prospective trials are ongoing with ²²³Ra in combination with other novel agents, including immune checkpoint inhibitors (NCT02814669).^71–73

Tumor-Directed Imaging and Therapy

Prostate-specific membrane antigen (PSMA), first discovered in 1993,⁷⁴ is a 750-amino acid type II transmembrane glycoprotein with folate hydrolase activity. It is produced in the cell membranes of prostate epithelial cells and is highly upregulated in the vast majority of prostate carcinomas. PSMA expression is also upregulated in high-grade, metastatic, and castration-resistant prostate cancer. However, PSMA is not only specific to prostate epithelial cells but is also expressed in other tissues including salivary glands, proximal renal tubules, duodenal mucosa, and neuroendocrine cells in colonic crypts. It remains unclear why PSMA is upregulated in prostate cancer as no known natural ligand exists; however, PSMA ligands undergo constitutive internalization by PSMA, making it an attractive imaging and molecular target for prostate cancer.

PSMA imaging was initially based on anti-PSMA antibodies, with the first clinically viable radiotracer, J591, described in 1997.⁷⁵ J591, which accumulates in PSMA-expressing PC cells by binding to the extracellular domain of PSMA, can be labeled with ¹¹¹In for scintigraphy or ⁸⁹Zr for positron emission tomography (PET). Although large molecule radiolabeled antibodies demonstrate good tumor detection, the practicality of antibody imaging can be limited by long delays between injection and imaging and slow clearance from circulation.

PSMA imaging for diagnosis and staging of PC became more feasible with the development of small-molecule ligands, the majority of which contain glutamine urea-lysine dimers. Over the last 3 decades, urea-based inhibitors⁷⁶ and PSMA inhibitors by phosphonamidothionate derivatives of glutamic acid⁷⁷ were developed, enabling the development of clinically available small-molecule ligands. Small-molecule ligands, which also internalize into prostate cancer cells upon binding to PSMA, offer an advantage over large-molecule monoclonal antibodies, with increased uptake and higher percentage of specific binding to PSMA, as well as increased permeability into solid tumors. They also demonstrate more rapid tissue distribution and tissue clearance than monoclonal antibodies.

The small-molecule PSMA ligands ¹²³I-MIP-1972 and ¹²³I-MIP-1095 (Molecular Insight Pharmaceuticals, Cambridge, MA) were first used in humans in 2008 for diagnosis with scintigraphy,⁷⁸ with subsequent development of ^99mTc-MIP-1404 and ^99mTc-MIP-1405 in 2010.^79,80 Subsequently, PSMA-labeled PET radiotracers were developed with ⁶⁸Ga-PSMA-11 used clinically for diagnosis since 2011, primarily for detecting recurrence or metastatic disease in the setting of biochemical recurrence following primary treatment. ⁶⁸Ga-PSMA-11 is not currently FDA-approved but is widely used in Europe and Australia.

Studies have shown that ⁶⁸Ga-PSMA-11 PET/CT has high sensitivity and specificity compared to alternative imaging methods used for detection of recurrent PC.^81,82 The probability of detecting tumor lesions increases with increased PSA levels, with a reported detection rate of about 50% at PSA <0.5 ng/mL and 80% at PSA >1.0 ng/mL.⁸² However, even with high PSA values (>10.0 ng/mL), not all patients have a positive ⁶⁸Ga-PSMA-11 PET/CT. Ongoing use of ADT at the time of study has been significantly associated with positive ⁶⁸Ga-PSMA-11 PET/CT. Additional PSMA-labeled radiotracers in use or under investigation include ¹⁸F-PSMA, ¹⁸F-DCFPyl, ¹⁸F-rh-PSMA-7, and ¹⁸F-si-PSMA-7, with similar promising results. However, as PSMA is not specific to prostate cancer, and as clinical experience with ⁶⁸Ga-PSMA-11 PET/CT has increased, more reports of PSMA-avid, nonprostate benign and malignant lesions have been published.

Since antibodies and small-molecule ligands are internalized once they bind to PSMA, these molecules were also determined to be an attractive target for radiopharmaceutical therapy for prostate cancer. Again, radiolabeled large monoclonal antibodies (⁹⁰Y or ¹⁷⁷Lu-PSMA-J591) were developed initially, with phase I and II clinical trials showing encouraging results.^83–85 However, due to molecule size and resultant poor permeability in solid tumors as well as slow clearance from circulation, these molecules can deliver increased absorbed doses to red marrow. Hematologic toxicity can result, sometimes irreversible. Tagawa et al, who treated 47 patients with ¹⁷⁷Lu-PSMA-J591, reported grade 4 thrombocytopenia in 46.8% of patients with 29.8% requiring platelet transfusions and grade 4 neutropenia in 25.5% of patients.⁸³ However, more recent phase I/II trials have shown that a fractionated regimen of ¹⁷⁷Lu-J591 allows for higher cumulative radiation dosing with greater decrease in PSA levels and longer survival compared to a single-dose regimen.⁸⁶

As with imaging, small-molecule inhibitors of PSMA have also been used in radiopharmaceutical therapy⁷⁹; the first agent used in clinical practice was ¹³¹I-MIP-1095 (Molecular Insight Pharmaceuticals, Inc. Cambridge, MA), which showed promising results with symptomatic relief, PSA decrease of >50% in up to 70.6% patients treated, and median time to PSA progression of 126 days. ¹³¹I-MIP-1095 also demonstrated milder hematologic toxicity compared with radiolabeled antibodies, with Afshar-Oromieh et al reporting no significant hematologic toxicity as per WHO CTC grading system in a study of 34 patients with mCRPC treated with up to 3 cycles of ¹³¹I-MIP-1095.⁸⁷ However, xerostomia was a significant side effect with ¹³¹I-MIP-1095. Grade 1 xerostomia was seen in 70.6% of patients, with grade of xerostomia increasing with number of cycles, although it was self-limited in the majority of patients.⁸⁸ While ¹³¹I is predominantly a beta emitter (606 keV; 90%), it also has relatively high gamma emission (364 keV, 10%) and a long half-life of 8.02 days, which makes it a less ideal radiopharmaceutical from a radiation safety point of view, compared to lower-energy emitters such as ¹⁷⁷Lu (half-life of 6.7 days;(Figure).

Figure.

(A) Mechanism of action of radium-223 (²²³Ra). ²²³Ra substitutes for calcium in hydroxyapatite complexes in woven bone surrounding prostate cancer metastatic lesions. ²²³Ra emits high-energy alpha particles over a range of ≤100 μm. The alpha radiation leads to localized cytotoxicity through the induction of DNA double-strand breaks in adjacent tumor cells, osteoblasts and osteoclasts, which disrupts the positive-feedback loops between these cells, leading to inhibition of tumor growth and pathological bone reaction and stabilization of the normal bone microenvironment. (B) Disease-specific theranostic agents, many being used in combination with other anticancer agents targeting distant metastatic disease, are in being used in routine clinical practice or are under preclinical or clinical investigation in mCRPC.

¹⁷⁷Lu-PSMA-617

Initial studies of the use of ¹⁷⁷Lu-PSMA-617 in patient cohorts heavily pretreated with agents including ADT, next-generation AR-axis targeting agents, and docetaxel demonstrated favorable therapeutic response with mild side effects; for example, in the initial phase I trial with 10 patients who received 1 cycle of RLT, 70% of patients demonstrated a decline in PSA, with 5 patients demonstrating a decline of >50% at 8 weeks and only 1 patient suffering grade 3/4 hematologic toxicity.⁸⁹ Ahmadzadehfar et al demonstrated similar results in a slightly larger cohort of patients who received up to 2 cycles of ¹⁷⁷Lu-PSMA-617.⁹⁰ Baum et al showed even more promising results with ¹⁷⁷Lu-PSMA-I&T in a cohort of patients with early-stage castration resistance and less prior chemotherapy exposure (25% of patients vs >75% in aforementioned studies), with reported PSA declines of >50% in 80% of patients and longer median OS of 13.7 months.⁹¹ The largest cohort published to date is a German multicenter retrospective analysis of 145 patients with mCRPC that mirrored the results of earlier trials, with PSA decline seen in 60% of patients and PSA decline >50% seen in 45% of patients.⁹² However, this study determined that the presence of visceral metastases, especially liver metastases and/or alkaline phosphatase >220 U/l, was a predictor of a poorer response.

Studies have suggested a clinical benefit with RLT; Rahbar et al demonstrated an estimated median survival in a group treated with ¹⁷⁷Lu-PSMA-617 of 29.4 weeks compared to 19.7 weeks in a historical control group (HR: 0.44; 95% CI: 0.20–0.95; P = 0.031),⁹² but survival benefit has not yet been proven. Subsequent studies that analyzed OS in patients receiving up to 8 cycles of ¹⁷⁷Lu-PSMA-617 RLT determined that any PSA decline after the first cycle was a significant prognostic marker of survival (68 vs 33 weeks and 59 vs 28 weeks, respectively), with a PSA decline of ≥21%, the optimal parameter for predicting improved OS in the multivariate analysis.⁹³ However, the same study also showed that in patients who do not respond to the first cycle of RLT, further therapy cycles should still be performed, since nearly one-third of the patients showed a delayed response after additional therapy cycles.⁹³

¹⁷⁷Lu-PSMA-617 has been well tolerated to date.^92,94 Hematologic side effects have been minimal, with grade 3/4 toxicities including anemia, leukopenia, and thrombocytopenia reported in 10%, 3%, and 4% of patients, respectively, treated with ¹⁷⁷Lu-PSMA-617. Use of ¹⁷⁷Lu-PSMA-617 RLT after radionuclide therapy with ²²³Ra dichloride has not demonstrated a higher probability of hematologic toxicity.⁹⁵ Although there is specific renal binding of PSMA ligands, to date, no grade 3/4 renal toxicities have been reported after RLT.⁹⁶ Eight percent of patients reported mild or transient xerostomia.

Although several ¹⁷⁷Lu-PSMA-617 trials have demonstrated favorable safety and therapeutic response,^89,91,92 these trials are limited as they are predominantly retrospective phase I/II in design. Also, PSA is only a surrogate marker for post-treatment effects, and an improved PSA response is not necessarily predictive of longer progression-free survival (PFS) and OS.^97,98 To date, only 1 prospective single-center phase II trial has been performed; 30 mCRPC patients who previously received abiraterone acetate, enzalutamide, or taxol chemotherapy received up to 4 cycles of ¹⁷⁷Lu-PSMA-617.⁹⁴ This group demonstrated a PSA decline ≥50% in 57% of patients, with an objective response in nodal or visceral disease reported in 14 of 17 (82%) patients with measurable disease. Additionally, 11 (37%) patients experienced a 10-point or greater improvement in global health score by the end of cycle 2.

The VISION trial is a prospective, multicenter, randomized phase III trial open to accrual that is examining whether adding ¹⁷⁷Lu-PSMA-617 RLT to standard-of-care therapy (SOCs) in mCRPC patients is more effective than SOCs alone⁹⁹ (NCT03511664). The study endpoints are radiographic PFS and OS. Patients randomized to receive RLT will receive 7.4 GBq (±10%) ¹⁷⁷Lu-PSMA-617 intravenously every 6 weeks for a maximum of 6 cycles. After 4 cycles, patients will be assessed for (1) evidence of response, (2) residual disease, and (3) tolerance to RLT and if the criteria for all 3 assessments are met, the patient may receive an additional 2 cycles of RLT. The trial is currently accruing, and results are pending; if they are positive, this may lead to regulatory approval for RLT in mCRPC. However, the VISION trial does have potential limitations—for example, patients on chemotherapy or ²²³Ra were not considered SOC due to safety concerns and the trial does not compare ¹⁷⁷Lu-PSMA-617 RLT to SOCs alone.

The TheraP phase II trial, however, is comparing ¹⁷⁷Lu-PSMA-617 with the second-line chemotherapy agent cabazitaxel in patients with mCRPC who have progressed on ADT and first-line chemotherapy with endpoints of PSA response rate, pain response, PFS, quality of life, and frequency and severity of adverse events¹⁰⁰ (NCT03392428). Accrual is complete and results are pending.

Future Developments

Combination therapies with ¹⁷⁷Lu-PSMA-617 and other RLTs—for example, ¹⁷⁷Lu-PSMA-R2 and ¹⁷⁷Lu-PSMA-I&T—are being investigated as potential treatment strategies, as further outlined in Table.

Table.

Summary of Selected Ongoing Clinical Trials Using Theranostic Agents in mCRPC

Agent	Mechanism of Action	Trial Design	Primary Endpoint	Estimated Completion Date	Clinical Trial ID
Alpha emitters
223Ra + Enzalutamide (vs enzalutamide only) “PEACE III”	AR inhibitor	Randomized Phase III	Radiographic PFS	December 2025	NCT02194842
223Ra + Docetaxel (vs Docetaxel only)	Microtubule inhibitor	Randomized Phase III	Overall survival	June 2023	NCT03574571
223Ra + Pembrolizumab (vs 223Ra only)	PD-1 inhibitor	Randomized Phase II	Extent of immune cell infiltration	June 2024	NCT03093428
223Ra + Olaparib (vs 223Ra only)	PARP inhibitor	Randomized Phase I/II	- MTD of olaparib and 223Ra - Radiographic PFS	April 2020	NCT03317392
225Ac-J591	Monoclonal Antibody	Phase I	- Change in the number of subjects with DLT - MTD	July 2024	NCT03276572
225Ac-PSMA	Radioligand	Phase I	Serum PSA	December 2021	NCT04225910
Beta-emitters
177Lu-PSMA-617 + SOC (vs SOC only) “VISION”	Radioligand	Randomized Phase III	Overall survival	June 2021	NCT03511664
177Lu-PSMA-617 vs Cabazitaxel “TheraP”	Radioligand	Randomized Phase II	PSA response rate	January 2021	NCT03392428
177Lu-PSMA-R2	Radioligand	Phase I/II	- Incidence of DLT during first cycle - PSA response rate	June 2022	NCT03490838
177Lu-PSMA-I&T	Radioligand	Phase I	Serum PSA	August 2020	NCT04188587
177Lu-PSMA-617 + Pembrolizumab “PRINCE”	Radioligand + PD-1 inhibitor	Phase Ib/II	- Adverse Events - PSA response	October 2021	NCT03658447
177Lu-PSMA-617 + Olaparib “LuPARP”	Radioligand + PARP inhibitor	Phase I	- DLT - MTD - Recommend Phase II dose	October 2022	NCT03874884
177Lu-PSMA-617 + idronoxil “LuPin”	Radioligand + Radiosensitizing agent	Phase I/II	- Toxicity profile - Anti-cancer efficacy	Not provided	ACTRN12618001073291
177Lu-PSMA-617 + 177Lu-J591	Radioligand + Monoclonal Ab	Phase I/II	- DLT of combination therapy - Cumulative MTD - PSA decline	June 2022	NCT03545165
227Th-BAY2315497	Monoclonal Ab	Phase I	MTD	November 2022	NCT03724747

mCRPC, metastatic castrate resistant prostate cancer; PSA, prostate specific antigen; PSMA, prostate specific membrane antigen; ²²³Ra, radium-223; ¹⁷⁷Lu, luteteim-177; ²²⁵Ac, actinium-225; ²²⁷Th, thorium-227; AR, androgen receptor; PD-1, programmed cell death 1; PARP, poly (ADP-ribose) polymerase; Ab, antibody; PFS, progression-free survival; MTD, maximum tolerated dose; DLT, dose limiting toxicity; SOC, best standard of care.

However, up to 30% of patients are nonresponders or develop resistance to ¹⁷⁷Lu-PSMA-617. Previously, studies in patients with neuroendocrine tumors refractory to beta-emitting RLT (⁹⁰Y or ¹⁷⁷Lu-somatostatin receptor analogs) have demonstrated a subsequent response to TAT with ²¹³Bi-DOTATAC.¹⁰¹ Because TATs have a shorter tissue-penetration range, they have a theoretical advantage in terms of hematologic toxicity, especially in patients with diffuse-type bone marrow infiltration, as seen in widespread bone metastases. Thus, TATs have been proposed as possible tumor-targeting agents in mCRPC. To date, ²²⁵Ac-PSMA-617 has been the most studied PSMA-targeted TAT, with phase I and II clinical trials studying its use predominantly in heavily pretreated patients with agents including ADT, enzalutamide, and docetaxel.

Kratochwil et al retrospectively reviewed 40 patients with mCRPC who received 3 cycles of ²²⁵Ac-PSMA-617 (100 kBq/kg) at 8-week intervals following failure on SOC therapy.¹⁰² They reported ≥50% PSA decline in 60% of patients, exceeding the biochemical response rates of ¹⁷⁷Lu-PSMA-617. In addition, complete response with regard to PSA and PSMA PET/CT was achieved in 13% of ²²⁵Ac-PSMA-617 patients; complete response with ¹⁷⁷Lu-PSMA RLT was reported in only 1% of patients, even with less advanced disease. They reported a median PFS of 7 months and an OS of 12 months within their cohort. However, as mentioned previously, PSA is only a surrogate marker for response and improvement in PSA does not necessarily predict longer PFS and OS in patients receiving ²²⁵Ac-PSMA-617 vs ¹⁷⁷Lu-PSMA.

Reported side effects of ²²⁵Ac-PSMA-617 have been more concerning than with ¹⁷⁷Lu-PSMA-617—most notably, xerostomia, with one-third of patients requesting to discontinue therapy due to this side effect in 1 study.¹⁰³ The use of ²²⁵Ac-PSMA-617 in combination with or following ¹⁷⁷Lu-PSMA-617 RLT has been limited. Khreish et al reported their experience of treating 20 patients with 1 cycle of tandem ²²⁵Ac-PSMA-617 and ¹⁷⁷Lu-PSMA-617 without safety concerns and interestingly with reported rates of xerostomia less than with ²²⁵Ac-PSMA-617 monotherapy,¹⁰⁴ although this finding is limited, as it is a subjective metric. Feuerecker et al reported the use of ²²⁵Ac-PSMA-617 in a cohort of 15 patients following failure of ¹⁷⁷Lu-PSMA-617 RLT, demonstrating a PSA decline in two-thirds of patients with one-third of patients showing a decline of ≥50%.¹⁰⁵ However, xerostomia was reported in all patients as well as significant hematologic toxicities: 27% of patients with grade 3/4 anemia and 13% of patients suffering grade 3 thrombocytopenia.

Although ²²⁵Ac as an alpha-emitting radioisotope for RLT shows early promising results, its development as a RLT may also be limited due to its scarcity. Annually, only 63 GBq (1.7 Ci) of ²²⁵Ac is produced globally, primarily derived from the build-up of ²²⁹Th through the decay of ²³³U stockpiles available from three sources (Canada, Germany, and Russia), which would facilitate ²²⁵Ac-PSMA-617 RLT for <1000 patients per year.¹⁰⁶

Other TATs have been proposed in patients with mCRPC who have failed SOCs. A first-in-human treatment concept with ²¹³Bi-PSMA-617 has recently been reported in a patient with progressive mCRPC.¹⁰⁷ Following 2 cycles of therapy (accumulative activity of 592 MBq), the patient demonstrated both a biochemical (PSA decline >80%) and radiological response on ⁶⁸Ga-PSMA PET/CT. However, further research is required to study the efficacy and safety of this therapy. Additionally, an ongoing phase I trial is investigating Thorium-227 BAY2315497, an alpha emitter conjugated to an antibody specific for PSMA, in patients with mCRPC¹⁰⁸ (NCT03724747).

Humanized IgG1 antibody hu11B6, which internalizes into prostate and prostate cancer cells by binding to the catalytic cleft of human kallikrein 2 (hK2), a prostate-specific enzyme directed by the AR pathway, has also been explored.¹⁰⁹ Preclinical studies investigating ²²⁵Ac-hu11B6¹¹⁰ and ¹⁷⁷Lu-hu11B6¹⁰⁹ can deliver therapeutic absorbed doses to prostate cancer xenografts with transient hematologic side effects, with both radiotracers demonstrating a therapeutic mechanism, a feed-forward mechanism coupled to the AR pathway driving DNA damage or clonal lineage selection. There is an ongoing pilot trial of this agent to establish targeting, as a prelude to a phase I therapeutic trial¹¹¹ (NCT04116164).

Finally, targeting of the fibroblast activation protein is currently being explored for different tumor types using PET imaging with the fibroblast activation protein inhibitor (FAPI), ⁶⁸Ga-FAPI-04, with early case reports of FAPI expression in mCRPC.^112,113 The first therapeutic applications of ⁹⁰Y-FAPI-04 have been applied in a patient with metastatic breast cancer, but this could potentially be an emerging imaging and therapeutic strategy in mCRPC.¹¹⁴

Conclusion

Theranostic agents in the treatment of prostate cancer were initially developed for targeting bone-specific disease but more recently, agents are being developed to target the tumor itself. ²²³Ra TAT remains an important component of the treatment paradigm for mCRPC, as to date, it is the only agent that has a proven survival benefit. ²²³Ra acts through multiple mechanisms to remodel pathologic bone cells, including DNA damage to tumor cells, and activates the cellular immune defenses within the bone microenvironment, which is important for understanding its role in combination with other agents such as cytotoxic chemotherapy and immunotherapy, for which initial preclinical trials are promising. However, the results of randomized controlled trials are required before ²²³Ra combinations can be used in clinical practice, especially in light of the unexpected findings of the ERA-223 trial, despite the convincing preclinical rationale for combining ²²³Ra with abiraterone to treat mCRPC.

The recent development of tumor-specific RLT is an exciting advancement for the role of theranostics in the treatment of mCRPC. Although early-phase I and II trials have been promising, the role of ¹⁷⁷Lu-PSMA-617 will be determined by the VISION trial; if successful, it will cement the role of theranostics and alter treatment paradigms, with PSMA-based imaging used to identify patients likely to benefit from treatment with ¹⁷⁷Lu-PSMA-617. However, if the results of ¹⁷⁷Lu-PSMA-617 are not successful, it will represent a substantial drawback for the field of theranostics.

Finally, tumor-specific TATs are in development which, due to their inherent properties, may offer therapeutic gain while minimizing damage to normal tissue. TATs may also allow targeting of small volume disease. Although initial experiences seem promising, with both biochemical and radiological responses, randomized controlled trials are again required to determine treatment efficacy. Studies are also required to determine in what specific situations RLT should be alpha- or beta-directed, or whether a combination of both may confer additional benefit.