Keywords

26.1 Introduction

Over the past decade and a half, many life-prolonging therapy agents have been approved for the treatment of metastatic castration-resistant prostate cancer (mCRPC), the lethal form of prostate cancer. These therapy agents fall into four categories, including chemotherapy (docetaxel and cabazitaxel), androgen-signaling-targeted inhibitors (abiraterone and enzalutamide), immunotherapy (Sipuleucel-T), and bone-targeting agent for skeletal metastases (radium-223 dichloride- 223RaCl2) [1,2,3,4,5,6]. Extensive application of these life-prolonging agents has not translated into commensurate reduction in mortality of patients with mCRPC. Prostate cancer mortality has remained stable or even increased in some countries of the world [7]. The multitude of the available life-prolonging agents for mCRPC has introduced a new challenge of the sequence to apply them in patients’ treatment. Longer survival advantage is conferred when an agent is applied earlier in the treatment cycle compared with its application later in the sequence of treatment. It is, therefore, not only necessary to select an agent that has survival benefit but also has tolerable side effects without associated negative impact on the quality of life earlier in the treatment sequence of mCRPC.

Radionuclide therapy targeting prostate-specific membrane antigen (PSMA), a transmembrane glycoprotein overexpressed on prostate cancer cells, has emerged as an attractive therapy option for men with mCRPC. PSMA radioligand therapy (PRLT) is more commonly applied using Lutetium-177-labeled PSMA (177Lu-PSMA) [8]. 225Ac-PSMA targeted therapy is an alternative PRLT agent for targeted alpha therapy (TAT), which is effective in the treatment of mCRPC, including patients who failed treatment with 177Lu-PSMA. In this chapter, we aim to present an update on the evidence in support of the use of 225Ac-PSMA as a TAT agent for mCRPC. We will review its effectiveness, safety profile, and its upfront application in the chemotherapy-naïve setting for the treatment of mCRPC.

26.2 177Lu-PSMA Versus 225Ac-PSMA PRT in mCRPC

Many centers across the world now administer 177Lu-PSMA therapy for PRLT of mCRPC. Consequently, several nuclear medicine societies have published guidance documents for safe application of 177Lu-PSMA therapy as a last-line therapy option in men who have exhausted, refused, or do not qualify for therapy with the life-prolonging therapy agents [9,10,11,12]. Following the encouraging results from an early German multicenter study which showed good efficacy with minimal side effects [13], 177Lu-PSMA has gained increasing acceptance as a viable treatment option in mCRPC [14]. Many studies have subsequently been published showing its efficacy and safety in different populations of patients with mCRPC including in men who are chemotherapy-naïve [15], have single functional kidney [16], have lymph node-predominant metastatic disease [17], and for rechallenge in patients who progressed after an initial response to 177Lu-PSMA therapy [18]. In a prospective phase II trial, 57% of heavily pretreated men with mCRPC achieved a prostate-specific antigen (PSA) decline of 50% or more with a median progression-free survival (PFS) and overall survival (OS) of 7.6 months (95%CI: 6.3–9) and 13.5 months (95%CI: 10.4–22.7), respectively [19]. The most common side effects seen in the patients were hematologic toxicity and xerostomia [19]. In a recent meta-analysis of 17 studies of 177Lu-PSMA treatment in men with mCRPC, 45% of patients had a PSA decline greater than 50% while an average of 74% of patients had any PSA decline [20].

It is evident from the preceding discussion that a significant proportion of patients with mCRPC may not respond to 177Lu-PSMA therapy. Up to 37% of patients (95CI: 33.9–40.3) who initially respond to treatment will experience PSA progression in the short term [20]. These nonresponders, as well as the relapsing patients who may have exhausted or are unfit for the available life-prolonging agents, need alternative treatment options. 177Lu decays by beta particle emission. Its beta particle can traverse between 20 to 60 cells [8]. This long path length of beta particles of 177Lu precludes its use in certain patterns of disease, particularly diffuse prostate cancer metastasis to the bone marrow in a superscan pattern, as this may result in severe bone marrow toxicity in patients who may already have a compromised bone marrow reserve [21]. Also, the ability of beta emission 177Lu to cause cellular damage is dependent on its penetration and the diameter of the tumor [22]. Dose deposited by 177Lu beta emission decline significantly as the diameter of lesion reduces, making effective eradication of micrometastases with 177Lu-PSMA an unrealizable goal [22, 23].

Actinium-225 (225Ac) decays with a physical half-life of 9.9 days via a cascade of six short-lived radionuclide daughters to stable Bismuth-209 generating four alpha particles of energies ranging from 5.8 to 8.4 MeV and associated soft tissue range of 47 to 85 μm [24]. Alpha particles cause irreparable double-stranded DNA damage making them particularly effective in tumor kill. As they traverse the tumor, alpha particles deposit ionizing energy that is up to a thousandth times higher than the energy deposited by beta particles [25]. The short range in the tissue of alpha particles ensures the deposition of high energy within a small radius, about 110 KeV per micron distance traveled compared with about 0.2–0.5 KeV per micron deposited by beta particles [25]. Alpha particles cause direct DNA damage independent of free radical-induced indirect DNA damage that heavily relies on adequate tissue oxygen tension. 225Ac-PSMA delivers a 14-fold higher radiation absorbed dose to the tumor compared with 223RaCl2 [26], another alpha-emitting radionuclide which prolongs the survival of patients with bone-predominant mCRPC [6]. The ability of 225Ac-PSMA to be internalized by tumor cells [27], compared with 223RaCl2, which is adsorbed to areas of increased turnover surrounding the tumor deposit in the bone makes 223Ac-PSMA theoretically better in causing an effective tumor killing than 223RaCl2.

26.3 Efficacy of 225Ac-PSMA as a Last-Line Therapy of mCRPC

The prospect of 225Ac-PSMA for TAT of mCRPC was first reported by Kratochwil et al. in two patients who had exhausted available therapy options [28]. One of these two patients had diffuse skeletal metastases in the typical superscan pattern that precluded therapy with 177Lu-PSMA while the other patients with visceral metastases of prostate cancer showed no response to 177Lu-PSMA. After treatment with 225Ac-PSMA, PSA in both patients declined to below detectable limits while imaging findings returned to normal. No bone marrow toxicity was seen in either patient, including the patient with diffuse skeletal metastases. Xerostomia was the only treatment-related side effect reported by both patients [28]. These first cases not only show the first evidence supporting the efficacy of 225Ac-PSMA in mCRPC but also lay the foundation of the type of patient who may benefit from this type of therapy as well as the efficacy of 225Ac-PSMA in the post−177Lu-PSMA setting.

In a study to define the optimum activity of 225Ac-PSMA-617 and the dose delivered to critical organs which included 14 patients with mCRPC, Kratochwil and colleagues further reported mean doses of 2.3 Sv, 0.7 Sv and 0.05 Sv to salivary glands, kidneys, and red marrow, respectively, per MBq of administered 225Ac-PSMA-617 assuming radiobiological effectiveness of five for the emitted alpha particles [29]. The corresponding mean doses to these same organs from their previous study in Gy/GBq of 177Lu-PSMA-617 were 1.38, 0.75, and 0.03, respectively [30]. In this dosimetry study, patients received different activities of 225Ac-PSMA-617, ranging from 50 to 200 kBq/kg body weight. Only one patient who received 200 KBq/kg had treatment-induced grade 2 hematotoxicity. Xerostomia was seen in the majority of patients treated with an activity of ≥100 KBq/kg. Administered activity of 150 to 200 KBq/kg was associated with good antitumor activity at the risk of increased treatment-induced toxicities leading to treatment discontinuation or de-escalation of administered activity. 100 KBq/kg of 225Ac-PSMA-617 provided a compromise between effective antitumor activity and tolerable treatment-induced toxicity, mainly xerostomia. In patients who received more than one cycle of treatment, there was a progressive PSA decline when treatment was repeated after every 2 months. In contrast, when there was a delay in the administration of subsequent treatment cycles after an initial response, resistance develops without significant response to the subsequent treatment cycles [29]. Taken together, this study established xerostomia as the dose-limiting toxicity in TAT with 225Ac-PSMA-617 showed the impact of the administered activity on the dynamics of antitumor activity and the appearance of toxicities, and the impact of timing of treatment cycles on PSA response [29].

In current routine medical practice, PRLT with either 177Lu or 225Ac-labeled PSMA is reserved for patients who have exhausted, declined, or are unfit for the life-prolonging approved therapy agents pending the availability of results of ongoing clinical trials evaluating the effectiveness and safety of PRLT in mCRPC and its comparative effectiveness versus the current standards of treatment. Treatment applied late in the sequence of therapy of mCRPC performs less well compared with the treatment given earlier in the therapy sequence. In the absence of a head-to-head comparison between 225Ac-PSMA and the life-prolonging therapy agents for mCRPC, the Heidelberg group, in their most recent study on this subject, used a Swimmer-Plot analysis to compare the duration of tumor control by 225Ac-PSMA-617 versus the currently used approved agents for mCRPC [31]. The median duration for any first-, second, third-, or fourth-line therapy, regardless of the drug, was 8.0, 7.0, 6.0, and 4.0 months, respectively. The median duration of abiraterone, docetaxel, enzalutamide, cabazitaxel, and 223RaCl2, regardless of the time in the treatment sequence at which they were applied, were 10.0, 6.5, 6.5, 6.0, and 4.0 months, respectively. For 225Ac-PSMA-617 applied as a last-line agent after patients have failed the approved agents, the median duration of tumor control was 9.0 months [31]. These results show the relative performance of TAT with 225Ac-PSMA in a group of heavily pretreated patients, and in the absence of results from formal trials evaluating the comparative performance of 225Ac-PSMA relative to the known life-prolonging agents, represent robust evidence in support of its use for mCRPC treatment.

In the largest series to date of men with mCRPC treated with 225Ac-PSMA-617, Sathekge et al. reported a PSA decline of 50% or higher in 70% of patients treated after a median of three treatment cycles [32]. Imaging findings returned to normal in about 29% of patients. After a median follow-up period of 9 months (range = 2–22), 18% patients had died while disease had progressed in 32% of patients given an estimated PFS and OS of 15.2 months (95% CI: 13.1–17.4) and 18 months (95% CI: 16.2–19.9), respectively. This study provides the first published insight into the efficacy of 225Ac-PSMA therapy in patients who are status post−177Lu-PSMA therapy for mCRPC. Prior 177Lu-PSMA therapy was associated with a shorter time to PSA progression. Median PFS in patients with prior 177Lu-PSMA therapy was 5.1 months (95% CI: 3.8–6.5) compared with 16.5 months (95% CI: 14.3–18.7) in patients without therapy [32]. The negative association of prior 177Lu-PSMA therapy with survival is especially significant, and it calls for proper selection of patients to either 177Lu-PSMA or 225Ac-PSMA therapy. 225Ac-PSMA therapy will be better suited for patients with diffuse bone marrow metastasis or patients with limited baseline bone marrow reserve as the short range of the emitted alpha particles will result in a lesser absorbed dose to the limited red marrow compared with the longer-ranged beta particles of 177Lu. Since beta particles of 177Lu are incapable of an effective eradication of micrometastases due to the inverse relationship between the size of micrometastases and the energy deposited in it [23], 225Ac-PSMA may be more suitable for the treatment of smaller lesions especially if they are widespread compared with 177Lu-PSMA.

Some factors have been found to significantly impact on survival of patients with mCRPC treated with 225Ac-PSMA. In the study by Sathekge and colleagues, patients who had any PSA decline, PSA decline of 50% or more, and without prior history of chemotherapy had a significantly longer OS [32]. Factors found to be significantly associated with a longer PFS were any PSA decline, PSA decline of 50% or more, achieving an undetectable serum level following treatment, normalization of 68Ga-PSMA PET/CT following treatment and absence of prior 177Lu-PSMA therapy. Also, patients who do not respond to 225Ac-PSMA therapy despite adequate expression of PSMA glycoprotein shown as intense tracer uptake in prostate cancer metastases on 68Ga-PSMA PET/CT imaging have been reported to harbor mutations in genes responsible for the repair of DNA damage [33]. While mutations in DNA damage repair genes are generally believed to be advantageous in cancer therapy owing to the cell cycle arrest and apoptosis that is triggered by the failure to repair DNA damage [34], damage in some specific DNA repair pathways may, however, translate into radioresistant which may account for the prevalence of these mutations in patients who do not respond to 225Ac-PSMA [35]. This finding is exciting and may justify combination therapy of 225Ac-PSMA with radiosensitizers such as the inhibitors of poly ADP ribose polymerase (PARP inhibitors) in qualifying patients with mCRPC.

Sufficient expression of PSMA glycoprotein on prostate cancer lesions is an essential prerequisite to PRLT [10,11,12]. mCRPC lesions express higher levels of PSMA compared with hormone-sensitive prostate cancer lesions. In patients with mCRPC, there is significant heterogeneity in the expression of PSMA within and between lesions [36]. In lesions with heterogeneous PSMA expression, foci without PSMA expression may be outside of a 2 mm radius from foci with high expression of PSMA. The implication of this is that even with the longer path length of beta particles of 177Lu that can travel an average distance of 2 mm in soft tissue, 177Lu-PSMA treatment of such lesions will result in lack of radiation dose delivery to regions of no PSMA expression lying outside of the zone within which the “cross-fire effect” may be effective. This heterogeneity in target expression, even in lesions with intense PSMA expression, is more problematic in TAT where the path length of the alpha particle is below 0.01 mm. Unfortunately, the limited resolution of the PET system makes delineation of the within-lesion heterogeneity of PSMA expression impossible. Combined 18F-FDG PET and 68Ga-PSMA PET may be advantageous to fully characterize tumor behavior and target expression before submitting patients to PRLT [37]. Low PSMA expression or discordance between 68Ga-PSMA PET and 18F-FDG PET imaging portends poor treatment outcome [38, 39].

26.4 Toxicities of 225Ac-PSMA for PRLT of mCRPC

The short path length of alpha particles ensures that energy deposition is limited to within cancer lesions with a relative sparing of surrounding normal tissues. PSMA expression is not exclusive to prostate cancer tissues. Normal tissues such as the salivary gland, renal tubular cells, lachrymal glands, and epithelial cells of the small bowel express PSMA as well [29, 40]. Off-target binding on radiolabeled PSMA ligand such as 225Ac-PSMA is an important cause of treatment-related side effects in PRLT.

Xerostomia is the most common toxicity resulting from 225Ac-PSMA therapy. Among all normal tissues that express PSMA, the salivary glands received the highest absorbed dose during 225Ac-PSMA therapy [29]. There is an intense accumulation of radiolabeled PSMA ligand in the salivary gland due to specific and nonspecific bindings [41]. The first symptoms of xerostomia are seen within a few days after 225Ac-PSMA infusion [29]. Partial recovery may occur in patients who receive limited cycles of treatment. More cycles of 225Ac-PSMA therapy produce additive salivary gland damage resulting in severe xerostomia. In one series, 10% of patients discontinued further 225Ac-PSMA therapy due to intolerable xerostomia [31]. Severe xerostomia may sometimes be associated with dysgeusia causing anorexia and consequently, weight loss, fatigue, dyspepsia, and constipation [32]. Several interventions for either preventing or reducing the impact of xerostomia on patients’ quality of life have been proposed [42]. These interventions include external cooling of the salivary gland to reduce dose delivery to them during therapy administration [43, 44]; injection of botulinum toxin into the salivary gland to induce vasospasm and hence dose reduction to the glands [45]; and sialendoscopy with dilatation, saline irrigation, and steroid injection to reduce radiation-induced inflammation in an attempt to prevent xerostomia [46]. To date, none of these interventions has been found sufficiently effective for noninvasive application in routine clinical practice.

Other approaches have been explored in mitigating the impact of 225Ac-PSMA therapy on salivary gland function, mostly by reducing the activity the radioligand administered for therapy [22]. In the approach popularized by our group – the dynamic de-escalation approach, 8 MBq of 225Ac-PSMA is administered for the first cycle of treatment. Response is evaluated by clinical evaluation, repeat 68Ga-PSMA imaging findings, and level of PSA decline. Administered activity is reduced to 6 MBq in cycle 2 for responders. A similar re-evaluation is done before cycle 3, and administered activity is reduced to 4 MBq in responders. In essence, the activity of the therapeutic agent between 4 and 8 MBq is titrated against the volume of residual malignant disease to reduce the tumor sink effect that causes intense off-target radioligand uptake in normal tissues as the volume of malignant disease reduces. Using this approach, 85% of our most recent cohorts reported grade I/II xerostomia [32]. No treated patients had severe xerostomia (grade III), and no patient declined further treatment due to xerostomia. Other approaches to reducing the incidence and severity of xerostomia complicating PRLT include administering a cocktail of 4 GBq of 177Lu-PSMA and 4 MBq 225Ac-PSMA and administration of lower activity of 225Ac-PSMA especially since the severity of xerostomia is proportional to the activity of the radioligand administered for therapy.

Hematologic toxicity may be seen in patients treated with 225Ac-PSMA. No treatment-induced grave IV hematologic toxicity has been reported. In our series of 73 patients treated with a median of three cycles of 225Ac-PSMA, we found grade I or II anemia, leucopenia and thrombocytopenia in 22, 7, and 6 patients, respectively [32]. We found grade III anemia, leucopenia, and thrombocytopenia in 5, 2, and 1 patient, respectively. We found no grade IV hematologic toxicity. The characteristics of the study population can explain this level of hematological toxicity. Out of 73 patients included, 28 (38%) of them had diffuse bone metastases with a superscan pattern, and 30 patients (41%) had a hemoglobin level of 10 g/dL or lower [32]. All patients who had any form of grade III hematologic toxicity had an abnormal hematologic profile at baseline assessment, indicating that these patients already had an impaired bone marrow function even before they were submitted to 225Ac-PSMA therapy.

The kidneys are exposed to radiation dose from 225Ac-PSMA due to the physiological expression of PSMA in the renal tubular cells and the renal route of excretion of the radioligand. Intravenous isotonic fluids such as normal saline (about 2 L of 0.9% NaCl) is coadministered with the radioligand to enhance its urinary excretion. A baseline 99mTc-MAG3 dynamic renal scintigraphy is necessary in patients with suspected obstructive uropathy who may benefit from ureteral stenting to relief obstruction prior to PRLT [11]. Intravenous frusemide may be necessary in addition to intravenous hydration in patients with dilated renal collecting system not associated with anatomic obstruction to enhance urinary flow rate and hence absorbed dose to the kidneys [11]. In our most recent series, any renal toxicity was seen in 23 patients – 32% of all patients (grade I or II =18, grade III = 3, and grade IV = 2) [32]. Again, all five patients who had either grade III or IV renal toxicity had a grade II renal toxicity at baseline assessment before therapy with 225Ac-PSMA [32].

The lachrymal gland is another organ with high PSMA expression and at risk of radiation damage during PRLT. In our series, we reported grade I or II xerophthalmia in 5% of patients [32].

26.5 Upfront Application of 225Ac-PSMA for Therapy of mCRPC in Chemotherapy-Naïve Patients

Docetaxel was the first agent to demonstrate a survival benefit in the treatment of mCRPC [1]. Cabazitaxel was shown in 2010 to have a survival benefit in men who progressed after docetaxel and has since been one of the second-line agents for the treatment of men with mCRPC [2]. Abiraterone and enzalutamide, two agents that act on the androgen signaling pathway, are other drugs with life-prolonging capabilities that are commonly applied in patients with mCRPC [3, 4]. In real-world practice, docetaxel was the most commonly used agent for first-line therapy of mCRPC before 2010. Beyond 2010, non-chemotherapeutic agents are increasingly used as the first-line agent for mCRPC [47]. This shift in the choice of agent is most probably related to the better safety profile of the non-chemotherapeutic agents acting on the androgen receptor/signaling pathway. Elderly patients aged 75 years and older also tend to have significantly more high-grade and fatal treatment-related toxicities when treated with docetaxel [48]. There is still no consensus on the sequence to apply the currently available agents for mCRPC treatment as a result of the absence of head-to-head comparisons of these agents in randomized clinical trials (RCTs). Results from large observational studies and systematic reviews of published studies are emerging to define the better sequence of application of the available agents for mCRPC [49, 50]. It is crucial to determine the most effective treatment sequence so that the most effective agent is applied earlier in the therapy sequence since the response to agents applied later in the sequence are generally less remarkable. Safety is another critical factor to be considered in the sequencing of therapy agents so that the most effective and, equally important, the safest agent is applied earlier to preserve and prolong quality life.

A randomized control trial (RCT) is required to define the efficacy and the place of any therapy intervention in medical practice. Results from RCTs evaluating the efficacy, safety, and the place PRLT either with 177Lu-PSMA or 225Ac-PSMA are still being awaited. It is also worth noting that a comparison of results from different RCTs is difficult due to the differences in the patient populations in the different trials. Many insights can be gained from the published retrospective observational studies that have reported the safety and efficacy of 225Ac-PSMA in mCRPC treatment. In the absence of an RCT, a Swimmer plot analysis is a useful pictorial representation of the duration of tumor control in an individual treated with different agents. In the series by Kratochwil and colleagues, using a Swimmer plot analysis, the authors show that 225Ac-PSMA used as a last-line agent performed better or similar to agents applied as the first-, second-, and third-line treatments [31]. This suggests that, perhaps, if applied earlier in the course of the disease, 225Ac-PSMA could have provided a longer duration of disease control than the currently approved agents.

In a study of 225Ac-PSMA therapy in chemotherapy-naïve patients, Sathekge and colleagues reported a PSA decline of 90% or more in 82% of patients and a PSA decline of ≥80% seen in 71% of patients after the first cycle of 225Ac-PSMA administered for mCRPC [51]. In 41% of patients, PSA declined to undetectable levels after two to three cycles of 225Ac-PSMA and remained undetectable for a median of 12 months posttreatment. Tolerable xerostomia was seen in all patients treated, but no patients withdrew from this treatment due to this side effect. No statistically significant decline was seen in the pretreatment versus posttreatment leucocyte count, hemoglobin level, serum creatinine level, or serum albumin level [49]. Docetaxel given in the same setting led to a PSA decline of ≥50% in 45% to 48% of patients with a median duration of PSA response of 7.7 to 8.2 months [1]. Docetaxel is significantly associated with neutropenia, alopecia, diarrhea, sensory neuropathy, dysgeusia, stomatitis, among other treatment-related toxicities warranting discontinuation of treatment in some patients [1]. Cabazitaxel is another chemotherapeutic agent with a survival benefit in mCRPC in the post-docetaxel setting. Used as a second-line agent in the post-docetaxel setting, cabazitaxel led to a ≥ 50% PSA decline in 39.2% of patients with a median time to PSA progression of 6.4 months [2]. Like docetaxel, cabazitaxel caused significant bone marrow toxicity causing any-grade neutropenia and anemia in more than 90% of patients treated. The severity of side effects led to treatment discontinuation in 18% of patients treated with cabazitaxel [2].

While the evidence from controlled trials in support of the use of 225Ac-PSMA in TAT of mCRPC is being awaited, the available data are already showing good efficacy and tolerability in patients treated in critical clinical situations [28,29,30,31, 52]. Here we make a case for the compassionate consideration of the use of 225Ac-PSMA in chemotherapy-naïve patients who may be considered unfit or have refused chemotherapy because of its potential side effects or other consideration, especially if they have previously failed therapy with the novel agents targeting the androgen receptor/signaling pathway (Fig. 26.1). In this setting, 225Ac-PSMA therapy is associated with better PSA response, longer duration of tumor control, better safety profile, and a survival advantage when compared, in an intra-individual fashion or with historical control, against the currently approved life-prolonging agents. While not the subject of discussion in this review, it is worthy to note that similar upfront application 177Lu-PSMA in the chemotherapy-naïve setting is associated with a better response than its application post-taxane chemotherapy [15]. In the work from Bad Berka, Barber and colleagues showed that taxane-naïve patients had significantly better survival with a median PFS and OS of 8.8 months and 27.1 months, respectively, compared with taxane-pretreated patients whose corresponding PFS and OS were 6.0 months and 10.7 months, respectively [15].

Fig. 26.1
3 illustrations of radiotherapy were given in March 2018, May 2018, and July 2018. The given dose has decreased progressively in the upcoming months of therapy.

A 76-year-old male treated with two cycles of 225Ac-PSMA-617 therapy in March and May 2018. He is known with a large cystic mass in the right kidney. His treatment history included androgen-deprivation therapy and radiotherapy to the spine. He had a remarkable response to 225Ac-PSMA-617 and his serum PSA has remained undetectable to date

Full size image

26.6 Conclusion and Future Perspectives

In recent times, many agents with the ability to prolong life are now available for routine clinical application in the treatment of men with mCRPC. This widespread availability of treatment options has not translated to consistent more prolonged survival in all climes. More agents, including immunotherapies, drugs targeting oncogenic and genomic pathways, and radionuclide therapies, are being evaluated for their efficacy and safety in mCRPC. Even with the available agents, the sequence to apply drug treatment for the most effective response and most prolonged survival is still a subject of research. TAT with 225Ac-PSMA has shown excellent PSA response, clinical symptom control, and tolerable side effects. It is believed that this excellent performance may be confirmed in controlled trials soon. The understanding of tumor biology is broadening, especially in the late-stage disease where genomic instability and mutations in multiple DNA repair genes are prevalent and drive resistance to therapy. This broadening understanding is providing insight that may guide the future application of combination therapies to attack multiple cancer targets reasonably and safely for effective therapy of mCRPC. 225Ac-PSMA, currently applied as a last-line agent, holds much promise to get a front-line application in the future owing to its excellent efficacy that compares with currently approved agents and its tolerability. Efforts must continue to address salivary gland toxicity. This may be in the form of ligand modification to improve specificity for tumor target, reduce administered activity in combination therapy with other effective agents, or effective pharmacologic salivary gland protection.

Special Paragraph for Prof Rich Baum

Dear Rich and Julitta,

Rich, you are one of the greatest leaders of Nuclear Medicine, I admire and appreciate your achievements and the time you have invested with regards to promoting targeted radionuclide imaging and therapy. To me you have always been a big brother, friend and mentor. I am grateful you are an encouragement, inspiration, and motivation. Julitta and you have always shown me the WARMTH and kindness. I thank you so kindly for making me part of the memorable “Festschrift in Honor of Prof. Baum.”

Big Hugs!!!

Mike

A photo of Professor Richard Baum with his colleagues.