Tumor > Therapy > Xofigo and other Prostate Agents

²²³Ra-dichloride (Xofigo)

- Clinical:

²²³Ra-dichloride (²²³RaCl₂) is an alpha (α) emitting bone seeking calcium mimetic that forms complexes with hydroxyapatite and will accumulate in areas of increased bone turnover/active mineralization without significant redistribution of the daughter radionuclides [1,2]. The agent is prepared from a long-lived ²²⁷Ac/²²⁷Th generator and has a physical half life of 11.4 days [1]. ²²³Ra has a complex decay scheme into stable lead (93.5% α emission, < 3.6% beta-particles, and <1.1% as gamma radiation) [4,5]. There are four α particles generated during each decay, resulting in high energy deposition (28.2 MeV), with 95% of the energy from the α emissions [1].

Alpha particles are monoenergenic positively charged helium nuclei (initial kinetic energy between 5-9 MeV) that are about 8000 times larger than beta particles [7,9]. Alpha emitters are 100 to 500 fold more potent than low-LET beta-particle emitters [2] and can produce 2000-7000 ion pairs per micrometer in water (one ionization every 2 nm) [11]. Because the diameter of the DNA double-helix is about 2 nm, the traversal of a single alpha-particle is enough to induce double-stranded, often blunt-ended, DNA breaks [11]. Beta-radiation results in fewer than 20 ion pairs per micrometer and the traversal of a single beta-particle causes only single stranded DNA breaks, whereas higher absorbed doses are needed to achieve double-stranded breaks, and then often with cohesive ends [11]. Because alpha particles have a short range (approximately 0.05-0.1 mm in human tissue vs several millimeters (0.05-12mm) for beta particles [7,10]), α-particles deliver a large amount of radiation to target tissue while relatively sparing normal surrounding tissue [5]. With beta particles, neighboring cells around the targeted cell are also irradiated (cross-fire effect) which is considered advantageous for targeting large tumors with a heterogeneous target distribution, but can have a negative effect on adjacent normal cells (such as bone marrow cells) [10]. As a result of the short range of α emissions, there should be less hemotoxicity from α emitters compared to beta emitters [1]. The high linear energy transfer of the α particle, compared to a beta emission (80-100 keV/?m (50-230 keV/?m [10]) versus 0.2 keV/?m [7,9]), also results in greater biological effectiveness with more irreversible double-stranded DNA breaks per unit absorbed dose that cells cannot repair and hence the damaged cells succumb to apoptosis [1,2,7]. The range of the particles (<100 um or a few cell diameters) is also shorter than the 0.7 cm path of ⁸⁹Sr and the 0.33 cm path of ¹⁵³Sm, which results in less irradiation to health tissue [1,2,9].

With regards to radiation exposure, a patient of average weight receiving 3.5 mBq of ²²³Ra-dichloride will emit radiation at a rate of 0.35 mSv/hr at one meter immediately following administration which entails minimal radiation safety precautions [7]. There are no contact precautions with the agent, but bathroom precautions are recommended (fecal excretion is the primary mode of clearance [7]) for one week and include multiple flushing and area clean up [5].

The agent is rapidly cleared from the blood with less than 1% remaining at 24 hours [1,4]. Most if the administered activity is rapidly taken up by bone (61% at 4 hours) [4]. The agent accumulates in the bone matrix in proportion to the extent of osteosclerotic bone remodeling [8]. Elimination is mainly through the GI tract (fecal elimination) with the median being 52% activity in the bowel at 24 hours [1,4,5]. Despite this, there is low GI tract toxicity [4]. Urinary excretion is minimal (typically < 5%) [1]. Limited imaging can be obtained from gamma emissions from ²²³Ra (1.1% abundance) and its daughter products [1,4].

Administration is based on body weight with a dose of 50 kBq/kg (1.35 uCi/kg) given as repeated injections for 6 doses [1]. For the first dose, the ANC should be 1.5 x 10⁹/L or greater, the platelet count 100 x 10⁹/L or greater, and the hemaglobin at least 10 g/dL or higher [1]. For subsequent doses, the ANC should be 1.0 or higher and the platelet count 50,000 or higher [1]. The agent should be discontinued if hematologic values do not recover within 6-8 weeks after the last administration despite supportive care [1].

Results:

The agent is presently approved for use in patients with bone metastases from castration resistant prostate cancer (and no known visceral metastatic disease) [1]. The existence of any visceral metastases is a contraindication and bone marrow involvement should also be a contraindication [6]. ²²³Ra therapy is effective in providing pain relief which can be seen in 52% of patients at 1 week, 60% at 4 weeks, and 56% at 8 weeks [1]. Bone alkaline phosphatase (ALP) is a marker for tumor response in these patients and a significant decrease in ALP is seen following ²²³Ra therapy (a decrease in ALP is more common than a decline in PSA [5]) [1]. A significant decrease in PSA levels also occurs following therapy (compare to placebo) [1]. However, lack of a PSA decrease does not indicate therapeutic failure and therapy should not be stopped prematurely [5,6]. The decision to discontinue treatment should be based on clinical symptomatology, therapeutic tolerability, and radiographic evidence of progression [6]. An approximately 3.6 month survival benefit has also been demonstrated in one study (14 vs 11.2 months) [1,5].

Although ²²³Ra therapy has been shown to improve survival, there is heterogeneity of response, with some patients showing a limited or poor response [3]. Some lesions on bone scan can improve following treatment [8].

The initial skeletal tumor burden identified on bone scan or ¹⁸F-flouride PET/CT has been correlated with worse overall survival following ²²³Ra therapy [3,8,12]. Additionally, high tumor involvement of bone identified on bone scan has also been shown to be associated with a greater likelihood of inability to complete ²²³Ra treatment due to disease progression or cytopenia [12].

Other factors associated with worse survival include an ALP greater than 146 U/L, a pain score greater than 3, skeletal related events, a PSA greater than 10 ng/mL, a hemoglobin less than 12.8 g/dL, visceral or nodal metastases, and older age [3].

Complications/Side effects:

The most common adverse reactions (>10%) are nausea, diarrhea, vomiting, and peripheral edema [5]. Hematopoietic toxicity is dose-related with a nadir occurring 2-4 weeks after treatment [1]. Generally, recovery occurs by 24 weeks [1]. It has been suggested that a greater extent of skeletal metastatic disease on bone scan is a significant risk factor for developing hematologic toxicity [8].

Combination use of ²²³Ra with abiraterone and prednisone (or prednisolone) has been associated with an increased risk for fractures [12].

Long-term followup for the agent is not yet available, but to date no myelodysplastic syndrome, aplastic anemias, or leukemias have been observed [1]. In one study, only 25% of patients were able to complete the entire 6-dose treatment regimen [5]. Advancing soft tissue disease is one of the primary reasons for cessation of therapy [5].

REFERENCES:

(1) J Nucl Med 2014; Pandit-Taskar N, et al. Bone-seeking radiopharmaceuticals for treatment of osseous metastases, part 1: α therapy with ²²³Ra-dichloride. 55: 268-274

(2) AJR 2014; Wadas T, et al. Molecular targeted α-particle therapy for oncologic applications. 203: 253-260

(3) J Nucl Med 2015; Etchebehere EC, et al. Prognostic factors in patients treated with ²²³Ra: the role of skeletal tumor burden on baseline ¹⁸F-flouride PET/CT in predicting overall survival. 56: 1177-1184

(4) J Nucl Med 2015; Chittenden S, et al. A phase 1, open-label study of the biodistribution, pharmaokinetics, and dosimetry of ²²³Ra-dichloride in patients with hormone-refractory prostate cancer and skeletal metastases. 56: 1304-1309

(5) J Nucl Med 2016; Iagaru AH, et al. Bone-targeted imaging and radionuclide therapy in prostate cancer. 57: 19S-24S

(6) J Nucl Med 2017; Ahmadzadehfar H, et al. ⁶⁸Ga-PSMA-11 PET as a gatekeeper for the treatment of metastatic prostate cancer with ²²³Ra: proof of concept. 58: 438-444

(7) AJR 2017; Jadvar H. Targeted radionuclide therapy: an evolution toward precision cancer treatment. 209: 277-288

(8) J Nucl Med 2018; Fosbol MO, et al. ²²³Ra therapy of advanced metastatic castration-resistant prostate cancer: quantitative assessment of skeletal tumor burden for prognostication of clinical outcome and hematologic toxicity. 59: 596-602

(9) J Nucl Med 2018; Poty S, et al. α-emitters for radiotherapy: from basic radiochemistry to clinical studies- part 1. 59: 878-884

(10) J Nucl Med 2019; Nicolas GP, et al. New developments in peptide receptor radionuclide therapy. 60: 167-171

(11) J Nucl Med 2020; Kratochwil C, et al. Patients resistant against PMSA-targeting alpha-radiation therapy often harbors mutations in DNA damage-repair-associated genes. 61: 683-688

(12) J Nucl Med 2021; Dittmann H, et al. The prognostic value of quantitative bone SPECT/CT before ²²³Ra treatment in metastatic castration-resistant prostate cancer. 62: 48-54

PMSA radioligand therapy:

PMSA is a type II transmembrane glycoprotein that is over-expressed in metastatic prostate cancer and the degree of PMSA expression positively correlates with tumor stage [1,2]. However, the ligand is not specific to the prostate gland and is expressed on other normal tissues including the normal prostate epithelium, salivary glands, duodenal mucosa, proximal renal tubular cells, and neuroendocrine cells in the colon crypts [1,2]. It is also expressed on certain neoplasms including transitional cell carcinoma, renal cell carcinoma, and colon cancer [1].

¹⁷⁷Lu-PMSA:

Radionuclide therapy with agents such as ¹⁷⁷Lu-labeled PMSA, although not curative, may be considered in patients who have confirmed progressive castrate resistant prostate cancer after exhaustion of approved therapies, including patients previously treated with taxane agents [2,58,95,105]. ¹⁷⁷Lu-PMSA is a low molecular weight ligand that binds to the cell surface of prostate carcinoma cells and is transported into the cell by receptor-mediated endocytosis [114]. The 497-keV beta-energy of ¹⁷⁷Lu corresponds to a mean and maximum tissue range of only 0.5 and 2 mm (10-50 cell diameters), respectively [58]. The agent has a long effective half-life in both skeletal and soft tissue metastases, approaching the physical half-life of ¹⁷⁷Lu and this results in a high mean absorbed tumor dose (the maximum doses obtained in lymph node mets was 468 Gy and in bone mets 260 Gy) [127]. Other authors quote dose estimates between 1.2-47.5 Gy/GBq (mean 13.1 Gy/GBq) [76]. The red marrow dose is low (0.03 Gy/GBq) [76]. Organs at risk are the kidneys (0.5-0.7 Gy/GBQ) and the salivary or lacrimal glands (1.2-28 Gy/GBq) [76].

Treatment: Patients should have confirmed PMSA expression by the tumor and metastatic foci- ideally demonstrated by baseline PMSA-directed imaging (such as with ⁶⁸Ga-PMSA PET/CT) [2]. Radiation dosimetry has shown that the SUVmean on ⁶⁸Ga-PMSA imaging correlates with absorbed tumor dose [8].

Patients should have a sufficient bone marrow reserve with a white blood cell count more than 3000 and a platelet count of more than 75,000, good renal and liver function (urinary tract obstruction increases the risk for excessive radiation dose to the kidneys), and no potentially myelosuppressive therapy for more than 6 weeks [2]. Patients should have laboratory testing within 2 weeks of planned treatment [2]. A drawback of the agent is that 50% of the administered activity is excreted within 4 hours of administration and nearly 70% by 12 hours [7].

Most sites use a standard activity of 6.0 to7.4 GBq and an 8 week interval between treatments [2]. Organs at risk for a critical radiation dose are the lacrimal, parotid, and salivary glands (salivary gland dose is 1.4 Gy/GBq) and kidneys (0.75 Gy/GBq) [1,2]. Ice packs for the salivary glands may be considered to reduce blood flow [2]. PMSA inhibitors such as 2-(phosphonomethyl) pentanedioic acid have been proposed to diminish renal PMSA binding [1].

On ligand binding, PMSA and its bound molecule are internalized via clathrin-coated pits and subsequent endocytosis [3]. While the beta-emitting component of ¹⁷⁷Lu is utilized for therapy, the gamma component can be used for imaging [3].

Results:

Between 59-80% of patients will demonstrate some decline in PSA levels following therapy [85,95,108,109,127].

A decrease in PSA of 50% or more (considered a biochemical response) can be seen in 32-64% of patients and this decline can be seen as early as after the first cycle of treatment [1,2,8,85,95,108,109,127]. Early changes in PSA following therapy have also been shown to be indicators of long term clinical outcome [128] with a decline in PSA after the first cycle of treatment associated with prolonged survival [2]. In another study following ¹⁷⁷Lu-PMSA therapy, a greater than or equal to 30% decline in PSA values at 6 weeks after treatment was associated with a longer survival (16.7 months) compared to patients with stable PSA (11.8 months) or PSA progression (6.5 months) [128]. PSA flare appears to be very uncommon after ¹⁷⁷Lu-PMSA treatment, as opposed to therapy with taxanes which can be associated with a PSA flare in 20% or more of patients (a PSA flare is defined as a PSA increase of 25% in the first 6 weeks after therapy followed by a decline below baseline levels at 12 weeks) [128].

In one study following treatment, the median progression-free survival was 13.7 months and the median overall survival was not reached during a 28 month followup period [127]. In another study, patients that achieved a PSA decline of at least 50% had a median survival of 18.4 months (compared to 8.7 months if the PSA decline was less than 50%) [8]. A meta-analysis has suggested an improved median survival in ¹⁷⁷Lu-PMSA treated patients of 2.5 months [109].

 There is a significant correlation between whole-body tumor dose (estimated by pre-treatment ⁶⁸GA-PMSA imaging) and PSA response [5]. Patients that receive less than a 10 Gy tumor dose are unlikely to achieve a fall in PSA of at least 50% [5]. Due to a tumor sink effect, patients with larger tumor burdens appear to have lower salivary and renal absorbed doses, which may permit higher administered activities for therapy [5].

Following treatment, in one study, 56% of patients with measurable soft-tissue disease achieved an objective response by RECIST 1.1 [8].

Pain relief can be seen in 33-70% of patients, an improved quality of life in 60%, and improved performance status in 74% [2]. 

However, one third (20-40%) of patients do not respond despite the presence of PMSA over-expression on pre-therapy PET scans [3,76] and therefore,  SUVmax on ⁶⁸Ga-PMSA imaging is not a predictor of response to therapy [95].

Factors associated with a better likelihood for a biochemical response include an alkaline phosphatase level of less than 220 U/L and the absence of visceral metastases [95]. Better overall survival following treatment is seen in patients that demonstrate a PSA decline in 2 months following the first cycle of therapy [95]. Interestingly, about 88-93% of patients with a PSA response after the first cycle will respond to further cycles, but up to 40% of non-responders may also respond to further therapy cycles [95].

The presence of any visceral metastases or a serum alkaline phosphatase 220 U/L or higher (an indication of more advanced bone marrow involvement) are predictive of a poor outcome [2].

¹⁷⁷Lu-PMSA retreatment in initial responders who ultimately relapse has been performed [6,8]. In one study, a PSA decline of at least 50% was seen in 73% of retreated patients, but the duration of response was shorter (no increased adverse effects were observed) [8]. Another study suggested that re-treatment has a lower efficacy and higher toxicity [6]. In that study, only 38% of patients demonstrated a 50% PSA decline and the median progression free survival was 3.3 months, compared to 12.4 months following the initial course of therapy [6].

Progressive disease following treatment most commonly involves the marrow (56% of cases) or liver (19% of cases) [8]. Progressive liver disease in these patients generally demonstrates low PMSA expression and high metabolic activity [8].

Side effects/Complications:

Serious hematologic adverse events can be seen in up to 12% of patients [2]. Other authors indicate grade 3 to 4 anemia in 10%, thrombocytopenia in 4%, and leukopenia in 3% [1]. A low blood cell count at baseline and diffuse bone marrow involvement pose a risk for serious hematotoxicity [2].

one of the major disadvantages of PSMA-radioligand therapy is the high accumulation of the agents in non-target tissues [129]. The PMSA receptor is also expressed in high levels on certain normal tissues including the proximal tubules of the kidneys, the brush border of the jejunum, and the salivary and lacrimal glands [114].

Xerostomia (Dry mouth)- Grade 1 dry mouth has been reported in up to 87% of patients [108] and grade 1-2 in 66% of patients [8], typically self-limiting. External cooling does not appear to reduce tracer uptake by the parotid glands [114].

Orally administered monosodium glutamate (MSG) has been shown to significantly decrease salivary gland, kidney, and other normal-organ uptake, but it also produces a decrease in tumor uptake as well [129].

Nausea- Grade 1-2 transient nausea can be seen in 50% of patients [8,108]. Typically within the first 24 hours of therapy, transient, and manageable with antiemetics [8].

Anemia/Leukopenia/Thrombocytopenia- Grade 3 or 4 anemia (3-10%), neutropenia (1-10%), lymphopenia (32%), and/or thrombocytopenia (2-13%) of patients, respectively [8,105,108].

Renal toxicity- The primary route of ¹⁷⁷Lu-PSMA excretion is renal. Grade 1-2 renal injury can be seen in 10% of patients [8]. Grade 3 renal toxicity is a very rare complication [105].

Mannitol infusion is a strategy to reduce renal uptake by acting as an osmotic diuretic, decreasing renal reabsorption [129].

It should be noted that chemotherapy with docetaxel can result in toxic side effects in up to 67% of patients, including grade 3-4 myelosuppression in 2-32% of patients [109]. Other toxicities include GI toxicity (0-60%), cardiac toxicity (24-48%), and treatment related death (0.3%) [109].

REFERENCES:

(1) AJR 2017; Jadvar H. Targeted radionuclide therapy: an evolution toward precision cancer treatment. 209: 277-288

(2) J Nucl Med 2017; Fendler WP, et al. ¹⁷⁷Lu-PMSA radioligand therapy for prostate cancer. 58: 1196-1200

(3) J Nucl Med 2017; Hadaschik BA, Boegemann M. Why targeting of PMSA is a valuable addition to the management of castration-resistant prostate cancer: the urologist's point of view. 58: 1207-1209

(4) J Nucl Med 2018; Rathke H, et al. Repeated ¹⁷⁷Lu-labeled PMSA-617 radioligand therapy using treatment activities of up to 9.3 GBq. 59: 459-465

(5) J Nucl Med 2019; Violet J, et al. Dosimetry of ¹⁷⁷Lu-PMSA-617 in metastatic castration-resistant prostate cancer: correlations between pretherapeutic imaging and whole-body tumor dosimetry with treatment options. 60: 517-523

(6) J Nucl Med 2019; Gafita A, et al. Early experience of rechallenge ¹⁷⁷Lu-PMSA radioligand therapy after intial good response in patients with advanced prostate cancer. 60: 644-648

(7) J Nucl Med 2019; Kelly JM, et al. Albumin-binding PSMA ligands: implications for expanding the therapeutic window. 60: 656-663

(8) J Nucl Med 2020; Violet J, et al. Long-term follow-up and outcomes of retreatment in an expanded 50-patient single-center phase II prospective trial of ¹⁷⁷Lu-PSMA-617 theranostics in metastatic castration-resistant prostate cancer. 61: 857-865

(58) J Nucl Med 2016; Kratochwil C, et al. PMSA-targeted radionuclide therapy of metastatic castration-resistant prostate cancer with ¹⁷⁷Lu-labeled PMSA-617. 57: 1170-1176

(76) J Nucl Med 2017; Eiber M, et al. Prostate-specific membrane antigen ligands for imaging and therapy. 58: 67S-76S

(85) J Nucl Med 2018; Donin NM, Reiter RE. Why targeting PMSA is a game changer in the management of prostate cancer. 59: 177-182

(95) J Nucl Med 2018; Ahmadzadehfar H, Essler M. Predictive factors of response and overall survival in patients with castration-resistant metastatic prostate cancer undergoing ¹⁷⁷Lu-PMSA therapy. 59: 1033-1034

(105) J Nucl Med 2019; Barber TW, et al. Clinical outcomes of ¹⁷⁷Lu-PMSA radioligand therapy in earlier and later phases of metastatic castration-resistant prostate cancer grouped by previous taxane chemotherapy. 60: 955-962

(108) AJR 2019; Subramaniam RM. Prostate cancer theranosis in clinical practice and in clinical trials- ⁶⁸Ga-prostate-specific member antigen (PSMA)-11 PET/CT and ¹⁷⁷Lu-PMSA-617 therapy. 213: 241-42

(109) AJR 2019; Yadav MP, et al. Radioligand therapy with ¹⁷⁷Lu-PMSA for metastatic castration-resistant prostate cancer: a systematic review and meta-analysis. 213: 275-285

(114) J Nucl Med 2019; Yilmaz B, et al. Effect of external cooling on ¹⁷⁷Lu-PMSA uptake by the parotid glands. 60: 1388-1393

(127)  J Nucl Med 2016; Baum RP, et al. ¹⁷⁷Lu-labeled prostate-specific membrane antigen radioligand therapy of metastatic castration-resistant prostate cancer: safety and efficacy. 1006-1013

(128) J Nucl Med 2020; Gafita A, et al. Early prostate-specific antigen changes and clinical outcome after 177Lu-PSMA radionuclide treatment in patients with metastatic castration-resistant prostate cancer. 61: 1476-1483

(129) J Nucl Med 2021; Harsini S, et al. The effects of monosodium glutamate on PSMA radiotracer uptake in men with recurrent prostate cancer: a prospective, randomized, doble-blind, placebo-controlled intraindividual imaging study. 62: 81-87

²²⁵Ac-PMSA therapy:

Another agent, the alpha emitter ²²⁵Ac-PMSA has also been studied for therapy. ²²⁵Ac is an alpha emitter with a half life of 9.9 days [1]. ²²⁵Ac has six daughter products (221Fr, 217At, 213Bi, 213Po, 209Pb, and 209Tl) with several alpha- and beta decays [1]. The agent has been shown to result in a PSA decline of more than 50% in 63% of patients, with a median duration of tumor control of 9 months [1]. A PSA decline of 50% or greater has been shown to be significantly associated with overall survival (PFS of 15.2 months and OS of 18-20 months) [1].

The agent is associated with a high incidence of intolerable xerostomia due to salivary tracer uptake [2]. Although other authors indicate xerostomia in 85% of patients (typically grade I or II), but not severe enough to discontinue treatment [1]. Dry eyes and anemia (37% of patients - typically grade I or II) can also occur, as can grade III or IV renal failure (especially in patients with baseline renal impairment) [1].

REFERENCES:

(1) J Nucl Med 2020; Sathekge M, et al. Predictors of overall and disease-free survival in metastatic castration-resistant prostate cancer patients receiving ²²⁵Ac-PMSA-617 radioligand therapy. 61: 62-69

(2) J Nucl Med 2018; Kratochwil C, et al. Targeted alpha-therapy of metastatic castrate resistant prostate cancer with ²²⁵Ac-PMSA-617: swimmer-plot analysis suggests efficacy regarding duration of tumor control. 59: 795-802