The incidence of prostate cancer is ever increasing. After various time intervals, the disease almost always becomes resistant to the standard hormone treatment (castration-resistant prostate cancer, CRPC). Most patients with CRPC either already have metastases at diagnosis or develop them during the early months of follow-up, which is associated with a relatively poor prognosis. The taxane-based chemotherapy for metastatic CRPC (mCRPC), first line with docetaxel and second line using cabazitaxel, are associated with a high incidence of adverse effects. The novel androgen-axis drugs (NAAD) used after chemotherapy are androgen biosynthesis inhibitor abiraterone acetate (combined with prednisolone), the androgen receptor blockers enzalutamide as well as the newer generation apalutamide and darolutamide. However, these treatment regimens only provide a meager survival benefit in mCRPC. Radium-223 targets only the osteoblastic metastases and does not treat nodal or visceral metastases. Therefore, there has been an unmet need for targeted therapy.

Indeed, rightly called by Prof. Baum as molecule of the decade, prostate-specific membrane antigen (PSMA) is a glutamate carboxypeptidase II overexpressed in prostate cancer. Although it has been identified many decades ago, PSMA was targeted by Prof. Pomper’s group for the first time in vivo using a urea-based compound targeting PSMA for diagnosis [1]. A milestone in precision oncology was theranostics of mCRPC based on molecular imaging using PET/CT with 68Ga-labeled PSMA ligands and molecular radiotherapy using PSMA-targeted radioligand therapy (PRLT) with beta-emitter (like Lutetium-177, 177Lu) and alpha-emitter (like Actinium-225, 225Ac)-based PSMA ligands [2,3,4,5]. PRLT involves selective targeting of PSMA using the radioligand, which then after specific binding, internalizes and retains within the tumor cell, causing the cell-killing.

177Lu-PRLT was first performed at Zentralklinik Bad Berka in February 2013 using 177Lu-labeled DOTAGA-FFK(Sub-KuE) – developed by Prof. Wester’s research group at the Technical University Munich (Fig. 18.1). Following this, PRLT was performed using the 177Lu-labeled therapeutic PSMA ligand (DOTAGA-(I-y)fk(Sub-KuE), also called PSMA I&T, for “imaging and therapy”) in a large cohort of patients. The comprehensive experience over the past 8 years using different radioligands since then indicates that PRLT is highly effective for the treatment of mCRPC, even in advanced cases, and potentially lends a significant benefit to overall and progression-free survival. Additionally, significant improvement in clinical symptoms and excellent palliation of pain can be achieved. It is safe and very well tolerated with minimal and acceptable adverse effects, including in patients with single kidney/renal insufficiency as well as previously compromised bone marrow function, for example, due to diffuse metastases [3,4,5,6]. 68Ga-PSMA PET/CT can be used for appropriate selection and follow-up of patients undergoing PRLT through the application of the concept of theranostics – we treat what we see, and we see what we treat.

Fig. 18.1
9 radiographs of the CT and PET CT scans of the patient with multiple tumors in the region of the heart, kidney, and bone. Fluorescence is present in the area of the tumor.

This 68-year-old patient with acinar prostate adenocarcinoma of the left lateral lobe with infiltration of the periprostatic tissue, initial tumor classification pT3a pN0 (0/5) L1 V1 PR1, Gleason score 6 (3 + 3), first diagnosed in 10/2004, status post surgery, radiotherapy, hormone-, and chemotherapy presented with increase in PSA (63.41 ng/mL from previously 10.35 ng/mL) for follow-up. The 68Ga-PSMA PET/CT demonstrated progression of disease with high PSMA expression in numerous new mediastinal and abdominal lymph node involvement, multiple pulmonary and trifocal osseous metastases, thereby confirming the indication for PSMA radioligand therapy (PRLT). He was the first patient treated at our center in February 2013 using 177Lu- DOTAGA-FFK(Sub-KuE). (a, maximum intensity projection (MIP) image of 68Ga-PSMA PET/CT; b, c, d, e, corresponding axial CT (upper panel) and fused PET/CT (lower panel); b, left retroclavicular lymph node; c, right obturator lymph node; d, pulmonary metastasis; e, bone metastasis)

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The patients currently receive PRLT under individual compassionate basis after exhaustion of the standard treatment options, i.e., following chemotherapy and NAAD. However, at this stage, the disease is already at a very advanced stage and possibly with aggressive mutants. Therefore, these patients are already at a disadvantage, receiving PRLT as a last-ditch effort. We demonstrated for the first time the benefit of providing earlier 177Lu PRLT to patients with metastatic prostate cancer [7]. The median overall survival in all patients was 27 months. Patients previously treated with chemotherapy had a significantly shorter survival (median of 19 months) than those not having received chemotherapy (38 months). Survival was also shorter in patients with previous radium-223 (223Ra) treatment (17 months). On the other hand, prior surgical or radiation treatment of the primary tumor had no significant effect on overall survival. Patients demonstrating a PSA decline of more than 50% after at least two PRLT cycles, lived significantly longer (38 months). In fact, additional treatment with newer antiandrogen agents Abiraterone or Enzalutamide in combination with 177Lu PRLT also prolonged survival. PRLT is a promising therapy with encouraging outcomes and minimal associated toxicity, also chemotherapy-naïve patient cohorts [8]. First retrospective data from an earlier application of Lu-177 PSMA in the hormone-sensitive stage of the disease showed even better response rates [9]. In 11 patients with metastatic prostate cancer without previous anti-hormonal therapy or orchiectomy (so-called “de novo RLT”) could be a PSA drop >50% in 9/11 patients (82%) and tumor control (DCR) can be achieved in 100% of patients (CR 1/11, PR 4/11, SD 6/11). First-line therapy was associated with the longest survival (all patients alive at 55 months).

We had addressed the issue of potential salivary gland toxicity in two of the initial patients treated with PRLT. The salivary glands were cooled using a special radiotherapy shield. However, no significant difference was observed in the salivary gland uptake in these patients, as compared to those treated without salivary gland protection. This can be explained by a rather non-specific tracer accumulation and a possible reflex hyperperfusion, which negates the whole purpose of trying to reduce the uptake due to vasoconstriction [10]. Indeed, a systemic analysis failed to prove the benefit of external salivary gland cooling using icepacks, as a means of salivary gland protection [11]. In 2018, our group could demonstrate the first proof-of-concept of a nonspecific tracer accumulation, where injection of botulinum toxin into a parotid gland achieved a 64% decrease in 68Ga-PSMA uptake ipsilaterally (Fig. 18.2, [12]).

Fig. 18.2
4 PET and C T scans of the patient with multiple tumors. An area with a speckled pattern is present in the chest cavity. The organs with higher metabolism are highlighted as well.

A 56-year-old patient with Gleason 9 metastatic castration-resistant prostate cancer s.p. cabazitaxel and enzalutamide progressed under 177Lu-PRLT. (a, b, c, d, MIP images of 68Ga-PSMA PET/CT; a, b, c demonstrate progression before first PRLT (a, PSA 0.93 ng/mL), after 2nd (b, PSA 11.2 ng/mL) and after third PRLR (c, PSA 137 ng/mL). After administration of the first tandem PRLT in January 2018 using a combination of 4.5 GBq 177Lu- and 5 MBq of 225Ac-PSMA-617. A good response to TANDEM PRLT was observed with partial remission of the multiple metastases. It is important to note that the PSA does not correlate with the tumor burden

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In our experience of about 500 patients treated with around 2000 cycles of 177Lu-PRLT over almost 8 years, there has been no significant xerostomia when using 177Lu alone. Although 177Lu is relatively safe, there are treatment failures, especially in more advanced tumors. Alpha emitters like 225Ac are more potent as they cause more frequent DNA double-strand breaks due to their high linear energy transfer as compared to beta emitters like 177Lu. However, xerostomia is a limiting adverse effect of 225Ac-PRLT, due to which patients discontinue the treatment [13]. In January 2018, we successfully administered the first tandem PSMA radioligand therapy, applying a combination of 225Ac-PSMA-617 and 177Lu-PSMA-617, in a patient who had progressed under 177Lu-PSMA-617 monotherapy (Fig. 18.2). The proposal was that administering a relatively lower radioactivity of the alpha emitter 225Ac-PSMA-617 to that already reported by the Heidelberg group [13], in addition to the beta emitter, might minimize the potential xerostomia because of the salivary gland irradiation by the alpha particles, while at the same time probably prove therapeutically effective (synergistic emission characteristics). In a very promising first analysis, 13/16 patients (82%) showed a biochemical response. In 3 cases, there was a PSA drop>99% [14]. The pain symptoms improved significantly in 8/16 patients with one very impressive improvement of the Karnofsky index (this, at the time of first presentation, wheelchair-bound patient, drove 1200 km himself for the second treatment). No serious xerostomia (but moderate and tolerable) was observed, which could have otherwise caused the treatment to be discontinued. Thus, tandem PRLT could be demonstrated as a fair compromise between effectiveness and side effects of alpha PRLT alone.

Like any other strategy in oncology, the stress should be on combination therapies, best selected depending upon tumor- and patient-specific factors. Quite early on in combination with PRLT, we treated 1 patient with an aggressive treatment-resistant prostate cancer with immune check-point inhibitor Nivolumab, and another was treated with the PARP inhibitor Olaparib. However, both these patients experienced severe side effects – esophagitis and bone-marrow suppression, respectively, causing treatment discontinuation. Indeed, a recent report suggests promise of this strategy in selected patients [15].

In a pilot study, we reported for the first time, a high frequency (35.8%) of germline mutations in a larger patient cohort referred for PRLT. The CHEK2 germline mutations seemed to be associated with the best PSA response. The treatment outcome appeared to not correlate with the presence of radiosensitizer (FANCA, BRCA1, ATR) or historically prognosis-determining (HOXB13 or BRCA2) germline gene variants [16]. The future of PRLT and precision radiomolecular oncology of prostate cancer lies in pharmacogenomics, metabolomics, and radiomics with the aim of selecting the right therapy at the right time for the patient.

Thank you, Prof. Baum, for the support, encouragement, and privilege of working with you. A great visionary, brilliant clinician, and an immaculate teacher and orator, your lectures have had long-lasting impression on thousands of minds like mine. Always up to date with preclinical research to promote clinical translation, there is always this strive to take the field of theranostics forward and to go out of the way to find the best possible treatment for the individual patient – ‘Aut viam inveniam aut faciam’ probably sums up the motto of your life!