Method of treating cancer with radioligand therapy (RLT)

Abstract

The present disclosure relates to a method of treating cancer with radioligand therapy (RLT) 5 comprising determining the circulating tumor DNA fraction (ctDNA%) on treatment and / or the ctDNA% dynamics at early treatment phase, and adapting the continued therapy based on the observed extent of ctDNA response.

Description

[0001] PAT060004-PCT-SEC01

[0002] - 1 -

[0003] METHOD OF TREATMENT

[0004] Description

[0005] FIELD OF THE INVENTION

[0006] The present disclosure relates to a method of treating cancer, in particular prostate cancer, with radioligand therapy (RLT), in particular comprising the radioligand therapeutic agent [177Lu]Lu-PSMA-617, comprising determining the circulating tumor DNA fraction (ctDNA%) on treatment and / or the ctDNA% dynamics at early treatment phase, and adapting the continued therapy based on the observed extent of ctDNA response.

[0007] BACKGROUND OF THE INVENTION

[0008] Radioligand therapy (RLT) and the need for biomarker

[0009] Despite proven clinical success of RLT, e.g. based on LUTATHERA ([177Lu]Lu-Dotatate) or PLUVICTO ([177Lu]Lu-PSMA617), there are still a non-negligible portion of cancer patients that is not responding sufficiently to said RLT. Therefore, there is a need to find reliable prognostic and response biomarkers that can assist in the treatment decision process.

[0010] The concepts of RLT are laid out in some more detail in the following based on PLUVICTO in PSMA-positive prostate cancer.

[0011] Prostate cancer

[0012] Prostate cancer is the second leading cause of cancer mortality in United States (US) and the third leading cause of cancer-related death in Europe in men (Malvezzi et al 2019, Siegel et al 2017). An estimated 1.1 million men worldwide were diagnosed and 307,000 died due to prostate cancer in 2012. Almost 70% of the diagnosed cases are in more developed regions due to the use of prostate-specific antigen (PSA) testing, but there is only modest variation in mortality rates globally which is driven by metastatic, and often castration-resistant disease (Bray et al 2012).PAT060004-PCT-SEC01

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[0014] There is an urgent need for more effective treatments to improve outcomes for participants with metastatic castration-resistant prostate cancer (mCRPC). The median age at diagnosis of mCRPC is 70 years (Flaig et al 2016). Once participants reach the mCRPC stage, their expected overall survival is low as was seen in the randomized phase 3 study of cabozantinib vs prednisone in men with mCRPC who had received prior docetaxel and abiraterone acetate and / or enzalutamide; the median overall survival of the prednisone control arm was 9.8 months (Smith et al 2016). In addition, there are significant comorbidities associated with mCRPC. Approximately 90% of mCRPC participants develop bone metastases (Kirby et al 2011) and 49% of them will develop a serious skeletal event within 2 years (Saad et al 2004). As a result, common presentations include bone pain, bone marrow failure, fatigue, or complications such as fractures and cord compression. These presentations typically require radiation or bone surgery, which can significantly impair physical, emotional, and functional well-being (Weinfurt et al 2005). These participants, can be extremely symptomatic and at risk of serious oncological complications. There can be a considerable challenge in the clinic due to the symptoms of metastatic soft tissue and visceral disease, general frailty and bone marrow impairment.

[0015] Four main drug classes have been approved for treatment for prolonging survival in mCRPC participants. These include ARDTs (i.e., abiraterone and enzalutamide), taxanes (docetaxel and cabazitaxel), immunotherapy (sipuleucel-T) and bone-targeted radiopharmaceutical (radium 223 dichloride). With the evolution in the treatment landscape of prostate cancer, some of these life-prolonging therapies (ARDT and docetaxel) are increasingly used in earlier stages (e.g. metastatic hormone sensitive prostate cancer and non-metastatic prostate cancer). This creates an even greater unmet medical need in mCRPC. Among participants who have previously received an ARDT therapy, several mechanisms have been implicated in development of resistance to the treatment (Attard et al 2009). The rPFS for participants that change ARDTs ranges from 3.6 to 15 months and OS from 11 to 23 months (de Bono et al 2020, de Wit et al 2019, Komura et al 2019). On the other hand, many participants do not receive chemotherapy primarily because of preexisting medical conditions or associated toxic effects. (Harris et al 2011, Engel Nitz et al 2011, Lissbrant et al 2013, Zielinski et al 2014). Sipuleucel-T is best used in mildly asymptomatic small volume disease; and radium 223 is used to treat men with bone-only disease. PARP inhibitors are an emerging drug class in mCRPC, but their use is restricted in a subgroup of mCRPC participants with homologous recombination repair gene mutations [PROfound (de Bono et al 2020, Hussain et al 2019) and TRITON2 (Abida et al 2019) studies].PAT060004-PCT-SEC01

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[0017] Prostate-specific membrane antigen

[0018] Prostate-specific membrane antigen (PSMA) is a transmembrane protein, also known as folate hydrolase or glutamate carboxypeptidase II. PSMA is highly overexpressed in nearly all prostate cancers, but has restricted and several hundred-fold lower expression in some normal tissues such as the duodenal mucosa, proximal renal tubules, and salivary glands (Bostwick et al 1998, Ghosh et al 2004), (Mannweiler et al 2009). Additionally, PSMA overexpression also correlates with advanced, high-grade, metastatic, androgen-independent disease (Ross et al 2003). The differential expression of PSMA from tumor to non-tumor tissue has resulted in numerous targeted strategies involving both disease localization using radioactive imaging as well as therapeutic intervention, and therefore may be an attractive target for men with mCRPC.

[0019] In addition to the expression pattern, the functionality of PSMA plays an equally important role in its value as a tumor-specific targeting mechanism. Specifically, the binding of a high affinity ligand to PSMA, such as the targeting moiety in 177Lu-PSMA-617, leads to internalization through endocytosis and a sustained retention of the ligand and its bound radioactive cargo within the cancer cell (Rajasekaran et al 2003). This functional feature of PSMA allows for the development of low-molecular-weight targeted radiopharmaceuticals with favorable pharmacokinetic and tumor penetration properties, rather than being restricted to antibodybased targeting strategies (Haberkorn et al 2016).

[0020] The result of both selective expression and ligand-based uptake using PSMA as a target is a reduction in background uptake and off-target toxicities as well as an increase in the amount of radioactivity that localizes at the tumor site.

[0021] 177Lu-PSMA-617 mechanism of action

[0022] The novel PSMA-targeted radioligand therapy 177Lu-PSMA-617 consists of the PSMA-binding ligand glutamate-urea-lysine and a DOTA-chelator, which are connected by a naphthyl and cyclohexyl containing linker. By design, 177Lu-PSMA-617 exhibits high PSMA binding affinity and internalization, prolonged tumor retention, and rapid kidney clearance (Benesova et al 2015). PSMA-617 was uniquely developed for both imaging and radio ligand therapy of prostate cancer and can be radiolabeled with gallium-68 (68Ga), lutetium-177 (177Lu), indium-111, copper-64, scandium-44, actinium-225, or yttrium-90.PAT060004-PCT-SEC01

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[0024] 177Lu, the radioactive cargo being delivered by PSMA-617, has physical properties that make it an appropriate radionuclide for the treatment of mCRPC. 177Lu is a medium energy P emitter (490 ke V) with a maximum energy of 0.5 Me V and a maximal tissue penetration of < 2 mm. The shorter p - range of 177Lu provides better irradiation of small tumors, in contrast to the longer P-range of 90Y (Emmett et al 2017). The shorter path length also acts to direct the energy within the tumor rather than in the surrounding normal tissues, while the path length is still sufficient to create bystander and crossfire effects within the tumor lesion. 177Lu has a relatively long physical half-life of 6.6 days that combines with the intratumoral retention of 177Lu-PSMA-617 to reduce the necessary dosing frequency. It is these physical properties, and the benefit of PSMA targeting, that allow for the delivery of effective activities of 177Lu to prostate cancer cells.

[0025] 177Lu-PSMA-617 for metastatic castration-resistant prostate cancer

[0026] The novel therapeutic drug 177Lu-PSMA-617 was developed by the German Cancer Research Center, Deutsches Krebsforschungszentrum (DKFZ) in collaboration with University Hospital Heidelberg for the treatment of participants with metastatic prostate cancer (Hillier et al 2009, Kratochwil et al 2015, Kulkarni et al 2018c).

[0027] PSMA binding affinity and compound internalization, prolonged tumor uptake, rapid kidney clearance, and high tumor-to-background ratio, 177Lu-PSMA-617 proceeded into clinical development at investigative sites in Germany.

[0028] Data evaluations based on compassionate use according to the German Medicinal Product Act, AMG §132b, Clinical Trial Notification (Australia) regulations, and other countries where expanded access programs are in place per local regulations, reported a favorable safety profile and promising results for PSA response rates of systemic radioligand therapy with 177Lu-PSMA- 617 in participants with mCRPC.

[0029] Dosimetry data suggest that 177Lu-PSMA-617 is targeted to PSMA-expressing tissue, which may include the salivary glands, kidneys, and small and large bowel. The highest exposure is to salivary glands; however in the prospective study xerostomia appears low grade and occurs at a rate of approximately 87% in treated participants. Clearance of 177Lu-PSMA-617 from the kidney occurs rapidly. To date nephrotoxicity has not been notable in any safety series. There are no reports of Grade 3 / 4 nephrotoxicity in the literature. The exposure to normal bone marrow tissue is predictably low as it does not express PSMA and corresponds with normal plasma clearance.PAT060004-PCT-SEC01

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[0031] There was some evidence of reversible hematological toxicity that occurred following 177Lu-PSMA-617 treatment that manifested as leukopenia and thrombocytopenia, with rates of 0 to 40% and 4% to 67% respectively.

[0032] The first published clinical series of 177Lu-PSMA-617 consisted of 10 participants (Ahmadzadehfar et al 2015) treated between Nov-2013 and Jan-2014, with 5.6 GBq / 150 mCi (4.1-6.1 GBq / 110-165 mCi). PSA decline > 50% occurred in 50% of participants, which increased to 60% after 2 cycles of 6 GBq / 160 mCi (4.1-7.1 GBq / 110-190 mCi). The level of PSA decline > 50% (most commonly used to assess tumor response in these studies) has remained remarkably consistent across several clinical series when 2 or more doses of ~6 GBq / 160 mCi are given. Hofman presented the first prospective open-label, single-arm, nonrandomized Phase 2 study of 177Lu-PSMA-617 in 50 metastatic castration-resistant prostate cancer participants dosed with up to 4 cycles of 4-8 GBq / 110-220 mCi administered every 6 weeks (Hofman et al 2018, Hofman et al 2019). The primary endpoints of this study were to evaluate both safety and efficacy, as measured by PSA response, bone pain score, quality of life measurements, imaging response and survival.

[0033] Of the screened participants, 70% were identified as PSMA-positive via PET imaging and eligible for treatment. Participants had been exposed to at least 1 taxane chemotherapy and either abiraterone or enzalutamide in the mCRPC setting. In this heavily pre-treated participant population with few therapeutic alternatives, 64% of participants on 177Lu-PSMA-617 showed a PSA response defined by a reduction in PSA of at least 50%, and 44% had a reduction of PSA of 80% or more. In 27 participants with measurable disease, the objective response rate in measurable disease as defined by RECIST criteria was 56% (complete response [CR] and partial response [PR]). Median overall survival was 13.3 months (95% confidence interval [Cl] 10.5-18.0). Therapy with 177Lu-PSMA-617 was well tolerated. These safety and efficacy data also translated into significantly improved quality of life scores and reduction in pain scores. More recently Hofman presented the first randomized prospective open-label Phase-ll study of 177Lu-PSMA-617 vs cabazitaxel in 200 docetaxel progressing metastatic castrationresistant prostate cancer. Participants dosed with up to 6 cycles of 177Lu-PSMA-617 (Hofman 2020). The primary endpoint was PSA response, defined as > 50% reduction in PSA from baseline. Secondary endpoints, included PSA progression-free survival, overall survival, and quality of life.

[0034] This first ever randomized study, showed that a significantly greater proportion of patients on 177Lu-PSMA-617 (66%) had a PSA decline >=50% compared to cabazitaxel (37%) (P<0.0001).PAT060004-PCT-SEC01

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[0036] In summary, over 40 compassionate use publications and prospective Phase 2 clinical trial data describe the use of 177Lu-PSMA-617 in participants who have been exposed to approved agents. In the post-taxane, post-androgen axis inhibitor setting 177Lu-PSMA-617 has demonstrated a well-established, predictable, well tolerated safety profile. Clinical series indicate the most common side effects, predominately Grade 1-2, of 177Lu-PSMA-617 treatment are dry mouth, nausea, vomiting, diarrhea, constipation, fatigue, anemia, thrombocytopenia and neutropenia. The incidence of Grade 3 / 4 toxicity in the series were very low, and mainly restricted to reversible hematological events. Efficacy has been demonstrated on multiple clinically significant endpoints, including PSA response, soft tissue lesion response measured by RECIST, progression-free survival (PFS), OS, pain and quality of life. No standard dose and schedule have been developed.

[0037] VISION (NCT03511664), a phase III trial evaluating best standard of care with or without 177Lu-PSMA-617 in men who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor-pathway inhibitor and one or two taxane regimens and who had PSMA-positive Gallium (68Ga) gozetotide ([68Ga]Ga-PSMA-11) positron emission tomographic-computed scans. VISION was designed as a registration trial for 177Lu-PSMA-617 with alternate primary endpoints of radiographic progression-free or overall survival. Key secondary endpoints were objective response, disease control, and time to symptomatic skeletal events.

[0038] 177Lu-PSMA-617 plus standard care significantly prolonged (Sartor et al 2021), as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [Cl], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% Cl, 0.52 to 0.74; P<0.001). All the key secondary end points favored 177Lu-PSMA-617. Among the 248 patients who had measurable target lesions according to RECIST, version 1.1, on independent central review at baseline, a complete response was noted in 17 of 184 patients (9.2%) in the 177Lu-PSMA-617 group and in none of the 64 patients in the control group. A partial response was noted in 77 patients (41.8%) in the 177Lu-PSMA-617 group and in 2 (3%) in the control group.

[0039] Treatment with 177Lu-PSMA-617 was associated with a low incidence of adverse events that led to dose reduction, interruption, or discontinuation. As of 27-Jan-2021, patients that received at least one dose of randomized treatment were 734 and included in the safety analysis. Of them, 519 patients (98.1%) and 170 (82.9%) reported at Treatment-emergent adverse events (TEAEs), in the 177Lu-PSMA-617 group and the control group, respectively. The incidence ofPAT060004-PCT-SEC01

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[0041] adverse events of grade 3 or above was higher with 177Lu-PSMA-617 group than control group (52.7% vs. 38.0%), but quality of life was not adversely affected. The most common treatment-emergent adverse events (TEAEs), being reported in > 12% of patients who received at least 1 dose of study therapy were fatigue (43.1% vs. 22.9%), dry mouth (38.8% vs. 0.5%), nausea (35.3% vs. 16.6%), anemia (31.8% vs. 13.2%), back pain (23.4% vs.

[0042] 14.6%), arthralgia (22.3% vs. 12.7%), decreased appetite (21.2% vs. 14.6%), constipation (20.2% vs. 11.2%), diarrhea (18.9% vs. 2.9%), vomiting (18.9% vs. 6.3%), thrombocytopenia (17.2% vs. 4.4%), lymphopenia (14.2% vs. 3.9%), leukopenia (12.5% vs. 2.0%) in the 177Lu-PSMA-617 group and the control group respectively (Sartor et al 2021)

[0043] Additionally, 177Lu-PSMA-617 plus SOC delayed time to worsening in health related quality of life (HRQoL) and pain, and delayed the time to first symptomatic skeletal event versus standard care alone in adults with advanced mCRPC (K. Fizazi et al 2021).

[0044] Despite the success of 177Lu-PSMA-617 in the VISION trail, i.e. in the post-taxane setting, it will need to be determined whether 177Lu-PSMA-617, given for up to 6 cycles at a dose of 7.4 GBq (200 mCi) + / - 10% improves the radiographic progression free survival (rPFS) or death compared to a change in treatment of androgen receptor-directed therapy (ARDT) in metastatic castrate resistant prostate cancer (mCRPC) participants that are previously treated with another ARDT but have not been exposed to a taxane-containing regimen in the CRPC or mHSPC settings and whether the data from such a clinical study support a label expansion of 177Lu-PSMA-617 as a treatment in mCRPC prior to the use of taxanes.

[0045] The vast majority of patients diagnosed with CRPC already present with metastases at time of diagnosis4, patients with metastatic prostate cancer have an approximate 3 in 10 chance of surviving 5 years. Despite recent advances, outcomes for those who progress after standard of care second-generation ARPI remain poor, and there is an urgent need for new targeted treatment options to help improve long-term outcomes.

[0046] SUMMARY OF THE INVENTION

[0047] The present disclosure is based on the findings from pivotal Phase III PSMAfore study with Pluvicto (INN: lutetium (177Lu) vipivotide tetraxetan), a prostate-specific membrane antigen (PSMA)-targeted radioligand therapy, including the biomarker evaluations. PluvictoPAT060004-PCT-SEC01

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[0049] demonstrated a statistically significant and clinically meaningful improvement in radiographic progression-free survival (rPFS) in patients with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) after treatment with androgen-receptor pathway inhibitor (ARPI) therapy, compared to a change in ARPI. No unexpected safety findings were observed in PSMAfore; data are consistent with the already-well established safety profile of Pluvicto.

[0050] The present disclosure provides the certain Phase III data of the PSMAfore trial.

[0051] Based on the data of the present disclosure, Pluvicto becomes the first radioligand therapy to demonstrate the beneficial effects of ctDNA fraction, in particular comprising the ctDNA fraction at day 1 of cycle 2 (C2D1), as prognostic, predictive, and response biomarker in a pivotal trial.

[0052] The on-treatment time point C2D1 provides the advantages over the baseline or over later timepoints (e.g. C3D1), that it is stronger associated with the therapy response, thus, more predictive / prognostic, and at the same time still rather early in the course of the therapy so that at a still early timepoint the continuation of the therapy can be (re-)considered.

[0053] The present disclosure provides method of treatments in the following aspects:

[0054] A method of treating cancer with radioligand therapy (RLT) in a patient in need thereof;

[0055] wherein said method comprises the steps of:

[0056] (1) Optionally, before starting with the RLT, taking a blood sample from said patient for determining the circulating tumor DNA fraction (ctDNA%) (i.e. baseline ctDNA%);

[0057] (2) Administering to said patient a certain specified first dose of a radioligand therapeutic agent (RLT agent);

[0058] (3) Taking a blood sample from said patient for determining the ctDNA% (i.e. on- treatment ctDNA%);

[0059] (4) Optionally, administering to said patient a certain specified second dose of said RLT agent;

[0060] (5) Continuing with the administration of further specified doses of the RLT agent in the “ctDNA response” cases of:

[0061] (i) the on-treatment ctDNA% is non-detectable (ND) or not exceeding a certain threshold (e.g. <0.5%), and / orPAT060004-PCT-SEC01

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[0063] (ii) there is a fractional decrease in the ctDNA from baseline to on- treatment, preferably, the decrease is from detectable (D) to ND or the decrease is from above a certain threshold to below said threshold (e.g. from >0.5% to <0.5%), or the ctDNA% is both, at baseline and on- treatment, ND or not exceeding a certain threshold (e.g. <0.5%); but discontinuing the administration of further amounts of the RLT agent and starting with an escalation therapy in the “ctDNA non-response” cases of: (iii) the on-treatment ctDNA% is detectable (D) or exceeding a certain threshold (e.g. >0.5%); and / or

[0064] (iv) there is no fractional decrease in the ctDNA from baseline to on- treatment.

[0065] In a further aspect, the present disclosure provides the use of the plasma ctDNA fraction of day 1 of cycle 2 (C2D1) of an RLT as prognostic and / or repsone biomarker.

[0066] Preferably, said radioligand therapeutic agent is [177Lu]Lu-PSMA-617 (lutetium (177Lu) vipivotide tetraxetan, commercially available under the brand name PLUVICTO) at a dose of 7.4 ± 10% GBq at the time of administration, the cancer is mCRPC, the baseline ctDNA% is of pre-dose C1D1, the on-treatment ctDNA% is of pre-dose C2D1, and a cycle is of 6 weeks (7.4 ± 10% GBq q6w, once every 6 weeks, up to 6 cycles).

[0067] BRIEF DESCRIPTION OF THE DRAWINGS

[0068] FIG. 1: Design of the PSMAfore clinical trial.

[0069] FIG. 2: PSMAfore study design: Patients were randomized 1:1 to 177Lu-PSMA-617 (7.4 GBq [200 mCi] ± 10% once every 6 weeks for 6 cycles) or ARPI change (abiraterone or enzalutamide).

[0070] FIG. 3: Higher ctDNA fraction was associated with worse rPFS and OS in individual Cox regression models,177Lu-PSMA-617 arm.PAT060004-PCT-SEC01

[0071] - 10 - FIG. 4: Lower baseline and C2D1 ctDNA fraction was associated with higher frequency of RECIST response,177Lu-PSMA-617 arm.

[0072] FIG. 5: PSA50 response was associated with lower baseline and C2D1 ctDNA fraction, with a stronger association for C2D1 ctDNA fraction,177Lu-PSMA-617 arm.

[0073] FIG. 6: ctDNA clearance from baseline to C2D1 and PSA50 response were associated with longer rPFS, Overall population.

[0074] FIG. 7: ctDNA clearance at C2D1 provided additional information to PSA50 in the rPFS model, Overall population (patients with detectable ctDNA at baseline).

[0075] FIG. 8: Plasma ctDNA was analyzed using a customized 585-gene sequencing assay at baseline (cycle 1, day 1 [C1D1]) and day 1 of cycle 2 [C2D1],

[0076] FIG. 9: ctDNA fraction summary.

[0077] FIG. 10: Higher baseline ctDNA fraction was associated with shorter rPFS

[0078] in the overall population (A) and in each treatment arm (B).

[0079] FIG. 11: ctDNA fraction was lower in responders than non-responders.

[0080] FIG. 12: Early ctDNA clearance was associated with longer rPFS.

[0081] FIG. 13: 8q amplifications (A), AR amplifications (B), and TP53 deleterious alterations (C) were associated with shorter rPFS in a univariable model adjusted for treatment.

[0082] DETAILED DESCRIPTION OF THE INVENTION

[0083] Herein after, the present disclosure is described in further detail and is exemplified.

[0084] EmbodimentsPAT060004-PCT-SEC01

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[0086] The methods of treatments of the present disclosure are provided in particular as following embodiments:

[0087] 1. A method of treating cancer with radioligand therapy (RLT) in a patient in need thereof;

[0088] wherein said method comprises the steps of:

[0089] (1) Optionally, before starting with the RLT, taking a blood sample from said patient for determining the circulating tumor DNA fraction (ctDNA%) (i.e. baseline ctDNA%);

[0090] (2) Administering to said patient a certain specified first dose of a radioligand therapeutic agent (RLT agent);

[0091] (3) Taking a blood sample from said patient for determining the ctDNA% (i.e. on- treatment ctDNA%);

[0092] (4) Optionally, administering to said patient a certain specified second dose of said RLT agent;

[0093] (5) Continuing with the administration of further specified doses of the RLT agent in the “ctDNA response” cases of:

[0094] (i) the on-treatment ctDNA% is non-detectable (ND) or not exceeding a certain threshold (e.g. <0.5%), and / or

[0095] (ii) there is a fractional decrease in the ctDNA from baseline to on- treatment, preferably, the decrease is from (detectable) D to ND or the decrease is from above a certain threshold to below said threshold (e.g. from >0.5% to <0.5%), or the ctDNA% is both, at baseline and on- treatment, ND or not exceeding a certain threshold (e.g. <0.5%); but discontinuing the administration of further amounts of the RLT agent and starting with an escalation therapy in the “ctDNA non-response” cases of: (iii) the on-treatment ctDNA% is detectable (D) or exceeding a certain threshold (e.g. >0.5%); and / or

[0096] (iv) there is no fractional decrease in the ctDNA from baseline to on- treatment.

[0097] 2. The method of embodiment 1, wherein the the interval between the first dose administration (step (2)) and the second dose administration ((step 4)) is (i.e. a cycle) of about 3 to about 12 weeks, about 4 to about 10 weeks, about 4 to about 8 weeks, about 6 to about 8 weeks, about 6 (±1) weeks, or about 6 weeks.PAT060004-PCT-SEC01

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[0099] 3. The method of any one of the preceding embodiments, wherein the blood samples are taken before the respective RLT agent administration (“pre-dose”), preferably about a week before, more preferably about one, two, or three days before, even more preferably before but on the same day of RLT agent administration [i.e. on day 1 of cycle 1 (C1D1) in step (1), on day 1 of cycle 2 (C2D1) in step (3)].

[0100] 4. The method of any one of the preceding embodiments, wherein the threshold is about 2%, about 1%, about 0.5%, about 0.4%, about 0.3%, about 0.2%, about 0.1%.

[0101] 5. The method of any one of the preceding embodiments, wherein the ctDNA evaluation comprises also determining the specific cancer-related alterations, e.g. gene mutations and amplifications, in ctDNA, in particular wherein said the alterations are selected from the group consisting of chromosome 8q amplifications, AR amplification, TP53 deleterious alterations, PTEN alterations, and wherein said amplifications / alterations are indicative for a suboptimal response to the RLT.

[0102] 6. The method of any one of the preceding embodiments, wherein said cancer is a prostate cancer (PC); said PC may be an oligometastatic or metastatic prostate cancer (OMPC or mPC), preferably is a mPC; said mPC may be a metastatic hormone-sensitive or a metastatic castration-resistant prostate cancer (mHSPC or mCRPC), preferably is a mCRPC.

[0103] 7. The method of any one of the preceding embodiments, wherein said cancer is a prostate cancer and is prostate-specific membrane antigen (PSMA)-positive (PSMA+).

[0104] 8. The method of any one of the preceding embodiments, wherein said cancer is a prostate cancer and the patient has been treated with androgen receptor pathway inhibitor (ARPI) therapy (i.e. pior ARPI therapy), and prior to or after taxane-based chemotherapy; preferably the patient has been treated with ARPI therapy, and prior to taxane-based chemotherapy (i.e. taxane-naive); more preferably the patient progressed under ARPI therapy, and prior to taxane-based chemotherapy; even more preferably, the patient progressed once on prior ARPI therapy and prior to taxane-based chemotherapy.PAT060004-PCT-SEC01

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[0106] 9. The method of any one of the preceding embodiments, wherein the RLT agent is a radiolabeled PSMA targeting agent, preferably said targeting agent is a low molecular weight (LMW) agent and not an antibody of a fragment thereof, more preferably a peptide or peptidomimetic, even more preferably said agent is selected from the group consisting of PSMA-617 (vipivotide tetraxetan), and PSMA l& T (zadavotide guraxetan), even more preferably is PSMA-617.

[0107] 10. The method of any one of the preceding embodiments, wherein the RLT agent is radiolabed with an alpha-particle, beta-minus particle, or Auger-electron emitting radionuclide, preferably a beta-minus particle emitting radionuclide, preferably selected from the group consisting of Lu-177, Tb-161, 1-131, and Cu-67; more preferably Lu-177 or Tb-161, even more preferably Lu-177.

[0108] 11. The method of any one of the preceding embodiments, wherein the the RLT agent is a beta-minus-particle emitting radionuclide and the specified dose is from about 5 to about 25 GBq, from about 5 to about 10 GBq, from about 6 to about 8.5 GBq, from about 6.5 to about 7.5 GBq, about 7.4 ± 10% GBq, or 7.4 ± 10% GBq.

[0109] 12. The method of any one of the preceding embodiments, wherein the escalation therapy is selected from the group of:

[0110] (a) radioactive dose increase, e.g. from 7.4 GBq (200 mCi) to 9.25 GBq (250 mCi); (b) change to a radionuclide with higher emitting particle energies, e.g. from Lu-177 to Y-90;

[0111] (c) change to radionuclide with higher LET (linear energy transfer), e.g. from beta-minus particle emitter to alpha-particle emitter or Auger-electron emitter, e.g. from Lu-177 to Ac-225 or Tb-161;

[0112] (d) combination therapies, e.g. combining the RLT with immune checkpoint inhibitors, radiosensitizers, e.g. DNA damage increasing agents, e.g. alkylating agents, TOPi, antimetabolites, DNA damage repair inhibitors, e.g. DNA-PKi, PARPi, ATMi, ARTi, HSP90i, TOPi, in the case of prostate cancer: androgen receptor (AR) degraders;

[0113] (e) chemotherapy, e.g. with taxanes.

[0114] 13. A method of treating mCRPC with a RLT comprising [177Lu]Lu-PSMA-617 in a taxane-naive patient who progressed once on a prior ARPI therapy;PAT060004-PCT-SEC01

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[0116] wherein said method comprises the steps of:

[0117] (1) Optionally, before starting with the RLT, taking a blood sample from said patient for determining the circulating tumor DNA fraction (ctDNA%) as baseline ctDNA% at C1D1, pre-dose;

[0118] (2) Administering to said patient a first dose of 7.4 ± 10% GBq of [177Lu]Lu-PSMA- 617;

[0119] (3) Taking a blood sample from said patient for determining the ctDNA% as on- treatment ctDNA% atC2D1, pre-dose (C2D1 being about 6 weeks after C1D1); (4) Optionally, administering to said patient a second dose of of 7.4 ± 10% GBq of [177Lu]Lu-PSMA-617;

[0120] (5) Continuing with the administration of further 7.4 ± 10% GBq doses of [177Lu]Lu- PSMA-617 in the “ctDNA response” cases of:

[0121] (v) the on-treatment ctDNA% is non-detectable (ND) or not exceeding a certain threshold (e.g. <0.5%), and / or

[0122] (vi) there is a fractional decrease in the ctDNA from baseline to on- treatment, preferably, the decrease is from (detectable) D to ND or the decrease is from above a certain threshold to below said threshold (e.g. from >0.5% to <0.5%), or the ctDNA% is both, at baseline and on- treatment, ND or not exceeding a certain threshold (e.g. <0.5%); but discontinuing the administration of further amounts of the RLT agent and starting with an escalation therapy in the “ctDNA non-response” cases of: (vii) the on-treatment ctDNA% is detectable (D) or exceeding a certain threshold (e.g. >0.5%); and / or

[0123] (viii) there is no fractional decrease in the ctDNA from baseline to on- treatment.

[0124] 14. Use of cell-free plasma ctDNA fraction of a blood sample taken on-treatment at day 1 of cycle 2 (C2D1), pre-dose, of a Radioligand therapy (RLT) as prognostic and / or predictive and / or response biomarker or as an (intermediate or final, primary or secondary or exploratory) endpoint for clinical benefit or for a clinical trial, together with or without the baseline ctDNA fraction, preferably, without the baseline ctDNA fraction.

[0125] In a particular embodiments of the present disclosure, the method of treating cancer with radioligand therapy (RLT) in a patient in need thereof;PAT060004-PCT-SEC01

[0126] - 15 -

[0127] may comprises the steps of:

[0128] (1) Optionally, before starting with the RLT, taking a blood sample from said patient for determining the circulating tumor DNA fraction (ctDNA%) (i.e. baseline ctDNA%);

[0129] (2) Administering to said patient a certain specified first dose of a radioligand therapeutic agent (RLT agent);

[0130] (3) Taking a blood sample from said patient for determining the ctDNA% (i.e. on- treatment ctDNA%);

[0131] (4) Optionally, administering to said patient a certain specified second dose of said RLT agent;

[0132] (5) Continuing with the administration of further specified doses of the RLT agent in the “ctDNA response” cases of:

[0133] (i) the on-treatment ctDNA% is non-detectable (ND) or not exceeding a certain threshold (e.g. <0.5%), and / or

[0134] (ii) there is a fractional decrease in the ctDNA from baseline to on- treatment, preferably, the decrease is from (detectable) D to ND or the decrease is from above a certain threshold to below said threshold (e.g. from >0.5% to <0.5%), or the ctDNA% is both, at baseline and on- treatment, ND or not exceeding a certain threshold (e.g. <0.5%); but discontinuing the administration of further amounts of the RLT agent and starting with an escalation therapy in the “ctDNA non-response” cases of: (iii) the on-treatment ctDNA% is detectable (D) or exceeding a certain threshold (e.g. >0.5%); and / or

[0135] (iv) there is no fractional decrease in the ctDNA from baseline to on- treatment.

[0136] In the embodiments of the present disclosure, the blood sample taken in steps (1) and / or (3) is / are used for determining ctDNA%, in particular cell-free plasma ctDNA%. The determination of ctDNA% may be formulated as additional step of the methods of the embodiments in the present disclosure. Said determination may comprise a 585-gene ctDNA panel. Said ctDNA% determination may comprise a 585-gene sequencing assay.

[0137] Methods of determining ctDNA% are described in the literature, e.g. in the following references the entire content of which is incorporated herein by reference:PAT060004-PCT-SEC01

[0138] - 16 -

[0139] E. Sanchez-Herrero, et al. Frontiers in Oncology, Front. Oncol. (July 2022) volume 12, article 943253. doi: 10.3389 / fonc.2022.943253, including the referenced articles of this review.

[0140] Fonseca NM, Maurice-Dror C, Herberts C, et al. Prediction of plasma ctDNA fraction and prognostic implications of liquid biopsy in advanced prostate cancer. Nat Commun 2024;15(1):1828.

[0141] Reichert ZR, Morgan TM, Li G, et al. Prognostic value of plasma circulating tumor DNA fraction across four common cancer types: a real-world outcomes study. Ann Oncol 2023;34(1):111-20.

[0142] Bono JSD, Morris MJ, Sartor O, et al. Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore. J Clin Oncol 2024;42(suppl 16):5008.

[0143] Vanwelkenhuyzen J, Van Bos E, Van Bruwaene S, et al. AR and PI3K genomic profiling of cell-free DNA can identify poor responders to Lutetium-177-PSMA among patients with metastatic castration-resistant prostate cancer. Eur Urol Open Sci 2023;53:63-66.

[0144] Kwan EM, Hofman MS, Ng SW, et al. Circulating tumour DNA fraction as a predictor of treatment efficacy in a randomized phase 2 trial of [177Lu]Lu-PSMA-617 (LuPSMA) versus cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel (TheraP ANZUP 1603). J Clin Oncol 2024;42(suppl 16):5055.

[0145] In the embodiments of the present disclosure, the interval between the first dose administration (step (2)) and the second dose administration ((step 4)) may be (i.e. a cycle) of about 3 to about 12 weeks, about 4 to about 10 weeks, about 4 to about 8 weeks, about 6 to about 8 weeks, about 6 (±1) weeks, or about 6 weeks.

[0146] In the embodiments of the present disclosure, the blood samples may be taken before the respective RLT agent administration (“pre-dose”), preferably about a week before, more preferably about one, two, or three days before, even more preferably before but on the samePAT060004-PCT-SEC01

[0147] - 17 -

[0148] day of RLT agent administration [i.e. on day 1 of cycle 1 (C1D1) in step (1), on day 1 of cycle 2 (C2D1) in step (3)].

[0149] In the embodiments of the present disclosure, the method the ctDNA% threshold may be about 2%, about 1%, or about 0.5%.

[0150] In the embodiments of the present disclosure, determining the ctDNA fraction (ctDNA%) primarily refers to quantification. However, it may also refer (in addition to quantification) to qualification, e.g. evaluating / determining specific genomic aberrations / alterations / amplifications, e.g. specific genomic aberrations in DNA-repair genes.

[0151] In the embodiments of the present disclosure, the ctDNA evaluation may comprise also determining the specific cancer-related alterations, e.g. gene mutations and amplifications, in ctDNA, in particular wherein said the alterations are selected from the group consisting of chromosome 8q amplifications, AR amplifications, TP53 deleterious alterations, PTEN alterations, and wherein said amplifications / alterations are indicative for a suboptimal response to the RLT.

[0152] In the embodiments of the present disclosure, the ctDNA evaluation may comprise also determining chromosome 8q amplifications, wherein said amplifications are indicative for a suboptimal response to the RLT.

[0153] Suboptimal response to the RLT may mean clinically insignificant changes of parameters that may be used as response biomarkers (e.g. standardized uptake value (SUV), prostate-speficic antigen (PSA) or >50% decrease in PSA levels from baseline (PSA50), in the field of prostate cancer therapy), clinically insignificant increase of radiographic progression free survival (rPFS, e.g. by BICR), clinically insignificant increase of PSA progression free survival (PSA-PFS, in the field of prostate cancer therapy) and / or clinically insignificant increase of overall survival (OS).

[0154] A clinically insignificant change may be a change of less than 25%, 20%, 15%, 10%, or 5%.

[0155] In the embodiments of the present disclosure, the cancer may be a prostate cancer (PC); said PC may be an oligometastatic or metastatic prostate cancer (OMPC or mPC), preferably is aPAT060004-PCT-SEC01

[0156] - 18 -

[0157] mPC; said mPC may be a metastatic hormone-sensitive or a metastatic castration-resistant prostate cancer (mHSPC or mCRPC), preferably is a mCRPC.

[0158] In the embodiments of the present disclosure, the cancer may be a prostate cancer and is prostate-specific membrane antigen (PSMA)-positive (PSMA+).

[0159] In the embodiments of the present disclosure, the cancer may be a prostate cancer and the patient may have been treated with androgen receptor pathway inhibitor (ARPI) therapy (i.e. pior ARPI therapy), and prior to or after taxane-based chemotherapy; preferably the patient has been treated with ARPI therapy, and prior to taxane-based chemotherapy (i.e. taxane-naïve); more preferably the patient progressed under ARPI therapy, and prior to taxane-based chemotherapy; even more preferably, the patient may have progressed once on prior ARPI therapy and prior to taxane-based chemotherapy.

[0160] In the embodiments of the present disclosure, the RLT agent may be a radiolabeled PSMA targeting agent, preferably said targeting agent is a low molecular weight (LMW) agent and not an antibody of a fragment thereof, more preferably a peptide or peptidomimetic, even more preferably said agent is selected from the group consisting of PSMA-617 (vipivotide tetraxetan), and PSMA l& T (zadavotide guraxetan), even more preferably is PSMA-617.

[0161] In the embodiments of the present disclosure, the RLT agent may be radiolabed with an alphaparticle, beta-minus particle, or Auger-electron emitting radionuclide, preferably a beta-minus particle emitting radionuclide, preferably selected from the group consisting of Lu-177, Tb-161, 1-131, and Cu-67; more preferably Lu-177 or Tb-161, even more preferably Lu-177.

[0162] In the embodiments of the present disclosure, the RLT agent may be a beta-minus-particle emitting radionuclide and the specified dose is from about 5 to about 25 GBq, from about 5 to about 10 GBq, from about 6 to about 8.5 GBq, from about 6.5 to about 7.5 GBq, about 7.4 ± 10% GBq, or 7.4 ± 10% GBq.

[0163] In the embodiments of the present disclosure, the escalation therapy may be selected from the group of:

[0164] (a) radioactive dose increase, e.g. from 7.4 GBq (200 mCi) to 9.25 GBq (250 mCi);PAT060004-PCT-SEC01

[0165] - 19 -

[0166] (b) change to a radionuclide with higher emitting particle energies, e.g. from Lu-177 to Y-90;

[0167] (c) change to radionuclide with higher LET (linear energy transfer), e.g. from beta-minus particle emitter to alpha-particle emitter or Auger-electron emitter, e.g. from Lu-177 to Ac-225 or Tb-161;

[0168] (d) combination therapies, e.g. combining the RLT with immune checkpoint inhibitors, radiosensitizers, DNA damage repair inhibitors, e.g. DNA-PK inhibitors, in the case of prostate cancer: androgen receptor degraders;

[0169] (e) chemotherapy, e.g. with taxanes.

[0170] The present disclosure provides for a method of treating patients with prostate-specific membrane antigen (PSMA)-positive metastatic castrati on- resista nt prostate cancer (mCRPC), whose cancer is progressing after receiving or having received a second-generation ARPI, with a therapeutically effective amount of a PSMA-binding radioligand therapeutic (RLT) agent, or a pharmaceutically acceptable salt, solvate, hydrate, co-crystal, crystalline form, amorphous form, stereoisomer, or tautomer thereof.

[0171] The methods of treatments as described herein in the various embodiments are also characterized in that they provide a higher, at least 50% higher, at least 75% higher, at least 100% higher, at least 150% higher, at least 200% higher, at least two-times higher, at least three-times higher rORR (radiographic Overall Response Rate) compared to a continued or alternate ARDT / ARPI / ARAT treatment with the previously used or different ARDT / ARPI / ARAT, respectively.

[0172] The methods of treatments as described herein in the various embodiments are also characterized in that they provide a higher, at least 20%, 30%, 40%, 50%, higher rDCR (radiographic Disease Control Rate) compared to a continued or alternate ARDT / ARPI / ARAT treatment with the previously used or different ARDT / ARPI / ARAT, respectively.

[0173] The methods of treatments as described herein in the various embodiments are also characterized in that they provide an at least three-times higher rORR (radiographic Overall Response Rate) compared to a continued or alternate ARDT / ARPI / ARAT treatment with the previously used or different ARDT / ARPI / ARAT, respectively.PAT060004-PCT-SEC01

[0174] - 20 -

[0175] In the embodiments of the present disclosure, the ligand may be selected from the group consisting of PSMA-617 (vipivotide tetraxetan), PSMA l& T (zadavotide guraxetan), PSMA-R2, MIP-1095, MIP-1545, MIP, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, PSMA-7 l& T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, and RPS-074, preferably selected from the group consisting of PSMA-617, PSMA l& T, and PSMA-R2, most preferably PSMA-617.

[0176] In the embodiments of the present disclosure, the ligand may be selected from the group consisting of PSMA-617, PSMA l& T, PSMA-R2, MIP-1095, MIP-1545, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, rhPSMA-10.1, Ludotadipep, PNT2001, PNT2002, PSMA-7 l& T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, RPS-074, RPS-072, NG001, ADVC00, PMI-21, HTK03121, IBU DAB PSMA, PSMA CM, or mcl-alb-M-PSMA.

[0177] In an embodiment, the PSMA targeting ligand, PSMA binding moiety or PSMA binding peptide, linked to or including the chelating agent, may comprise the chemical structure selected from the group consisting of glutamate-urea-lysine (GUL); GUL-Nal; GUL-2-Nal; GUL-2-Nal-TXA; PSMA-617 (vipivotide tetraxetan); KuE; KuE-Sub; (KuE-Sub)kf; (KuE-Sub)kff; (KuE-Sub)kfy; (KuE-Sub)kf(l-y); (KuE-Sub)kf(l-y); DOTAGA-(l-y)fk(Sub-KuE); PSMA l& T (zadavotide gurexetan); FPI-2265; PSMA-R2; MIP-1095; MIP-1545; MIP-1555; MIP1558; CTT1403; FC705; BAY-2315497; BAY-3563254; BAY-3546828; TLX-007; TLX591; TLX592; PSMA-TCC; rhPSMA; rhPSMA-7; rhPSMA-7.3; rhPSMA-10.1; ludotadipep; PNT2001; PNT2002; CONV01; AB001; BisPSMA; SAR-bisPSMA; PSMA-1; PSMA-7; LNTH-1404; EB-PSMA-617; PSMA-ALB-02; PSMA-ALB-053; PSMA-ALB-056; P16-093; PSMA-93; RPS-074; ADV001; JNJ-6420; LNC-1003; PSMA-11; DCPyL; MIP-1404; PSMA-1007; THP-PSMA; and iPSMA; preferably PSMA-617, PSMA l& T, PSMA-R2, MIP-1095, MIP-1545, MIP, MIP-1555, MIP-1557, MIP-1558, CTT1403, FC705, BAY-2315497, TLX592, PSMA-TCC, rhPSMA, rhPSMA-7, rhPSMA-7.3, PSMA-7 l& T, EB-PSMA-617, PSMA-ALB-02, PSMA-ALB-053, PSMA-ALB-056, P16-093, PSMA-93, and RPS-074, more preferably selected from the group consisting of PSMA-617, PSMA l& T, and PSMA-R2, more even more preferably PSMA-617.

[0178] In the embodiments of the present disclosure, the radionuclide may be selected from the group consisting of Lu-177, Tb-161, 1-131, Tc-99m, Y-90, Sc-47, Cu-67, Re-188, Pb-212, Bi-213, Ac-PAT060004-PCT-SEC01

[0179] - 21 -

[0180] 255, and Th-227, preferably selected from the group consisting of Lu-177 and Tb-161, most preferably Lu-177.

[0181] In the embodiments of the present disclosure the 177Lu radionuclide can be of the quality “carrier added” (c.a. 177Lu, e.g. produced by the direct production route, 176Lu (neutron, gamma)177Lu, and thus comprising also 177mLu), or of the quality “no-carrier added” or “carrier-free” (n.c.a. 177Lu, e.g. produced by the indirect reactor production route 176Yb (neutron, gamma) 177Yb beta-minus decay 177Lu, essentially free of 177mLu). In preferred embodiments, the radionuclide 177Lu is in the quality n.c.a.

[0182] “labeled” in generally and in particular in the wording like “Lutetium-177 (177Lu) labeled prostate-specific membrane antigen (PSMA) binding radioligand therapeutic (RLT) agent” means that the radionuclide is complexed or chelated to the chelator-moiety of the RLT agent, e.g. the DOTA or DOTAGA chelator.

[0183] In certain embodiments, the prostate-specific membrane antigen (PSMA) positive (+) metastatic castration-resistant prostate cancer (mCRPC), is a PSMA+ mCRPC that is progressive or progressing after a first ARDT (e.g. the cancer progresses under or after treatment with second generation ARDT, such as abiraterone, enzalutamide, darolutamide, and apalutamide).

[0184] RADIONUCLIDES

[0185] In the embodiments of the present disclosure, the radionuclide may be a radionuclide that undergoes a beta-minus (β-) decay and emits electrons from the nucleus. Said electrons are also referred to as beta-minus (β⁻) particles or negatrons.

[0186] In the embodiments of the present disclosure the beta-minus-particle emitting radionuclides may be a transition metal or a lanthanide.

[0187] In the embodiments of the present disclosure the beta-minus-particle emitting radionuclides may be a lanthanide.

[0188] In the embodiments of the present disclosure, the radionuclide may be a radionuclide that undergoes beta-minus (β⁻) decay but also other decay modes, wherein the beta-minus decayPAT060004-PCT-SEC01

[0189] - 22 -

[0190] occurs at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, at least about 99%, of all decays of said radionuclide.

[0191] In the embodiments of the present disclosure, the radionuclide may be a radionuclide that undergoes substantially only beta-minus (β⁻) decay.

[0192] In the embodiments of the present disclosure, the beta-minus particles have a continuous spectrum of energies between zero and maximum value(s). Said maximum values are also referred to as endpoint energy / energies.

[0193] One radionuclide may have more than one kind of beta-minus emission, e.g. one emission as the most intensive beta emission (i.e. the beta-minus emission with the highest probability), and another emission as the beta-minus emission with the highest endpoint energy.

[0194] The energy of the beta-minus decay of the radionuclides may be also represented by the average beta-minus decay energy value which is typically about 1 / 3 of the endpoint energy values.

[0195] In the embodiments of the present disclosure, the radionuclide may have a most intensive beta emission endpoint energy from about 0.3 to about 0.8 MeV (Mega electron Volt), from about 0.4 to about 0.7 MeV, from about 0.4 to about 0.6 MeV, or from about 0.5 to about 0.6 MeV.

[0196] In the embodiments of the present disclosure, the radionuclide may have a most intensive beta emission endpoint energy from about 0.3 to about 2.5 MeV (e.g. 32P, 47Sc, 67Cu, 89Sr, 90Y,105Rh, 1311, 133Xe, 143Ce, 153Sm, 161Tb, 166Ho, 169Er, 177Lu, 183Ta, 186Re, 188Re), from about 0.3 to about 0.6 MeV (e.g. 47Sc, 67Cu,105Rh, 1311, 133Xe, 161Tb, 169Er, 177Lu, 183Ta), from about 0.4 to about 0.6 MeV, or from about 0.5 to about 0.6 MeV, with a highest endpoint energy from about 0.5 MeV to about 1.0 MeV, from about 0.6 MeV to about 0.9 MeV, from about 0.6 MeV to about 0.8 MeV, from about 0.6 to about 0.7 MeV, or about 0.6 MeV.PAT060004-PCT-SEC01

[0197] - 23 -

[0198] In the embodiments of the present disclosure, the radionuclide may have a most intensive beta emission endpoint energy from about 0.5 to about 0.6 MeV, with a highest endpoint energy from of about 0.5 MeV, about 0.6 MeV, about 0.7 MeV, about 0.8 MeV, about 0.9 MeV, or about 1.0 MeV.

[0199] In the embodiments of the present disclosure, the radionuclide may have a most intensive beta emission endpoint energy from about 0.5 to about 0.6 MeV, with a highest endpoint energy from about 0.5 MeV to about 0.8 MeV (e.g. 1311, 161Tb, 177Lu, 183Ta).

[0200] In the embodiments of the present disclosure, the radionuclide may have a most intensive beta emission endpoint energy of about 0.5 MeV with a highest endpoint energy of about 0.5 to about 0.6 MeV (e.g. 161Tb, 177Lu).

[0201] In the embodiments of the present disclosure, the radionuclide may have an average betaminus decay energy from about 100 keV to about 200 keV, from about 120 keV to about 180 keV, from about 120 keV to about 170 keV, from about 130 keV to about 170 keV, or from about 130 keV to about 160 keV.

[0202] In the embodiments of the present disclosure, the beta-minus particle emitting radionuclide may have a half-life (T% or t%) of about half a day (about 12 hours (h)) to about 100 days (d), from about 1 d to about 50 d, from about 1 d to about 20 d, from about 1 d to about 10 d, from about 2 d to 10 d, from about 3 d to about 10 d, from about 3 d to about 8 d, from about 3 d to about 7 d, from about 5 d to about 7, from about 6 d to about 7 d, from about 6.5 d to about 7.0 d, or from about 6.6 d to about 6.9 d.

[0203] Table 1: Beta-minus particle emitting radionuclides

[0204] Radionuclide Half-life most intensive highest average betabeta emission endpoint minus decay endpoint energy (if energy (keV) energy (MeV) exceeding

[0205] energy of most

[0206] intensive

[0207] emission)

[0208] (MeV)

[0209]

[0210] PAT060004-PCT-SEC01

[0211] - 24 -

[0212] 32 p 14.27 d 1.7

[0213] 47Sc 3.35 d 0.4 0.6

[0214] 67Cu 61.9 h 0.4 0.6

[0215] 89Sr 50.56 d 1.5

[0216] goy 64.05 h 2.4

[0217] 105Rh 33.36 h 0.6

[0218] 121Sn 27.03 h 0.38

[0219] 1311 8.03 d 0.6 0.8

[0220] 133Xe 5.25 d 0.3

[0221] 143Ce 33.04 h 1.1 1.5

[0222] 143Pr 13.57 d 0.9

[0223] 153Sm 46.28 h 0.7 0.8

[0224] 161Tb 6.89 d 0.5 0.6 156

[0225] 166Dy 81.5 h 0.4 0.5

[0226] 166Ho 26.82 h 1.8

[0227] 169Er 9.39 d 0.4

[0228] 172Tm 63.6 h 1.8 1.9

[0229] 175Yb 4.185 d 0.5

[0230] 177Lu 6.64 d 0.5 134

[0231] 183Ta 5.1 d 0.6 0.7

[0232] 186Re 3.72 d 1.1

[0233] 188Re 17.00 h 2.1

[0234] 198Au 2.6941 d 1.0

[0235] 199Au 3.139 d 0.3 0.5

[0236]

[0237] In other embodiments of the present disclosure, the radionuclide may be a radionuclide that undergoes an alpha (a) decay and emits alpha-particles from the nucleus. Said alpha-particles are also referred to as Helium (He) nuclei each composed of two protons and two neutrons.

[0238] In the embodiments of the present disclosure the alpha-particle emitting radionuclides may be a lanthanide or an actinide.PAT060004-PCT-SEC01

[0239] - 25 -

[0240] In the embodiments of the present disclosure the alpha-particle emitting radionuclides may be an actinide.

[0241] In the embodiments of the present disclosure, the radionuclide may be a radionuclide that undergoes an alpha (a) decay but also other decay modes (e.g. beta-minus-decay, double beta-minus emission, cluster emission spontaneous fission), wherein the alpha decay occurs at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 98%, or at least about 99%, of all decays of said radionuclide.

[0242] In the embodiments of the present disclosure, the radionuclide may be a radionuclide that undergoes substantially only alpha (a) decay.

[0243] In the embodiments of the present disclosure, the alpha particles may have a specific energies from about 3 to about 8 MeV (e.g.149Tb,211At,212Pb,212Bi,213Bi,223Ra,224Ra,225Ac,227Th,230U), from about 4 to about 7 MeV, from about 5 to about 7, from about 5.0 to about 6.5 MeV, or from about 5.5 to about 6.5 MeV.

[0244] One radionuclide may have more than one kind of alpha emission, e.g. one emission as the most intensive alpha emission (i.e. the alpha emission with the highest probability), and one of more alpha emissions with lower probabilities.

[0245] The transition energy of the alpha decay is the sum of the alpha particle (kinetic) energy and the recoil energy of the daughter nuclide. Most relevant for the characteristics of the radionuclide in the embodiments of the present disclosure is the alpha particle (kinetic) energy.

[0246] In the embodiments of the present disclosure, the radionuclide may be characterized by the alpha particle energy of the highest emission probability, also referred to as the most intensive alpha particle energy from about 5 to about 7, from about 5.0 to about 6.5 MeV, or from about 5.5 to about 6.5 MeV.

[0247] In the embodiments of the present disclosure, the radionuclide may be characterized by the highest alpha particle energy which may exceed the energy of the one with the highestPAT060004-PCT-SEC01

[0248] - 26 -

[0249] emission probability and may range from about 5.5 to about 8, from about 5.5 to about 7 MeV, or from about 5.8 to about 6.5 MeV.

[0250] In the embodiments of the present disclosure, the radionuclide may be characterized by the alpha particle energy of the highest emission probability, also referred to as the most intensive alpha particle energy, and the highest alpha particle energy.

[0251] In the embodiments of the present disclosure, the alpha particle emitting radionuclide may have a half-life (T% or t%) from about 30 min to about 50 days, from about 5 h to about 50 days, from about 10 h to about 50 days, from about 1 day to about 50 days, from about 2 days to about 40 days, from about 3 days to about 30 days (e.g.223Ra,224Ra,225Ac,227Th,230U), from about 5 days to about 20 days, from about 5 days to about 15 days, from about 7 days to about 13 days, from about 8 days to about 12 days, from about 9 days to about 11 days, or about 10 days.

[0252] In the embodiments of the present disclosure, the alpha particle emitting radionuclide may have short lived daughter nuclides that emits further alpha particles and may form additional characteristics of the radionuclides of the present disclosure.

[0253] In the embodiments of the present disclosure, the alpha particle emitting radionuclide may have from 1 to 5, from 2 to 5, from 3 to 5, or from 3 to 4 alpha-particle emitting daughter nuclides.

[0254] In some embodiments, the radionuclide indicated as alpha-particles emitting radionuclide may not itself emit such an alpha-particle but its daughter nuclide does. In such a case, it is the halflife of the mother radionuclide but the alpha particle energy of the daughter radionuclide that is the relevant characteristic value.

[0255] In the embodiments of the present disclosure, the radionuclide may be characterized by the alpha particle energy of the highest emission probability, also referred to as the most intensive alpha particle energy, and the half-life.PAT060004-PCT-SEC01

[0256] - 27 -

[0257] In the embodiments of the present disclosure, the radionuclide may be characterized by the alpha particle energy of the highest emission probability, also referred to as the most intensive alpha particle energy, and the highest alpha particle energy, and the half-life.

[0258] Table 2: alpha particle emitting radionuclides

[0259] Radionuclide Half-life most highest alpha Number of further intensive particle energy alpha particle emitting alpha particle (if exceeding daughter nuclides energy (MeV) energy of most

[0260] intensive

[0261] emission)

[0262] (MeV)

[0263] 149Tb 4.1 h 3.97 0

[0264] 211At 7.214 h 5.8695 0

[0265] 212Pb 10.622 h 6.051 (212Bi) 6.09 (212Bi) 0

[0266] 212Bi 60.55 m 6.051

[0267] 213Bi 45.61 m 5.875 (213Bi) 0

[0268] 8.376 (213PO)

[0269] 223Ra 11.4366 d 5.7162 3:219Rn,215Po,211Bi224Ra 3.6319 d 5.6854 3:220Rn,216Po,212Bi225Ac 9.92 d 5.83 3:221Fr,217At,213Po227Th 18.697 d 6.038 4:223Ra,219Rn,215Po,

[0270] 211Bi

[0271] 230U 20.23 d 5.888 5:226Th,223Ra,219Rn,

[0272] 215Po,211Bi

[0273]

[0274] In other embodiments of the present disclosure, the radionuclide may be a radionuclide that emits Auger electrons (AE) and / or internal conversion (IC) electrons.

[0275] Said AE or IC electron emitters may be selected from the group consisting of 67Ga, 99mTc, 111ln, 117Sn, 119Sb, 1231, 1251, 161Tb, 191Pt, 193mPt, 195mPt, 197Hg, 197mHg,and 201TI.PAT060004-PCT-SEC01

[0276] - 28 -

[0277] Preferably, the AE emitters are selected from 67Ga, 111ln, and 1251, and the IC electron emitter is selected from 117Sn.

[0278] The beta-minus particle emitters have a linear energy transfer (LET) of < 1 keV / μm.

[0279] The alpha-particle emitters have a linear energy transfer (LET) of 50-230 keV / μm.

[0280] The Auger electron or Internal conversion electron emitters have a linear energy transfer (LET) of 1 - 23 keV / μm.

[0281] MEDICAL USE LANGUAGE FORMATS:

[0282] Some embodiments herein are formulated as method of treatment claims. They may be likewise formulated into any other medical use formats, such as illustrated in the following, with DRUG being the RLT agent (alone or in combination with other agents), with INDICATION being the cancer as specified in the embodiments above, with FEATURES being those characterizing features as mentioned in the embodiments above:

[0283] The present invention / disclosure provides [DRUG] or any pharmaceutically acceptable salt thereof for use in the treatment of [INDICATION], characterized in that [FEATURES].

[0284] Alternatively, the present invention / disclosure provides a method for the treatment of [INDICATION] in human patients in need of such treatment which comprises administering an effective amount of [DRUG] or any pharmaceutically acceptable salt thereof, wherein said treatment is characterized in that [FEATURES].

[0285] As a further alternative the present invention / disclosure provides the use of [DRUG] or any pharmaceutically acceptable salt thereof for the preparation of a medicament for the treatment of [INDICATION], characterized in that [FEATURES].

[0286] As a further alternative the present invention / disclosure provides the use of [DRUG] or any pharmaceutically acceptable salt thereof for the treatment of [INDICATION], characterized in that [FEATURES],PAT060004-PCT-SEC01

[0287] - 29 -

[0288] As a further alternative the present invention / disclosure provides a medicament for the treatment of [INDICATION] comprising [DRUG] or any pharmaceutically acceptable salt thereof, characterized in that [FEATURES].

[0289] For example, the first embodiment of the present disclosure can be re-formulated as in the following:

[0290] A radioligand therapeuic agent (RLT agent) for use in a method of treating cancer in a patient;

[0291] wherein said method comprises the steps of:

[0292] (1) Optionally, before starting with the RLT, taking a blood sample from said patient for determining the circulating tumor DNA fraction (ctDNA%) (i.e. baseline ctDNA%);

[0293] (2) Administering to said patient a certain specified first dose of a radioligand therapeutic agent (RLT agent);

[0294] (3) Taking a blood sample from said patient for determining the ctDNA% (i.e. on- treatment ctDNA%);

[0295] (4) Optionally, administering to said patient a certain specified second dose of said RLT agent;

[0296] (5) Continuing with the administration of further specified doses of the RLT agent in the “ctDNA response” cases of:

[0297] (i) the on-treatment ctDNA% is non-detectable (ND) or not exceeding a certain threshold (e.g. <0.5%), and / or

[0298] (ii) there is a fractional decrease in the ctDNA from baseline to on- treatment, preferably, the decrease is from detectable (D) to ND or the decrease is from above a certain threshold to below said threshold (e.g. from >0.5% to <0.5%), or the ctDNA% is both, at baseline and on- treatment, ND or not exceeding a certain threshold (e.g. <0.5%); but discontinuing the administration of further amounts of the RLT agent and starting with an escalation therapy in the “ctDNA non-response” cases of: (iii) the on-treatment ctDNA% is detectable (D) or exceeding a certain threshold (e.g. >0.5%); and / or

[0299] (iv) there is no fractional decrease in the ctDNA from baseline to on- treatment.PAT060004-PCT-SEC01

[0300] - 30 -

[0301] All embodiments herein directed to a method of treating cancer or RLT agent for use in a method of treating cancer, may also / alternatively be formulated as:

[0302] A method for assessing a cancer;

[0303] wherein said method comprises the steps of (a) steps (1) to (4) in those embodiments directed to methods of treating cancer; and (b) classifying said cancer as being likely to respond to the RLT by finding the criteria being met as laid out in step (5) (i) and (ii) in those embodiments directed to methods of treating cancer.

[0304] All embodiments herein directed to a method of treating cancer may also / alternatively be formulated as:

[0305] A method for selecting a cancer treatment for a human having a cancer;

[0306] wherein said method comprises the steps of (a) steps (1) to (4) in those embodiments directed to methods of treating cancer; and (b) selecting the cancer treatment for said human by applying the criteria as laid out in step (5) in those embodiments directed to methods of treating cancer.

[0307] DEFINITIONS

[0308] “about” in respect of a value means ± 25%, preferably ± 20%, more preferably ± 15%, even more preferably ± 10%, even more preferably ± 5%.

[0309] “about” in respect of a weeks or cycles means ± 2, preferably ± 1.

[0310] D: detectable or detected

[0311] ND: non-detectable or non-detected

[0312] ctDNA: circulating tumor DNA

[0313] The terms radionuclide and radioisotopes can be exchanged in this disclosure and its embodiments. Where it is technically meaningful, the term radiometal and radiohalogen can be also used as alternative.

[0314] Instead of indicating the radionuclide in the form of e.g.177Lu or Lu-177 or Lutetium-177, the form 177Lu is used as alternative herein. Therefore, wherever the mass number, e.g. 177, is not superscripted (e.g. 177Lu) throughout the disclosure, it is nevertheless meant to refer to the superscripted version177Lu.PAT060004-PCT-SEC01

[0315] - 31 -

[0316] PSMA-617 or vipivotide tetraxetan means the “cold” ligand (ligand without radionuclide) of PLUVICTO, i.e. INN: lutetium (177Lu) vipivotide tetraxetan, and may be represented by formula (I):

[0317]

[0318] PSMA l& T (zadavotide guraxetan) means the “cold” ligand (ligand without radionuclide) of [177Lu]Lu-PSMA l& T (INN: lutetium (177Lu) zadavotide guraxetan), and is commercially available by ABX, Radeberg, Germany, and may be represented by formula (II).

[0319]

[0320] The drug substance, the product and methods to produce a drug product for clinical use with this RLT agent are described in US 11,129,912 B1 and US 11,491,246 B2, and WO 2002 / 013610. The glutamic acid / glutamate residue next to the / part of the chelator in PSMA l& T can be in the L- or in the D-configuation, or a mixture of both (e.g. a racemic mixture, or an optically enriched mixture of either the L-configuration in excess or the D-configuration in accesss, preferably it is in the D-configuation.

[0321] PSMA-R2 may be represented by formula (III), preferably with the glutamic acid and the lysine adjacent to the urea in the L-configuration:PAT060004-PCT-SEC01

[0322] - 32 -

[0323]

[0324] Any radionuclides, e.g. radiometals, such like 177Lu, can be complexed by the DOTA or DOTAGA residue, the latter acting as chelators for the radiometal. This will then lead to the 177Lu-labeled RLT agent.

[0325] [68Ga]Ga-PSMA-11 (INN: gallium (68Ga) gozetotide, drug names: LOCAMETZ, ILLUCCIX) may be represented by formula (IV).

[0326]

[0327] (IV)

[0328] 18F-DCFPyL (INN: piflufolastat (18F), drug names; PYLARIFY, PYLCLARI) may be represented by formula (V).

[0329]

[0330] PAT060004-PCT-SEC01

[0331] - 33 -

[0332] 18F( / natGa)-rhPSMA-7.3 (INN: Flotufolastat (18F), drug name: POSLUMA) may be represented by formula (VI).

[0333]

[0334] (VI)

[0335] Regarding Taxene and Taxane-based chemotherapy:

[0336] Taxanes are a class of diterpenes typically contain a taxadiene core. Paclitaxel (Taxol) and docetaxel (Taxotere) are widely used as chemotherapy agents. Cabazitaxel was FDA approved to treat hormone-refractory prostate cancer.

[0337] Hormonal therapy may including any androgen directed treatment such as finasteride, dutasteride, bicalutamide, apalutamide, abiraterone, enzalutamide, or combinations thereof. Taxane based chemotherapy may include docetaxel or cabazitaxel, or combinations thereof. Other cancer drugs used in the context of the present disclosure may include abiraterone, orteronel, galeterone, seviteronal, apalutamide, enzalutamide, or combinations thereof.

[0338] Further cancer drugs used in the context of the present disclosure may include palifosfamide, 5-flourouracil, capecitabine, pemetrexed, cisplatin, carboplatin, gemcitabine, paclitaxel, vinorelbine, eribuline, docetaxel, cyclophosphamide, doxorubicin, regorafenib, or combinations thereof.

[0339] No-carrier added (NCA, nca, n.c.a.): A preparation of a radioactive isotope which is essentially free from stable isotopes of the element in question. The production of n.c.a.177Lu is known and may be done for example from176Yb via177Yb, e.g. 176Yb (n, gamma) 177Yb, the latter undergoing beta-minus decay to 177Lu (sometimes referred to as “indirect” reactor production route). The method involves radiochemical separation steps to isolate the desiredPAT060004-PCT-SEC01

[0340] - 34-

[0341] n.c.a. 177Lu from Yb isotopes. No-carrier added is sometimes also referred to as carrier-free.

[0342] The following response types and response rates are used herein:

[0343] Best overall response

[0344] Complete response (CR)

[0345] Partial response (PR)

[0346] Stable disease (SD)

[0347] Progressive disease (PD)

[0348] Unknown (UNK)

[0349] Overall Response Rate (ORR: CR+PR)

[0350] Disease Control Rate (DCR: CR+PR+SD)

[0351]

[0352] In the embodiments herein, the features in brackets (...) or [...] are referring to features that can be omitted or can be included and therefore refer to sub-types of the respective embodiments.

[0353] REFERENCES

[0354] AH publications, patents and patent applications referred to herein are incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

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[0437] Tomlins SA, Alshalalfa M, Davicioni E, et al (2015) Characterization of 1577 primary prostate cancers reveals novel biological and clinicopathologic insights into molecular subtypes. Eur. Urol. 555-67.

[0438] Violet J, Sandhu S, Iravani A, et al (2020) 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. J. Nucl. Med. 857-865. Vlachostergios, P. J., Conteduca, et al (2019) Prognostic value of BRCA2 and AR gene alterations in advanced prostate cancer patients treated with PSMA-targeted radionuclide therapies. Cancer Res 2019 (79) (13 Supplement) 4865.PAT060004-PCT-SEC01

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[0440] Webster K, Celia D, Yost K (2003) The Functional Assessment of Chronic Illness Therapy (FACIT) Measurement System: properties, applications, and interpretation. 1:79.

[0441] Weinfurt KP, Li Y, Castel LD, et al (2005) The significance of skeletal-related events for the health related quality of life of patients with metastatic prostate cancer. 16(4): 579-84.

[0442] Wright G L, Grob, Haley, et al (1996) Upregulation of prostate-specific membrane antigen after androgen-deprivation therapy (2):326-34.

[0443] Wright, Haley, Beckett, et al (1995) Expression of prostate-specific membrane antigen in normal, benign, and malignant prostate tissues. Urol. Oncol. 18-28.

[0444] Yadav MP, Ballal S, Bal C, et al (2020) Efficacy and Safety of 177Lu-PSMA-617 Radioligand Therapy in Metastatic Castration- Resistant Prostate Cancer Patients. Clin Nucl Med 19-31. Yadav MP, Ballal S, Tripathi M, et al (2017) 177Lu-DKFZ-PSMA-617 therapy with metastatic castration resistant prostate cancer: safety, efficacy, and quality of life assessment. 44(1): 81 -91.

[0445] Yordanova A, Becker A, Eppard E, et al (2017) The impact of repeated cycles of radio ligand therapy using [177Lu]Lu-PSMA-617 on renal function in patients with hormone refractory metastatic prostate cancer, p. DOI 10.1007 / s00259-017-3681-9.

[0446] You S, Knudsen BS, Erho N, et al (2016) Integrated Classification of Prostate Cancer Reveals a Novel Luminal Subtype with Poor Outcome. Cancer Res. 4948-58.

[0447] Zhao SG, Chang SL, Spratt DE, et al (2016) Development and validation of a 24-gene predictor of response to postoperative radiotherapy in prostate cancer: a matched, retrospective analysis. Lancet Oncol. 1612-1620.

[0448] Zielinski RR, Azad AA, Chi KN, et al (2014) Population-based impact on overall survival after the introduction of docetaxel as standard therapy for metastatic castration resistant prostate cancer. 8(7-8): E520-3.

[0449] de Bono J, Mateo J, Fizazi K, et al (2020) Olaparib for Metastatic Castration-Resistant Prostate Cancer 382:2091-102.

[0450] de Wit R, de Bono J, Sternberg CN, et al (2019) Cabazitaxel versus Abiraterone or Enzalutamide in Metastatic Prostate Cancer 2506-2518.

[0451] van Kalmthout L, Braat A, Lam M, et al (2019) First Experience With 177Lu-PSMA-617 Therapy for Advanced Prostate Cancer in the Netherlands. Clin Nucl Med 446-451.PAT060004-PCT-SEC01

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[0453] EXAMPLES

[0454] Hereinafter, the present invention is described in more details and specifically with reference to the examples, which however are not intended to limit the present invention.

[0455] EXAMPLE 1:

[0456] CLINICAL TRIAL

[0457] The clinical phase 3 trial with the title “177Lu-PSMA-617 vs. Androgen Receptor-directed Therapy in the Treatment of Progressive Metastatic Castrate Resistant Prostate Cancer (PSMAfore)” is described at ClinicalTrials.gov with the Identifier: NCT04689828 (the entire disclosure of that webpage as accessible at the filing date is incorporated herein by reference). The trial is also described as:

[0458] PSMAfore: A phase III, Open-label, Multi-Center, Randomized Study Comparing177Lu-PSMA-617 vs. a Change of androgen receptor-directed therapy in the Treatment of Taxane Naive Men with Progressive Metastatic Castrate Resistant Prostate Cancer, CAAA617B12302. Study design:

[0459] See FIG. 1.

[0460] Clinical protocol:

[0461] Protocol CAAA617B12302

[0462] number

[0463] Study Title PSMAfore: A phase III, Open-label, Multi-Center, Randomized Study Comparing177Lu-PSMA-617 vs. a Change of androgen receptor- directed therapy in the Treatment of Taxane Naive Men with Progressive Metastatic Castrate Resistant Prostate Cancer

[0464] Brief Title Open-label study comparing177Lu-PSMA-617 vs. a change of androgen receptor-directed therapy drugs in the treatment of mCRPC Sponsor and Novartis,

[0465] Clinical phase Phase III

[0466]

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[0469] Investigation Drug

[0470] type

[0471] Study type Interventional

[0472] Purpose and The purpose of this study is to determine whether177Lu-PSMA-617, rationale given for 6 cycles at a dose of 7.4 Gigabecquerel (GBq) (200 Millicuries (mCi)) + / - 10%, improves the radiographic progression free survival (rPFS) or death compared to a change in androgen receptor-directed therapy (ARDT) in metastatic castrate resistant prostate cancer (mCRPC) participants that were previously treated with an alternate ARDT and not exposed to a taxane-containing regimen in the castrate resistant prostate cancer (CRPC) or metastatic hormone-sensitive prostate cancer (mHSPC) settings.

[0473] Primary To evaluate whether treatment with177Lu-PSMA-617 improves the time Objective to radiographic progression by BICR according to Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 or death in participants with progressive PSMA-positive mCRPC compared to participants treated with ARDT

[0474] Key To evaluate whether treatment with177Lu-PSMA-617 improves the Secondary overall survival (OS) in participants with progressive PSMA-positive Objective mCRPC compared to participants treated with ARDT treatment Secondary • To estimate the time to radiographic progression by BICR or death in Objectives participants treated with ARDT who subsequently crossover to177Lu- PSMA-617 after radiographic progression (rPFS2)

[0475] • To evaluate Progression free survival (PFS) by investigator's assessment

[0476] • To evaluate the second progression Free Survival (PFS2) by investigator's assessment

[0477] • To evaluate whether treatment with177Lu-PSMA-617 improves the biochemical response as detected by Prostate specific antigen (PSA) halving compared to participants treated with ARDT

[0478] • To evaluate whether treatment with177Lu-PSMA-617 improves the time to first symptomatic skeletal event (TTSE) compared to participants treated with ARDT

[0479]

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[0482] • To evaluate whether treatment with177Lu-PSMA-617 improves the time to radiographic soft tissue progression compared to participants treated with ARDT

[0483] • To evaluate whether treatment with177Lu-PSMA-617 improves the time to chemotherapy compared to participants treated with ARDT • To evaluate whether treatment with177Lu-PSMA-617 improves the health-related quality of life (HRQoL) compared to participants treated with ARDT

[0484] • To evaluate the safety and tolerability of177Lu-PSMA-617 Exploratory • To evaluate whether treatment with177Lu-PSMA-617 improves the Objectives overall response by Blinded Independent Central Review (BICR)

[0485] assessment and according to PCWG3-modified RECIST v1.1 compared to participants treated with ARDT

[0486] • To evaluate whether treatment with177Lu-PSMA-617 improves the disease control by BICR assessment compared to participants treated with a change in ARDT

[0487] • To evaluate whether treatment with177Lu-PSMA-617 improves the duration of response by BICR compared to participants treated with ARDT

[0488] • To evaluate whether treatment with177Lu-PSMA-617 improves the time to PSA progression compared to participants treated with ARDT • To evaluate whether treatment with177Lu-PSMA-617 improves the time to pain progression compared to participants treated with ARDT • To assess molecular biomarkers, e.g. ctDNA fraction i.a. at C1D1 and C2D1, associated with response, resistance to treatment and / or safety

[0489] • Germany only: To determine the kidney absorbed dose in the first cycle

[0490] Study Design This is a phase III, open label, multicenter randomized study for PSMA- positive metastatic CRPC participants previously treated with an ARDT and where it is considered appropriate to delay taxane-based chemotherapy.

[0491] The study aims at evaluating the superiority of177Lu-PSMA-617 over a

[0492]

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[0495] change of ARDT treatment in prolonging rPFS. The primary endpoint of rPFS will be assessed via blinded independent centralized review of radiographic images provided by the treating physician and as outlined in PCWG3 Guidelines.

[0496] The study will also evaluate whether177Lu-PSMA-617 improves the overall survival (OS) in participants with progressive PSMA-positive mCRPC compared to participants treated with a change in ARDT treatment. OS is defined as the time from randomization to death due to any cause.

[0497] Screening period

[0498] Screening procedures are carried out after signature of informed consent and within 28 days prior to randomization in Interactive Response Technology (IRT) system. At screening, the participants will be assessed for eligibility and will undergo a68Ga-PSMA-11 positron emission tomography (PET) / computed tomography (CT) scan to evaluate PSMA positivity by central review. Only participants with PSMA positive cancer and confirmed eligibility criteria will be randomized. Randomization will be stratified by prior ARDT use in castrate-resistant prostate cancer (CRPC) vs. HSPC setting and by symptomatology i.e. asymptomatic or mildly symptomatic (score on item 3 of the Brief Pain Inventory Short Form (BPI-SF) questionnaire (symptomatic = score >3 on item 3 of the BPI-SF questionnaire).

[0499] For all participants, the treating physician will make a choice of which ARDT (abiraterone or enzalutamide) will be administered to the participant should they get randomized to the ARDT arm. If the participant gets randomized to receive177Lu-PSMA-617, the choice of change of ARDT treatment will be discarded.

[0500] Randomization period

[0501] Randomization occurs within the 28 days screening period once all eligibility criteria are met. The participants will be randomized 1:1 to receive177Lu-PSMA-617 or a change of the ARDT treatment. The ARDT change will include approved Androgen Receptor (AR) axis targeted therapy (abiraterone or enzalutamide). Supportive care will be allowed in both arms at the discretion of the investigator and includes available

[0502]

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[0505] care for the eligible participant according to best institutional practice for mCRPC treatment, including androgen deprivation therapy (ADT). Investigational agents, biological products, immunotherapy, cytotoxic chemotherapy, other systemic radioisotopes (e.g. radium-223), Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors or hemibody radiotherapy treatment must not be administered during the study treatment period. ARDT must not be administered concomitantly with177Lu-PSMA-617.

[0506] Treatment period

[0507] •177Lu-PSMA-617 treatment arm

[0508] Participants randomized to the investigational arm must begin177Lu- PSMA-617 dosing within 14 days after randomization. Participants will receive 7.4 GBq (200 mCi) + / - 10%177Lu-PSMA-617 once every 6 weeks for 6 cycles. Best supportive care, including ADT, may be used. After the last day of study treatment period of177Lu-PSMA-617 (i.e. after completion of 6 cycles of treatment OR treatment discontinuation for any reason) [for e.g. upon radiographic progression as assessed by blinded centralized review]) or upon radiographic progression as assessed by blinded centralized review, the participants must have an End of Treatment (EOT) visit performed ≤ 7 days and enter the Post-treatment Follow-up.

[0509] In the absence of safety concerns, every effort should be made to keep the participant on the randomized treatment until BICR-determined radiographic progression or until the completion of the 6 cycles of177Lu- PSMA-617.

[0510] • ARDT treatment arm

[0511] For participants randomized to the ARDT treatment arm, the change of ARDT treatment for each participant will be selected by the treating physician prior to randomization and will be administered per the physician’s orders. Best supportive care, including ADT, may be used. After the last day of study treatment (treatment discontinuation for any reason) or upon radiographic progression as assessed by blinded centralized review, the participants must have an End of Treatment (EOT) visit performed ≤ 7 days and enter the Post-treatment Follow-up.

[0512]

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[0515] In absence of safety concerns, every effort should be made to keep the participant on the randomized treatment until BICR-determined radiographic progression.

[0516] End of Treatment

[0517] Randomized treatment may be discontinued if:

[0518] • The participant, sponsor or investigator chooses to discontinue treatment

[0519] • Toxicity

[0520] • Completion of the 6 cycles of177Lu-PSMA-617

[0521] • Serious non-compliance to the protocol

[0522] • BICR-determined progression

[0523] It is important that the scheduled imaging assessments continue until BICR-determined progression. PSA progression is strongly discouraged as a criterion for initiation of a new neoplastic therapy prior to BICR- determined progression. PCWG3 guidelines should be followed to guide discontinuation of treatment

[0524] End of Treatment visit must be performed ≤ 7 days after the last day of study treatment period. EOT is to occur before the participant is to enter the post-treatment Follow-up period of the study and before the initiation of any subsequent anticancer treatment, outside of what is allowed in the study.

[0525] If a participant withdraws consent for the treatment period of the study, an EOT must be done and the participant will enter the Post- treatment Follow-up unless he specifically withdraws post- treatment Follow-up. Crossover period

[0526] Upon confirmation of rPFS by BICR, participants randomized to the ARDT arm will either be allowed to cross over to receive177Lu-PSMA- 617 within 28 days of central confirmation of radiographic disease progression, or may continue to receive any other therapy per the discretion of the treating physician in the Post-treatment Follow-up. In order for a participant randomized to the change in ARDT arm to cross over to receive177Lu-PSMA-617, he must meet the following criteria:

[0527] • Confirmed radiographical progression as assessed by BICR

[0528]

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[0531] • No intervening antineoplastic therapy is administered after the randomized treatment

[0532] • Any unresolved toxicity from prior therapy should be controlled and must be no greater than CTCAE grade ≤2 or baseline at the time of registration. for crossover

[0533] • ECOG performance status 0-1 at the time of registration for crossover

[0534] • Adequate organ function at the time of registration for crossover:

[0535] • Bone Marrow reserve:

[0536] o ANC ≥1.5 x 109 / L

[0537] o Platelets ≥100 x 109 / L

[0538] o Hemoglobin ≥9 g / dL

[0539] • Hepatic

[0540] o Total bilirubin (TBIL) < 2 x ULN (upper limit of normal).

[0541] For participants with known Gilbert’s Syndrome <3 x ULN is permitted

[0542] o Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN OR ≤5.0 x ULN for patients with liver metastases

[0543] • Renal:

[0544] o eGFR ≥ 50 mL / min / 1.73m2using the Modification of Diet in Renal Disease (MDRD) equation

[0545] • Agreement to continue with the study visit schedule

[0546] A participant, who is deemed to have disease progression per investigator assessment, but not by BICR, is not eligible to cross over at that time. Such participant should continue to receive randomized study treatment until progression determined by BICR.

[0547] If crossover to177Lu-PSMA-617 is selected, then177Lu-PSMA-617 will be administered with the same dose / schedule as for participants who were initially randomized to receive177Lu-PSMA-617 as described

[0548]

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[0551] above.

[0552] After the last day of study treatment period of177Lu-PSMA-617 or upon second radiographic progression (rPFS2), the participants must have a second End of Treatment (EOT2) visit performed ≤ 7 days and enter the Post-treatment Follow-up. The participant can receive any other therapy per the discretion of the treating physician in the Post-treatment Followup.

[0553] Post-treatment Follow-up period

[0554] • 30 day Safety Follow-up

[0555] All randomized and / or treated participants should have a safety followup conducted approximately 30 days after the EOT visit.

[0556] • Long term follow-up

[0557] Long term follow-up starts after the 30 Days Safety follow-up and lasts until the accrual of events for the planned OS-based analysis (key secondary endpoint).

[0558] In long term follow-up safety and efficacy information will be collected:

[0559] • Safety: During the long term follow-up, all medically significant adverse events (all SAEs) deemed to be related to177Lu-PSMA-617 will be collected. This will include potential late onset radiation toxicity. For participants who received177Lu-PSMA-617 in the177Lu-PSMA-617 arm or in crossover, the following adverse events will be captured beyond the 30 day safety period regardless of relationship to study treatment and whether new anticancer therapy has been initiated: hematologic toxicities with primary focus on myelosuppression and thrombocytopenia (including need for transfusion or use of growth factors), renal failure, xerostomia, xerophthalmia, secondary malignancies.

[0560] • Efficacy: In any participant entering long term follow-up discontinuing for reasons other than BICR-determined radiographic progression, tumor assessments must be performed every 8 weeks after first dose of study treatment for the first 24 weeks (week 9, 17, 25) and then every 12 weeks (week 37, 49, etc) until confirmation of radiographic progression by BICR

[0561] The long-term follow-up period will also include the collection of survival

[0562]

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[0565] information and other assessments.

[0566] Other: Other data collected during long-term follow-up includes blood sampling for hematology, chemistry testing, coagulation, DNA and tumor samples for biomarkers. The visits will be carried out every 12 weeks (± 28 days) until death, lost to follow-up, withdrawal of consent (WoC) / opposition to use data / biological samples or accrual of the number of events required for the planned analyses for OS for the study, whichever occurs first. This follow-up will allow to collect information on medically significant long-term toxicities such as longterm radiotoxicity. Duration of long term follow-up is expected to continue till end of study.

[0567] If the participant withdraws consent for the collection of blood samples, physical exams PROs and imaging assessments during the long-term follow-up, information on survival, AEs related to study treatment and post-treatment antineoplastic therapy will be collected.

[0568] Participants who have received177Lu-PSMA-617 and remain in followup on the trial at the sponsor’s completion of the study will be asked to join a separate study of long-term safety for a duration of up to 10 years.

[0569] Study Adult PSMA-positive men previously treated with an ARDT where it is Population considered appropriate to delay taxane-based chemotherapy.

[0570] Approximately 450 participants will be randomized (225 per treatment group).

[0571] Inclusion Participants eligible for inclusion in this study must meet all of the Criteria following criteria:

[0572] 1. Signed informed consent must be obtained prior to participation in the study

[0573] 2. Participants must be adults ≥ 18 years of age

[0574] 3. Participants must have an ECOG performance status of 0 to 1 4. Participants must have histological pathological, and / or cytological confirmation of

[0575] adenocarcinoma of the prostate

[0576] 5. Participants must be68Ga-PSMA-11 PET / CT scan positive, and eligible as determined by the sponsor’s central reader

[0577]

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[0580] 6. Participants must have a castrate level of serum / plasma testosterone (< 50 ng / dL or

[0581] < 1.7 nmol / L)

[0582] 7a. Participants must have progressed only once on prior second generation ARDT

[0583] (abiraterone, enzalutamide, darolutamide, or apalutamide).

[0584] first generation androgen receptor inhibitor therapy (e.g. bicalutamide) is allowed but

[0585] not considered as prior ARDT therapy

[0586] • second generation ARDT must be the most recent therapy received

[0587] 8. Participants must have progressive mCRPC. Documented progressive mCRPC will

[0588] be based on at least 1 of the following criteria:

[0589] • Serum / plasma PSA progression defined as 2 increases in PSA measured at least 1 week apart. The minimal start value is 2.0 ng / mL; 1.0 ng / mL is the minimal starting value if confirmed rise in PSA is the only indication of progression.

[0590] • Soft-tissue progression defined [PCWG3-modified RECIST v1.1 (Eisenhauer et al 2009, Scher et al 2016)]

[0591] • Progression of bone disease: two new lesions; only positivity on the bone scan defines metastatic disease to bone (PCWG3 criteria (Scher etal 2016))

[0592] 9a. Participants must have ≥ 1 metastatic lesion that is present on baseline CT, MRI, or

[0593] bone scan imaging obtained prior to randomization

[0594] 10. Participants must have recovered to ≤ Grade 2 from all clinically significant toxicities

[0595] related to prior therapies (i.e. prior chemotherapy, radiation, etc.) except alopecia

[0596] 11. Participants must have adequate organ function:

[0597] • Bone marrow reserve:

[0598] • ANC ≥ 1.5 x 109 / L

[0599]

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[0602] • Platelets ≥100 x 109 / L

[0603] • Hemoglobin ≥ 9 g / dL

[0604] • Hepatic:

[0605] • Total bilirubin < 2 x the institutional upper limit of normal (ULN). For participants

[0606] with known Gilbert’s Syndrome < 3 x ULN is permitted

[0607] • ALT or AST ≤ 3.0 x ULN OR ≤ 5.0 x ULN for participants with liver metastases

[0608] • Renal:

[0609] • eGFR ≥ 50 mL / min / 1.73m2using the Modification of Diet in Renal Disease (MDRD)

[0610] equation

[0611] 12. Albumin ≥ 2.5 g / dL

[0612] 13a. Candidates for change in ARDT as assessed by the treating physician

[0613] • Participants cannot have previously progressed nor had intolerable toxicity to both enzalutamide and abiraterone.

[0614] Exclusion Participants meeting any of the following criteria are not eligible for criteria inclusion in this study:

[0615] 1. Previous treatment with any of the following within 6 months of randomization:

[0616] Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium- 223, hemi-body

[0617] irradiation

[0618] 2. Previous PSMA-targeted radioligand therapy

[0619] 3a. Prior treatment with cytotoxic chemotherapy for castration resistant

[0620] or castrate sensitive prostate cancer (e.g., taxanes, platinum, estramustine,

[0621] vincristine, methotrexate, etc.), immunotherapy or biological therapy [including

[0622] monoclonal antibodies], [Note: Taxane exposure (maximum 6 cycles) in the adjuvant

[0623]

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[0626] or neoadjuvant setting is allowed if 12 months have elapsed since completion of this

[0627] adjuvant or neoadjuvant therapy. Prior treatment with sipuleucel-T is allowed]

[0628] 4. Any investigational agents within 28 days prior to day of randomization

[0629] 5. Known hypersensitivity to any of the study treatments or its excipients or to drugs of

[0630] similar classes

[0631] 6a. Concurrent cytotoxic chemotherapy, immunotherapy, radioligand therapy, PARP

[0632] inhibitor, biological therapy, or investigational therapy 7. Transfusion or use of bone marrow stimulating agents for the sole purpose of making

[0633] a participant eligible for study inclusion

[0634] 8a. Participants with a history of CNS metastases who are neurologically unstable,

[0635] symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic

[0636] integrity. Participants with CNS metastases are eligible if received therapy (surgery,

[0637] radiotherapy, gamma knife), asymptomatic and neurologically stable without

[0638] corticosteroids. Participants with epidural disease, canal disease and prior cord

[0639] involvement are eligible if those areas have been treated, are stable, and not

[0640] neurologically impaired.

[0641] 9. Symptomatic cord compression, or clinical or radiologic findings indicative of

[0642] impending cord compression

[0643] 10. History or current diagnosis of the following ECG abnormalities indicating significant

[0644] risk of safety for study participants:

[0645]

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[0648] • Concomitant clinically significant cardiac arrhythmias, e.g. sustained ventricular

[0649] tachycardia, complete left bundle branch block, high-grade AV block (e.g.,

[0650] bifascicular block, Mobitz type II and third degree AV block)

[0651] • History of familial long QT syndrome or known family history of Torsades de Pointe

[0652] • Cardiac or cardiac repolarization abnormality, including any of the following: History

[0653] of myocardial infarction (Ml), angina pectoris, or CABG within 6 months prior to

[0654] starting study treatment

[0655] 11a. Concurrent serious (as determined by the Principal Investigator) medical

[0656] conditions, including, but not limited to New York Heart Association class III or IV

[0657] congestive heart failure, history of congenital prolonged QT syndrome, uncontrolled

[0658] infection, known active hepatitis B or C or other significant co-morbid conditions

[0659] that in the opinion of the investigator would impair study participation or cooperation.

[0660] • HIV-infected participants who are at a low risk of AIDS-related outcomes may

[0661] participate in this trial.

[0662] • Participants with an active documented COVID-19 infection (any grade of disease

[0663] severity) at time of informed consent may be included only when completely

[0664] recovered (in accordance with local guidance).

[0665] 12a. Diagnosed with other malignancies that are expected to alter life expectancy or

[0666] may interfere with disease assessment. However, participants with a prior history

[0667]

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[0670] of malignancy that has been adequately treated and who have been disease free

[0671] and treatment free for more than 3 years prior to randomization, are eligible, as are

[0672] participants with adequately treated non-melanoma skin cancer and superficial

[0673] bladder cancer

[0674] 13a. Sexually active males unwilling to use a condom during intercourse while taking

[0675] study treatment and for 14 weeks after stopping study treatment. A condom is

[0676] required for all sexually active male participants to prevent them from fathering a

[0677] child AND to prevent delivery of study treatment via seminal fluid to their partner.

[0678] In addition, male participants must not donate sperm for the time period specified

[0679] above. If local regulations deviate from the contraception methods listed above to

[0680] prevent pregnancy, local regulations apply and will be described in the IGF

[0681] 14a. Unmanageable concurrent bladder outflow obstruction or urinary incontinence.

[0682] Note: Participant with bladder outflow obstruction or urinary incontinence, which is

[0683] manageable and controlled with best available standard of care (incl. pads,

[0684] drainage) are allowed.

[0685] 15. History of somatic or psychiatric disease / condition that may interfere with the

[0686] objectives and assessments of the study

[0687] 16. Any condition that precludes raised arms position 17a. Eligible for treatment(s) other than ARDT based on presence of any mutations or biomarkers that are known as predictors of better

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[0691] response (e.g., AR-V7 or BRCA).

[0692] 18. Not able to understand and to comply with study instructions and requirements

[0693] Study177Lu-PSMA-617 or approved ARDT (abiraterone or enzalutamide) Treatment

[0694] Treatment of177Lu-PSMA-617

[0695] interest

[0696] Efficacy • Radiographic imaging for tumor assessments:

[0697] Assessments • CT with contrast / magnetic resonance imaging (MRI)

[0698] • Bone scans with technetium-99m labeled diphosphonates

[0699] • PCWG3-modified RECIST v1.1

[0700] • Symptomatic skeletal events

[0701] • Clinical progression

[0702] • PSA levels

[0703] Key safety • Adverse Events (AEs)

[0704] assessments • Serious Adverse Events (SAEs)

[0705] • Vital signs, physical examinations

[0706] • ECGs

[0707] • Laboratory parameters including hematology, clinical chemistry and coagulation

[0708] • Concomitant medications and / or therapies

[0709] Other

[0710] assessments • ECOG Performance Status scale

[0711] • Biomarkers (e.g. ctDNA at C1D1 and C2D1)

[0712] • Health-related quality of life:

[0713] • European Quality of Life (EuroQol) 5 Domain 5 Level scale questionnaire (EQ-5D-5L)

[0714] • Functional Assessment of Cancer Therapy - Prostate (FACT-P) • Brief Pain Inventory - Short Form (BPI-SF)

[0715] Data analysis The following data analyses are planned for the study:

[0716] • Primary rPFS Analysis

[0717] Assuming proportional hazards model for rPFS, the null hypothesis will

[0718]

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[0721] be tested at one-sided 2.5% level of significance: H01 (null hypotheses): 0 > 0 vs. Ha1 (alternative hypotheses): 0 < 0, where 0 is the log hazard ratio of rPFS in the177Lu-PSMA-617 (investigational) arm vs. a change of ARDT treatment (control) arm.

[0722] The primary efficacy analysis to test this hypothesis and compare rPFS, the primary efficacy variable, between the two treatment groups will be using a stratified log-rank test at an overall one-sided 2.5% level of significance in favor of the177Lu-PSMA-617 arm. The stratification will be based on following randomization stratification factors (prior ARDT use: CRPC vs. HSPC setting; and symptomatology: asymptomatic or mildly symptomatic (score of 0-3 on Brief Pain Inventory Short Form (BPI-SF) questionnaire) vs symptomatic (score >3 on BPI-SF questionnaire).

[0723] Analyses will be based on the FAS population according to the randomized treatment group and strata assigned at randomization. The rPFS distribution will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves, median and associated 95% confidence intervals will be presented for each treatment group. The hazard ratio for rPFS will be calculated, along with its 95% confidence interval, from a stratified Cox model using the same stratification factors as for the logrank test.

[0724] The primary rPFS analysis will only be carried out after all participants have been randomized and 156 events have been observed.

[0725] • OS Interim and Final Analysis

[0726] OS, as the key secondary variable, will be formally statistically tested, if the primary variable rPFS is statistically significant.

[0727] The key secondary efficacy analysis is to compare the two treatment groups and will consist of a stratified log-rank test at an overall onesided 2.5% level of significance using randomization stratification factors (prior ARDT use: CRPC vs. HSPC setting; and symptomatology: asymptomatic or mildly symptomatic vs symptomatic). The key secondary efficacy variable, OS, will be analyzed at the interim analysis and final analysis of a 3-look group sequential design with a Lan- DeMets (O’Brien-Fleming) alpha spending function using information

[0728]

[0729] PAT060004-PCT-SEC01

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[0731] fractions of (0.25,0.75, 1).

[0732] The first interim will occur when the rPFS primary analysis is performed and is expected to occur at approximately 0.25 information fraction. The second interim analysis will be performed at 0.75 information fraction. The interim analyses are planned after approximately 74 and 223 of the approximately 297 targeted OS events have been observed. The primary intent of the interim analyses is to stop early for superior efficacy. There is no intent to assess futility at these interim analyses. The first interim analysis (at the time of primary rPFS analysis) will only be carried out after all participants have been randomized.

[0733] Analyses will be based on the full analysis set (FAS) population according to the randomized treatment group and strata assigned at randomization. The OS distribution will be estimated using the Kaplan- Meier method, and Kaplan-Meier curves, median and associated 95% confidence intervals will be presented for each treatment group. The hazard ratio for OS will be calculated, along with its 95% confidence interval, from a stratified Cox model using the same stratification factors as for the log-rank test. Other secondary endpoints including time to Symptomatic skeletal events (SSE), Objective Response Rate (ORR), Disease Control Rate (DCR), duration of response, Proportion of participants who are have achieved a > 50% decrease from baseline that is confirmed by a second PSA measurement >4 weeks (PSA50 response), time to PSA progression, and Health-Related Quality of Life (HRQoL) (FACT-P, BPI-SF, EQ-5D-5L) will also be analyzed. Detailed statistical methodology for these analyses will be provided in the statistical analysis plan.

[0734] Key words177Lu-PSMA-617, ARDT, mCRPC, rPFS, CRPC, HSPC, PSMA

[0735]

[0736] Biomarker Assessment in Blood Samples

[0737] Approximately 16 mL of whole blood will be collected in all participants at pre-dose on Cycle 1 Day 1, Cycle 2 Day 1, Cycle 4 Day 1, Cycle 6 Day 1 (and corresponding crossover visits if the participant is a crossover), Cycle 7 Day 1 and every 12 weeks thereafter during the treatment period for ARDT arm only, end of treatment (EOT / EOT2), then every 12 weeks during the long-PAT060004-PCT-SEC01

[0738] - 60 -

[0739] term follow-up. The cell pellet from the Cycle 1 Day 1 plasma collection will be stored and potentially used as a normal tissue control.

[0740] Exploratory biomarker analysis in blood samples collected at baseline, on treatment, posttreatment follow-up period and at disease progression will include cytokines and soluble protein biomarkers. In particular, the sequencing of specific gene panels and determination of mutation load using circulating tumor DNA (ctDNA) will be performed.

[0741] Biomarker sample collection plan:

[0742] Sample Type Volume Visit Time point Blood samples

[0743] Mandatory Blood Plasma for circulating 16 mL C1D1** Pre-dose plasma for biomarker analysis biomarkers. 16 mL C2D1** Pre-dose

[0744] (including clDNA)

[0745]

[0746] Pre-dose

[0747] 16 ml C6DT* Pre-dose

[0748] 16 ml C7D1. C3D1, Pre-dose C9D1, etc. (every

[0749] 12 weeks starting

[0750] C7D1 for ARDT

[0751] arm;

[0752] 16 mL EOT and EOT2** Anytime

[0753] 16 ml Every 2 weeks Anytime

[0754] during long-term

[0755] follow-up**

[0756] ** Including visits for crossover participants from ARDT to177Lu PSMA-617 treatment

[0757] Rationale:

[0758] Rationale for study design

[0759] The purpose of this study is to determine whether 177Lu-PSMA-617, given for 6 cycles at a dose of 7.4 GBq (200 mCi) + / - 10%, improves the rPFS compared to a change in ARDT in mCRPC participants that were previously treated with an alternate ARDT and were not exposed to a taxane-containing regimen in the CRPC or HSPC settings. rPFS is an important endpoint in mCRPC recognized by PCWG3 as well as several other trials conducted in this setting.PAT060004-PCT-SEC01

[0760] - 61 -

[0761] After radiographic progression, follow up for survival will continue. The key secondary objective is to evaluate whether 177Lu-PSMA-617 improves the overall survival (OS) compared to participants treated with a change in ARDT treatment.

[0762] Eligible participants will be randomized to one of two treatment arms. Randomization will be stratified to avoid bias in treatment selection. Treatment will be open-label. Upon confirmation of rPFS by BICR, participants randomized to the ARDT arm will be allowed to cross over to receive 177Lu-PSMA-617.

[0763] The preliminary clinical evidence indicates that 177Lu-PSMA-617 may demonstrate clinical benefit for men with mCRPC, improving rPFS and OS compared with a change in ARDT. Data from this study will complement the data from the VISION study for 177Lu-PSMA-617 as a treatment in mCRPC prior to the use of taxanes.

[0764] Rationale for choice of background therapy

[0765] Supportive care will be allowed in both arms and includes available care for the eligible participant according to best institutional practice for mCRPC treatment, including ADT. This is allowed in order to maintain serum testosterone levels, and management of the overall disease symptomatology per discretion of the treating physician.

[0766] Investigational agents, biological products, immunotherapy, cytotoxic chemotherapy, other systemic radioisotopes (e.g. radium-223), Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors or hemi-body radiotherapy treatment must not be administered prior to radiographic progression assessed by blinded centralized review (primary endpoint). ARDT must not be administered concomitantly with 177Lu-PSMA-617.

[0767] Rationale for dose / regimen and duration of treatment

[0768] The basic principle of 177Lu-PSMA-617 radioligand therapy is to systemically deliver low dose rate radiation specifically to multiple PSMA positive prostate cancer lesions, while sparing normal tissues. To date, 12 dosimetry studies have been conducted in 158 participants. The results are consistent across the studies and demonstrate exposure that correlates well with the expected rapid clearance of a small molecule, and the limited distribution pattern of a PSMA-targeted radionuclide. The primary sites of non-tumor uptake were the salivary glands, lacrimal glands, and kidneys, with excretory mechanisms contributing to exposure in the kidneys where approximately 50% of the injected dose is cleared within 48 hours (KratochwilPAT060004-PCT-SEC01

[0769] - 62 -

[0770] et al 2016). PSMA-negative tissues like the bone marrow, are exposed transiently to 177Lu-PSMA- 617 while in circulation, however this exposure is minimized due to its rapid elimination.

[0771] 177Lu-PSMA-617 is well tolerated according to the clinical experience that has been documented in over 53 publications, summarizing the safety and or efficacy information from over 1280 participants.

[0772] Across these studies doses have ranged from 1.1 - 12.0 GBq, and schedules have typically followed an administration schedule of once every 4 to 12 weeks, for 1 - 9 cycles. Although the German Society of Nuclear Medicine 2016 recommended a 6.0 GBq dose every 8 weeks for 3 cycles, the majority of these publications have used a regimen of 4 cycles of 6 GBq every 8 weeks. However, efficacy and safety information from a prospective phase 2 study suggested that dosing of 4.0-8.9 (mean 7.5) GBq every 6 weeks for 4 cycles was well tolerated and efficacious (Violet et al 2020). Clinical series now show reports of more than 4 cycles of 177Lu-PSMA-617 being administered safely as a means to maximize the benefit to the participant (Bräuer et al 2017, Kessel K et al 2019, Kulkarni et al 2018a, Kulkarni et al 2018b, Kulkarni et al 2018c, Maffey Steffan et al 2020, Rahbar et al 2018, Yadav et al 2020, Yordanova et al 2017, van Kalmthout et al 2019).

[0773] In the phase II TheraP study (ANZLIP protocol 1603, NCT03392428), 200 Australian men with mCRPC were randomly allocated (1:1) to treatment with either 177Lu-PSMA-617 or cabazitaxel. The starting dose for 177Lu-PSMA-617 was 8.5 GBq and was reduced by 0.5 GBq per cycle, i.e. 8.5, 8, 7.5, 7, 6.5, 6, for a maximum of 6 cycles given every 6 weeks. This equates to a cumulative dose of 43.5 GBq, which is similar to that for this proposed study. The clinical safety review and detailed analyses of the radiation exposure support the intended dose and frequency of 177Lu-PSMA-617 administration in this clinical trial.

[0774] Rationale for choice of control drugs (comparator / placebo) or combination drugs

[0775] Four main drug classes have been approved for treatment for prolonging survival in mCRPC participants. These include ARDTs (i.e., abiraterone and enzalutamide), taxanes (docetaxel and cabazitaxel), immunotherapy (sipuleucel-T) and bone-targeted radiopharmaceutical (radium 223 dichloride). With the evolution in the treatment landscape of prostate cancer, some of these life-prolonging therapies (ARDT and docetaxel) are increasingly used in earlier stages (e.g. metastatic hormone sensitive prostate cancer and non-metastatic prostate cancer). This creates an even greater unmet medical need in mCRPC. Among participants who havePAT060004-PCT-SEC01

[0776] - 63 -

[0777] previously received an ARDT therapy, several mechanisms have been implicated in development of resistance to the treatment (Attard et al 2009). The rPFS for participants that change ARDT treatment ranges from 3.6 to 15 months and OS from 11 to 23 months (de Bono et al 2020, de Wit et al 2019, Komura et al 2019). On the other hand, many participants do not receive chemotherapy primarily because of preexisting medical conditions or associated toxic effects. (Engel Nitz et al 2011, Harris et al 2011, Lissbrant et al 2013, Zielinski et al 2014). Sipuleucel-T is best used in mildly asymptomatic small volume disease; and radium 223 is used to treat men with bone-only disease. PARP inhibitors are an emerging drug class in mCRPC, but their use is restricted in a subgroup of mCRPC participants with homologous recombination repair gene mutations [PROfound (de Bono et al 2020, Hussain et al 2019) and TRITON2 (Abida et al 2019) ESMO 2019 studies],

[0778] ARDTs such as abiraterone and enzalutamide have shown efficacy and are approved for treatment of mCRPC among participants who have not previously been treated with taxane-based chemotherapy, and are a relevant comparator for this study.

[0779] STUDY DRUGS

[0780] The second generation ARDT abiraterone, enzalutamide, darolutamide, and apalutamide (all four drug names are rINN) are commercially available as registered drug products.

[0781] The radioligand imaging agent68Ga-PSMA-11 (rINN: gallium (68Ga) gozetotide) is commercially available as kit for labeling with Ga-68 under the drug product brand names ILLUCCIX and LOCAMETZ.

[0782] The radioligand therapeutic agent177Lu-PSMA-617 (rINN: lutetium (177Lu) vipivotide tetraxetan) is commercially available under the drug product brand name PLUVICTO.

[0783] The content of the drug labels of all those drug products (prescribing information, summary of product characteristics) is herewith incorporated by reference.

[0784] RESULTS

[0785] Summary of Results

[0786] Key parameter Definition Outcome

[0787]

[0788] PAT060004-PCT-SEC01

[0789] - 64 -

[0790] Primary Endpoint* Radiographic progression-free survival At the primary analysis (using 02- (rPFS) based on blinded independent Oct-2022 DCO), a statistically central review (BICR) as per Prostate significant benefit in rPFS was Cancer Working Group 3 (PCWG3)- observed in favor of the modified Response Evaluation Criteria [177Lu]Lu-PSMA-617 arm with a in Solid Tumors 1.1 (RECIST 1.1) HR (95% CI) of 0.41 (0.29, 0.56); criteria one-sided p-value: <0.0001 (59% risk reduction in radiographic progression or death). Median rPFS (95% CI) was 9.30 months (6.77, NE) in the [177Lu]Lu-PSMA-617 arm vs. 5.55 months (4.04, 5.95) in the ARDT arm.

[0791] rPFS results were consistent across all pre-planned sensitivity analyses and across demographic and prognostic subgroups.

[0792] An updated analysis of rPFS was conducted as an exploratory analysis with a nominal p-value at the time of the 2nd interim OS analysis (using 21 -Jun-2023 DCO); results were consistent with the primary analysis, with more mature and robust estimates of median rPFS (95% CI) of 12.02 months (9.30, 14.42) in the [177Lu]Lu- PSMA-617 arm vs. 5.59 months (4.17, 5.95) in the ARDT arm.

[0793]

[0794] PAT060004-PCT-SEC01

[0795] - 65 -

[0796] Safety Incidence of AEs All AEs: 98.2 % in [177Lu]Lu- PSMA-617 arm vs. 96.1% in ARDT arm

[0797] Grade > 3: 34.4% in [177Lu]Lu- PSMA-617 arm vs. 43.5% in ARDT arm

[0798] AE leading to discontinuation: 5.7% in [177Lu]Lu-PSMA-617 arm vs 5.2% in ARDT arm

[0799] AEs leading to dose adjustment: 3.5% in [177Lu]Lu-PSMA-617 arm vs. 15.1% in ARDT arm

[0800] AEs leading to dose interruption: 11.9% in [177Lu]Lu-PSMA-617 arm vs. 16.8% in ARDT arm AEs requiring additional therapy: 71.4% in [177Lu]Lu-PSMA-617 arm vs. 78.0% in ARDT arm Safety Incidence of Serious AEs All Serious AEs: 20.3% in

[0801] [177Lu]Lu-PSMA-617 arm vs. 28.0% in ARDT arm

[0802] Fatal serious AEs: 1.8% in [177Lu]Lu-PSMA-617 arm vs. 2.2% in ARDT arm

[0803]

[0804] *The data presented in this document are based on the most recent data from the central vendor using the original primary analysis data cut-off date of 02-0ct-2022 and second interim OS analysis data cut-off date of 21-Jun-2023.

[0805] DCO = data cut-off; RPSFT = rank preserving structural failure time; NE: not estimable / not reached.

[0806] At the time of the primary rPFS analysis (DCO of 02-0ct-2022):PAT060004-PCT-SEC01

[0807] - 66 -

[0808] The study was ongoing. The duration of study (from randomization to data cut-off) was 7.26 months for the [177Lu]Lu-PSMA-617 arm vs 7.28 months for the ARDT arm.

[0809] The median follow-up for rPFS was 3.38 months (from randomization to censoring or rPFS event as per BICR). The minimum - maximum rPFS follow-up was 0.03-12.62 months. A total of 125 (53.6%) participants in the [177Lu]Lu-PSMA-617 arm vs 97 (41.5%) participants in the ARDT arm were censored as ‘Ongoing without event’ prior to the median duration of study in each arm.

[0810] At the time of the 2nd interim analysis (DCO of 21 -Jun-2023):

[0811] The study was ongoing. The duration of study (from randomization to data cut-off) was 15.87 months for the [177Lu]Lu-PSMA-617 arm vs 15.89 months for the ARDT arm.

[0812] The median follow-up for rPFS was 5.98 months (from randomization to censoring or rPFS event as per BICR). The minimum - maximum rPFS follow-up was 0.03-20.30 months. A total of 76 (32.5%) participants in the [177Lu]Lu-PSMA-617 arm vs 29 (12.4%) participants in the ARDT arm were censored as ‘Ongoing without rPFS event’ prior to the median duration of study in each arm.

[0813] A total of 123 participants (123 / 234 (52.6%)) of all ARDT participants or 123 / 168 (73.2%) of ARDT participants with confirmed radiographic progression) had crossed over from the ARDT arm to the [177Lu]Lu-PSMA-617 arm after notification of confirmed radiographic progression by BICR.

[0814] Treatment arms were balanced in terms of demography and baseline characteristics.

[0815] Treatment discontinuations were reported for 41.0% of the participants in the [177Lu]Lu-PSMA-617 arm and 82.5% in the ARDT arm. The main reasons for treatment ([177Lu]Lu-PSMA-617 vs ARDT) discontinuation were progressive disease (21.8% vs 62.4%), physician decision (10.7% vs 12.4%) and adverse event (5.6% vs 5.1%).

[0816] The median (min - max) duration of exposure to study treatment was 8.41 months (0.36 -11.63) in the [177Lu]Lu-PSMA-617 arm and 6.52 months (0.03 - 20.99) in the ARDT arm (prior to crossover and from start of treatment to last administration of study treatment as per data cut-off date of 21-Jun-2023). The median duration of exposure was 6.36 months (0.69 -20.99) for participants who received abiraterone, 6.59 months (0.03 - 20.99) for participants who received enzalutamide and 4.67 months (0.49-11.04) for participants who werePAT060004-PCT-SEC01

[0817] - 67 -

[0818] randomized to the ARDT arm who crossed over to [177Lu]Lu-PSMA-617 (hereafter referred to as [177Lu]Lu-PSMA-617 crossover participants).

[0819] The median (min-max) relative dose intensity was 97.6% (78.5 - 102.9) in the randomized [177Lu]Lu-PSMA-617 arm and 100 % (51.6 - 100) in the ARDT arm. The median (min-max) relative dose intensity was 100% (53.9 - 100) for participants who received abiraterone, 100% (51.6 - 100) for participants who received enzalutamide and 97.5% (76.0 - 105.4) for [177Lu]Lu-PSMA-617 crossover participants.

[0820] The study met its primary objective: the primary endpoint of radiographic progression-free survival (rPFS) based on blinded independent central review as per PCWG3-modified RECIST 1.1 criteria (using a DCO date of 02-0ct-2022) was statistically significant between the treatment arms (stratified log-rank test p<0.0001, one-sided) with an estimated 59% risk reduction in the [177Lu]Lu-PSMA-617 arm (n=233) compared to the ARDT arm (n=234) (hazard ratio: 0.41 with 95% Cl: (0.290.56)). There were 60 (25.8%) events in the [177Lu]Lu-PSMA-617 arm and 106 (45.3%) in the ARDT arm. Median rPFS (95% CI) was 9.30 months (6.77, NE) and 5.55 months (4.04, 5.95), respectively (

[0821] Table 5-1 a). The estimated rPFS probabilities (95% Cl) at 6 months were 69.0% (60.7, 75.9) for the 177Lu]Lu-PSMA-617 arm vs. 40.6% (32.1, 48.8) for the ARDT arm.

[0822] rPFS results were consistent across all preplanned sensitivity analyses and across demographic and prognostic subgroups.

[0823] Based on a DCO date of 21-Jun-2023, an updated analysis of rPFS was conducted as an exploratory analysis, demonstrating an estimated 57% risk reduction in the [177Lu]Lu-PSMA-617 arm (n=234) compared to the ARDT arm (n=234) (HR: 0.43 with 95% Cl: (0.33 0.54)). There were 115 (49.1%) events in the [177Lu]Lu-PSMA-617 arm and 168 (71.8%) in the ARDT arm. Median rPFS (95% Cl) was 12.02 months (9.30, 14.42) and 5.59 months (4.17, 5.95), respectively (see following Table).

[0824] [177Lu]Lu-PSMA-617 N=234 ARDT N=234 Number of events - n(%) 115 (49.1) 168 (71.8) Radiographic progression 105 (44.9) 161 (68.8)

[0825] Death [1] 10 (4.3) 7 (3.0)

[0826] Number censored - n(%) 119 (50.9) 66 (28.2)

[0827]

[0828] PAT060004-PCT-SEC01

[0829] - 68 -

[0830] Ongoing without event [2] 91 (38.9) 36 (15.4) Adequate assessment no longer 13 (5.6) 11 (4.7)

[0831] available [3]

[0832] Withdrew consent 4 (1.7) 3 (1.3)

[0833] Event documented after two or 11 (4.7) 16 (6.8)

[0834] more missing tumor

[0835] assessments

[0836] Lost to follow-up [4] 0 0

[0837] Hazard ratio (95% Cl) [177Lu]Lu-PSMA-617 vs ARDT [5] 0.43 [0.33, 0.54] P-value [177Lu]Lu-PSMA-617 vs ARDT [6] 0.0000000000005 Percentiles (95% Cl)

[0838] 25th 5.72 [3.71, 6.08] 2.30 [2.14, 2.69] 50th (Median) 12.02 [9.30, 14.42] 5.59 [4.17, 5.95] 75th 19.65 [17.15, NE] 10.91 [8.38, 13.63] Kaplan-Meier estimates (%) (95% Cl)

[0839] 3 months 84.5 [78.9, 88.6] 68.5 [61.9, 74.2] 6 months 71.4 [64.9, 76.9] 40.9 [34.2, 47.5] 9 months 58.0 [51.0, 64.4] 25.9 [20.0, 32.2] 12 months 50.3 [42.9, 57.2] 21.3 [15.6, 27.7] NE=not estimable.

[0840] [1] Death without radiographic progression.

[0841] [2] Participants without event and had adequate follow-up as of data cut-off.

[0842] [3] Participants censored without adequate evaluations for a specified period prior to data cutoff or without adequate baseline assessment.

[0843] [4] Recorded on the End of treatment or End of post-treatment follow-up disposition CRF.

[0844] [5] Hazard ratio obtained from stratified Cox PH model. [6] One-sided p-value at 2.5% level of significance obtained from stratified log-rank test. Stratification factors from IRT data: prior ARDT use in CRPC vs HSPC; asymptomatic and mildly symptomatic (score of 0-3 on item 3 of the Brief Pain Inventory Short Form (BPI-SF) questionnaire) vs symptomatic (score >3 on item 3 of the BPI-SF questionnaire).

[0845] The DCO of 21 -Jun-2023 from the 2nd interim analysis was used for an updated analysis of rPFS as an exploratory analysis with a nominal p-value.

[0846]

[0847] PAT060004-PCT-SEC01

[0848] - 69 -

[0849] Best overall radiological response accounting for soft tissue and bone disease based on BICR (Recist analysis set - participants with measurable disease at baseline)

[0850] [177Lu]Lu-PSMA-617 ARDT

[0851] N=71 N=74

[0852] n (%) n (%)

[0853] Participant with measurable 71 (100) 74 (100)

[0854] disease at baseline

[0855] Best overall response

[0856] Complete response (CR) 15 (21.1) 1 (1.4)

[0857] Partial response (PR) 20 (28.2) 9 (12.2)

[0858] Stable disease (SD) 20 (28.2) 32 (43.2)

[0859] Progressive disease (PD) 14 (19.7) 27 (36.5)

[0860] Unknown (UNK) 2 (2.8) 5 (6.8)

[0861] Overall Response Rate 35 (49.3) 10 (13.5)

[0862] (ORR: CR+PR)

[0863] 95% Cl (37.2, 61.4) (6.7, 23.5)

[0864] Disease Control Rate 55 (77.5) 42 (56.8)

[0865] (DCR: CR+PR+SD)

[0866] 95% Cl (66.0, 86.5) (44.7, 68.2)

[0867]

[0868] Responses are based on soft tissue assessment and bone lesion progression.

[0869] Best overall responses of CR and PR were confirmed by repeat assessments that were performed not less than 4 weeks after the criteria for response were first met.

[0870] CR may include participants with residual but non-progressive bone disease.

[0871] Result: [177Lu]Lu-PSMA-617 shows at least three times higher rORR compared to ARDT and a higher rDCR compared to ARDT

[0872] 177Lu-PSMA-617 delayed time to SSE versus ARPI change as it can be seen from the following table.

[0873] 177Lu-PSMA-617 ARPI change

[0874] (n = 234) (n = 234)

[0875]

[0876] PAT060004-PCT-SEC01

[0877] Number of events, n (%) 25 (10.7) 59 (25.2)

[0878] SSE 21 (9.0) 54 (23.1)

[0879] Death 4 (1.7) 5 (2.1)

[0880] Median time to SSE, months (95% Cl) NE (NE, NE) NE (15.61, NE)

[0881] HR (95% Cl) 0.35 (0.22, 0.57)

[0882] Median time to SSE (excluding death) NE (NE, NE) NE (15.61, NE)

[0883] HR (95% Cl) 0.32 (0.19, 0.54)

[0884]

[0885] ARPI, androgen receptor pathway inhibitor; Cl, confidence interval; DCO, data cut-off; HR, hazard ratio; NE, not estimable; OS, overall survival; PSMA, prostate-specific membrane antigen; SSE, symptomatic skeletal event, Interim OS analysis, DCO: June 2023.

[0886] Key secondary endpoint: OS analysis adjusted for crossover and by ITT Prespecified primary crossover-adjusted analysis

[0887] HR: 0.80 (95% Cl: 0.48, 1.33)

[0888] Median, months (95% Cl):

[0889] 19.25 (16.95, NE) vs 19.55 (14.95, NE)

[0890] Number of events 69 (29.5%)avs 36 (15.4%)

[0891] Prespecified supplementary unadjusted (ITT) analysis

[0892] HR: 1.16 (95% Cl: 0.83, 1.64)

[0893] Median, months (95% Cl):

[0894] 19.25 (16.95, NE) vs 19.71 (17.81, NE)

[0895] Number of events 69 (29.5%) vs 65 (27.8%)

[0896] Median OS follow-up time, months (range):

[0897] 12.72 (0.82, 23.00) vs 13.08 (1.54, 22.64)

[0898] aThree patients died prior to receiving177Lu-PSMA-617. ARPI, androgen receptor pathway inhibitor; Cl, confidence interval; DCO, data cut-off; HR, hazard ratio; ITT, intention-to-treat; NE, not estimable; OS, overall survival; PSMA, prostate-specific membrane antigen, Interim OS analysis (DCO: June 2023).PAT060004-PCT-SEC01

[0899] - 71 -

[0900] Regarding the key secondary endpoint:

[0901] The prespecified primary analysis method for OS was rank-preserving structural failure time (RPSFT) to adjust for crossover:

[0902] Rank-preserving structural failure time1,2

[0903] ■ Accepted model-based method to adjust for crossover in clinical trials

[0904] ■ Adjusts survival times for patients randomized to ARPI change who crossed over to177Lu-PSMA-617

[0905] ■ Assumes each patient progresses through disease towards death at their own speed (accelerated failure time model)

[0906] ■ Assumes that177Lu-PSMA-617 slows / quickens this speed by the same factor (X) whether177Lu-PSMA-617 is given at randomization or at crossover

[0907] - Uses a grid search to find the value of X that balances survival times between arms

[0908] ■ Multiplies observed survival times by X to obtain adjusted survival times for all patients who received177Lu-PSMA-617

[0909] - Uses a re-censoring algorithm to maintain assumption of independent random censoring required for unbiased estimation

[0910] ■ Observed survival times in177Lu-PSMA-617 arm are compared with adjusted survival times in ARPI change arm to estimate treatment effect as if crossover had not occurred ARPI, androgen receptor pathway inhibitor; OS, overall survival; PSMA, prostate-specific membrane antigen; RPSFT, rank-preserving structural failure time. 1. Morden JP et al. BMC 2011;11;4. 2. Ouwens M et al. Med Decis Mak 2018;38:509-19

[0911] Safety

[0912] The following adverse events (AEs) were reported in the [177Lu]Lu-PSMA-617 and ARDT (prior to crossover) arms, respectively (Table 6-1):

[0913] Any AEs: 98.2% vs. 96.1%

[0914] Grade > 3 AEs: 34.4% vs. 43.5%

[0915] Treatment-related: 11.0% vs. 12.5%

[0916] Serious AEs: 20.3% vs. 28.0%PAT060004-PCT-SEC01

[0917] - 72 -

[0918] Treatment-related: 3.1% vs. 2.2%

[0919] AEs leading to discontinuation: 5.7% vs. 5.2%

[0920] Treatment-related: 3.1% vs. 2.6%

[0921] AEs leading to dose adjustment 3.5% vs. 15.1%

[0922] AEs leading to dose interruption 11.9% vs. 16.8%

[0923] AEs requiring additional therapy 71.4% vs. 78.0%

[0924] The most common adverse events by Preferred Term (PT) (>10% in either arm) in the [177Lu]Lu-PSMA-617 versus ARDT arm were Dry mouth (57.3% vs. 2.2%), Asthenia (31.7% vs. 28.9%), Nausea (31.3% vs. 12.1%), Anaemia (24.2% vs. 16.8%), Fatigue (22.9% vs.

[0925] 25.4%), Constipation (22.0% vs. 13.4%), Decreased appetite (21.1% vs. 18.1%), Arthralgia (18.9% vs. 20.7%), COVID-19 (16.3% vs. 11.2%), Diarrhoea (16.3% vs. 8.6%), Back pain (12.3% vs. 16.4%), Vomiting (11.5% vs. 4.7%), Oedema peripheral (8.4% vs. 11.2%), and Weight decreased (6.6% vs. 12.1%) (Table 6-2).

[0926] Overview Adverse events, Safety set

[0927] [177Lu]Lu-PSMA-617 ARDT

[0928] N=227 N=232

[0929] All Grades Grade >=3 All Grades Grade >=3 Category n (%) n (%) n (%) n (%) Adverse events 223 (98.2) 78 (34.4) 223 (96.1) 101 (43.5) T reatm ent- 196 (86.3) 25 (11.0) 142 (61.2) 29 (12.5) related

[0930] Serious adverse 46 (20.3) 41 (18.1) 65 (28.0) 59 (25.4) events

[0931] T reatm ent- 7 (3.1) 6 (2.6) 5 (2.2) 5 (2.2) related

[0932] Fatal serious 4 (1.8) 4 (1.8) 5 (2.2) 5 (2.2) adverse events

[0933] T reatm ent- 0 0 1 (0.4) 1 (0.4) related

[0934] Adverse events 13 (5.7) 8 (3.5) 12 (5.2) 9 (3.9) leading to

[0935] discontinuation

[0936]

[0937] PAT060004-PCT-SEC01

[0938] - 73 -

[0939] T reatm ent- 7 (3.1) 4 (1.8) 6 (2.6) 3 (1.3) related

[0940] Adverse events 8 (3.5) 3 (1.3) 35 (15.1) 8 (3.4) leading to dose

[0941] adjustment

[0942] Adverse events 27 (11.9) 13 (5.7) 39 (16.8) 18 (7.8) leading to dose

[0943] interruption

[0944] Adverse events 162 (71.4) 48 (21.1) 181 (78.0) 74 (31.9) requiring

[0945] additional

[0946] therapy

[0947] Numbers (n) represent counts of participants. Adverse events with missing relationship to study treatment are counted as ‘Treatment-related1. Summary of adverse events that occurred on or after first dose of study treatment to the earlier of below dates 1) latest of end of treatment disposition date + 30 days or (last dose date of ARDT + 30 days or last dose date of [177Lu]Lu-PSMA-617 + 41 days), as applicable; 2) the day before start of crossover treatment, if applicable. MedDRA version 26.0, CTCAE version V5.0.

[0948]

[0949] Adverse events by preferred term (with at least 10% incidence in either arm) (Safety set)

[0950] [177Lu]Lu-PSMA-617 ARDT

[0951] N=227 N=232

[0952] All Grades Grade >=3 All Grades; Grade >=3 Preferred term n (%) n (%) n (%) n (%) Number of 223 (98.2) 78 (34.4) 223 (96.1) 101 (43.5) participants with

[0953] at least one

[0954] event

[0955] Dry mouth 130 (57.3) 3 (1.3) 5 (2.2) 0

[0956] Asthenia 72 (31.7) 1 (0.4) 67 (28.9) 8 (3.4) Nausea 71 (31.3) 0 28 (12.1) 1 (0.4) Anaemia 55 (24.2) 14 (6.2) 39 (16.8) 14 (6.0) Fatigue 52 (22.9) 0 59 (25.4) 4 (1.7) Constipation 50 (22.0) 1 (0.4) 31 (13.4) 0

[0957]

[0958] PAT060004-PCT-SEC01

[0959] - 74 -

[0960] Decreased 48 (21.1) 0 42 (18.1) 1 (0.4) appetite

[0961] Arthralgia 43 (18.9) 0 48 (20.7) 1 (0.4) COVID-19 37 (16.3) 1 (0.4) 26 (11.2) 1 (0.4) Diarrhoea 37 (16.3) 0 20 (8.6) 1 (0.4) Back pain 28 (12.3) 2 (0.9) 38 (16.4) 5 (2.2) Vomiting 26 (11.5) 0 11 (4.7) 0

[0962] Oedema 19 (8.4) 0 26 (11.2) 0 peripheral

[0963] Weight 15 (6.6) 2 (0.9) 28 (12.1) 5 (2.2) decreased

[0964]

[0965] Numbers (n) represent counts of participants. Preferred terms are sorted by descending frequency in [177Lu]Lu-PSMA-617 'All grades' column. Summary of adverse events that occurred on or after first dose of study treatment to the earlier of below dates 1) latest of end of treatment disposition date + 30 days or (last dose date of ARDT + 30 days or last dose date of [177Lu]Lu-PSMA-617 + 41 days), as applicable; 2) the day before start of crossover treatment, if applicable. MedDRA version 26.0, CTCAE version V5.0.

[0966] Serious adverse events by preferred term (with at least 1% incidence in either arm) (Safety set)

[0967] [177Lu]Lu-PSMA-617 ARDT

[0968] N=227 N=232

[0969] All Grades Grade >=3 All Grades Grade >=3 Preferred term n (%) n (%) n (%) n (%) Number of 46 (20.3) 41 (18.1) 65 (28.0) 59 (25.4) participants with

[0970] at least one event

[0971] Anaemia 4 (1.8) 3 (1.3) 3 (1.3) 3 (1.3) Urinary tract 4 (1.8) 3 (1.3) 4 (1.7) 4 (1.7) infection

[0972] Sepsis 3 (1.3) 3 (1.3) 0 0

[0973]

[0974] PAT060004-PCT-SEC01

[0975] - 75 -

[0976] Acute kidney 2 (0.9) 2 (0.9) 3 (1.3) 3 (1.3) injury

[0977] Femur fracture 2 (0.9) 2 (0.9) 3 (1.3) 3 (1.3) Spinal cord 2 (0.9) 2 (0.9) 5 (2.2) 5 (2.2) compression

[0978] COVID-19 1 (0.4) 1 (0.4) 3 (1.3) 1 (0.4) Pain 1 (0.4) 1 (0.4) 4 (1.7) 4 (1.7) Pneumonia 1 (0.4) 1 (0.4) 3 (1.3) 3 (1.3) Urinary retention 1 (0.4) 1 (0.4) 3 (1.3) 1 (0.4) Haematuria 0 0 3 (1.3) 3 (1.3) Numbers (n) represent counts of participants. Preferred terms are sorted by descending frequency in [177Lu]Lu-PSMA-617 'All grades' column. Summary of adverse events that occurred on or after first dose of study treatment to the earlier of below dates 1) latest of end of treatment disposition date + 30 days or (last dose date of ARDT + 30 days or last dose date of [177Lu]Lu-PSMA-617 + 41 days), as applicable; 2) the day before start of crossover treatment, if applicable. MedDRA version 26.0, CTCAE version V5.0.

[0979]

[0980] Incidences of grade > 3 AEs, serious AEs and AEs leading to dose adjustment were lower with 177Lu-PSMA-617 versus ARPI change as can be seen from the following table.

[0981] AEs, n (%) All grades Grades 3-5

[0982] 177Lu-PSMA- ARPI change177Lu-PSMA- ARPI

[0983] 617 (n = 232) 617 change

[0984] (n = 227) (n = 227) (n = 232) Any 223 (98.2) 223 (96.1) 78 (34.4) 101 (43.5) T reatment-related 196 (86.3) 142 (61.2) 25 (11.0) 29 (12.5) SAEs 46 (20.3) 65 (28.0) 41 (18.1) 59 (25.4) T reatment-related 7 (3.1) 5 (2.2) 6 (2.6) 5 (2.2) Fatal 4 (1.8) 5 (2.2) 4 (1.8) 5 (2.2)

[0985] T reatment-related fatal 0 1 (0.4) 0 1 (0.4) Leading to dose 8 (3.5) 35 (15.1) 3 (1.3) 8 (3.4) adjustment

[0986]

[0987] PAT060004-PCT-SEC01

[0988] - 76 -

[0989] Leading to dose 27 (11.9) 39 (16.8) 13 (5.7) 18 (7.8) interruption

[0990] Leading to 13 (5.7) 12 (5.2) 8 (3.5) 9 (3.9) discontinuation

[0991]

[0992] AE, adverse event; ARPI, androgen receptor pathway inhibitor; DCO, data cut-off; OS, overal survival; PSMA, prostate-specific membrane antigen; SAE, serious adverse event. Interim OS analysis (DCO: June 2023).

[0993] AEs occurring in > 10% patients in either arm as can be seen from the following table

[0994] AEs, n (%) All grades Grades 3-5

[0995] 177Lu-PSMA- ARPI change177Lu-PSMA- ARPI change 617 (n = 232) 617 (n = 232) (n = 227) (n = 227)

[0996] Dry mouth 130 (57.3) 5 (2.2) 3 (1.3) 0 Asthenia 72 (31.7) 67 (28.9) 1 (0.4) 8 (3.4) Nausea 71 (31.3) 28 (12.1) 0 1 (0.4) Anaemia 55 (24.2) 39 (16.8) 14 (6.2) 14 (6.0) Fatigue 52 (22.9) 59 (25.4) 0 4 (1.7) Constipation 50 (22.0) 31 (13.4) 1 (0.4) 0 Decreased appetite 48 (21.1) 42 (18.1) 0 1 (0.4) Arthralgia 43 (18.9) 48 (20.7) 0 1 (0.4) COVID-19 37 (16.3) 26 (11.2) 1 (0.4) 1 (0.4) Diarrhoea 37 (16.3) 20 (8.6) 0 1 (0.4) Back pain 28 (12.3) 38 (16.4) 2 (0.9) 5 (2.2) Vomiting 26 (11.5) 11 (4.7) 0 0 Oedema peripheral 19 (8.4) 26 (11.2) 0 0 Weight loss 15 (6.6) 28 (12.1) 2 (0.9) 5 (2.2)

[0997]

[0998] AE, adverse event; ARPI, androgen receptor pathway inhibitor; DCO, data cut-off; OS, overal survival; PSMA, prostate-specific membrane antigen, Interim OS analysis (DCO: June 2023).

[0999] To summarize, 177Lu-PSMA-617 prolonged rPFS versus ARPI change and had a good safety and tolerability profile in taxane-naive patients with mCRPC.

[1000] ■177Lu-PSMA-617 significantly prolonged rPFS versus ARPI changePAT060004-PCT-SEC01

[1001] - 77 -

[1002] At the time of the second interim OS analysis:

[1003] ■ There was a trend towards longer crossover-adjusted but not unadjusted OS

[1004] ■ The crossover rate was high

[1005] ■ 45.1 % of the target number of deaths had occurred

[1006] - OS data collection is ongoing

[1007] ■ PSA response, ORR and DOR favoured177Lu-PSMA-617

[1008] ■ Time to worsening in health-related quality of life and pain measures favoured177Lu- PSMA-617

[1009] ■177Lu-PSMA-617 had a good safety profile and was well-tolerated

[1010] Subject disposition

[1011] Patient disposition (Full analysis set)

[1012] Disposition Reason [177Lu]Lu-PSMA-617 ARDT All Subjects N=233 N=234 N=467

[1013] n (%) n (%) n (%) Subjects randomized 233 (100) 234 (100) 467 (100)

[1014] T reated 226 (97.0) 232 (99.1) 458 (98.1) Not Treated 7 (3.0) 2 (0.9) 9 (1.9) Reason for not being treated

[1015] Subject decision 3 (1.3) 1 (0.4) 4 (0.9) Adverse event 3 (1.3) 0 3 (0.6) Physician decision 1 (0.4) 0 1 (0.2) Protocol deviation 0 1 (0.4) 1 (0.2) Treatment ongoing * 141 (60.5) 122 (52.1) 263 (56.3) Completed treatment 25 (10.7) 0 25 (5.4) Discontinued from 60 (25.8) 110 (47.0) 170 (36.4) treatment

[1016] Reason for discontinuation

[1017] Progressive disease 34 (14.6) 77 (32.9) 111 (23.8) Physician decision 14 (6.0) 21 (9.0) 35 (7.5) Adverse event 9 (3.9) 7 (3.0) 16 (3.4) Subject decision 2 (0.9) 3 (1.3) 5 (1.1)

[1018]

[1019] PAT060004-PCT-SEC01

[1020] - 78 -

[1021] Death 0 2 (0.9) 2 (0.4) No longer clinically 1 (0.4) 0 1 (0.2) benefitting

[1022] * Ongoing at the time of the data cut-off date 2022-10-02.

[1023]

[1024] Demographics and other baseline characteristics

[1025] Demographics and baseline characteristics (Full analysis set)

[1026] Characteristic [177Lu]Lu-PSMA-617 ARDT All Subjects Categories / Statistic N=233 N=234 N=467 s

[1027] Age (years) -n 233 234 467 Mean (SD) 71.0 (8.72) 71.9 (7.65) 71.4 (8.20) Median 71.0 72.0 72.0 Min-Max 43-94 53-91 43-94 Age group -n (%)

[1028] < 65 years 50 (21.5) 44 (18.8) 94 (20.1) >= 65 years 183 (78.5) 190 (81.2) 373 (79.9) Race -n (%)

[1029] Asian 1 (0.4) 2 (0.9) 3 (0.6) Black or African 7 (3.0) 5 (2.1) 12 (2.6) American

[1030] White 211 (90.6) 214 (91.5) 425 (91.0) Unknown 14 (6.0) 13 (5.6) 27 (5.8) Ethnicity -n (%)

[1031] Hispanic or Latino 14 (6.0) 14 (6.0) 28 (6.0) Not Hispanic or 174 (74.7) 187 (79.9) 361 (77.3) Latino

[1032] Not Reported 37 (15.9) 28 (12.0) 65 (13.9) Unknown 5 (2.1) 5 (2.1) 10 (2.1) Missing 3 (1.3) 0 3 (0.6) ECOG performance status -n (%)

[1033]

[1034] PAT060004-PCT-SEC01

[1035] - 79 -

[1036] 0 145 (62.2) 116 (49.6) 261 (55.9) 1 86 (36.9) 114 (48.7) 200 (42.8) Missing 2 (0.9) 4 (1.7) 6 (1.3) Race / ethnicity data is not collected for some countries. Height, weight and ECOG performance status are the last available values on or before randomization date.

[1037]

[1038] Subject exposure

[1039] Duration of exposure to study treatment (Safety set)

[1040] ARDT N=232

[1041] [177Lu]Lu- Abiraterone Enzalutamide All ARDT PSMA-617 Subjects N=226

[1042] Duration of exposure (months)

[1043] n 226 100 132 232 Mean (SD) 4.83 (2.826) 4.57 (2.950) 4.62 (3.261) 4.60 (3.124) Median 4.25 4.20 3.55 3.90 Min-Max 0.3-10.3 0.0-12.4 0.0-13.3 0.0-13.3 Number of 226

[1044] [177Lu]Lu-PSMA- 617 injections - n

[1045] Mean (SD) 3.4 (1.70)

[1046] Median 3.0

[1047] Min-Max 1-6

[1048] Number of [177Lu]Lu-PSMA-617 injections (categories) -n (%)

[1049] At least 1 226 (100)

[1050] injection

[1051] At least 2 195 (86.3)

[1052] injections

[1053] At least 3 141 (62.4)

[1054] injections

[1055] At least 4 107 (47.3)

[1056] injections

[1057]

[1058] PAT060004-PCT-SEC01

[1059] - 80 -

[1060] At least 5 69 (30.5)

[1061] injections

[1062] 6 injections 40 (17.7)

[1063] Subject-time 90.9 38.1 50.8 88.9 (years)

[1064] Subject-time is the sum of each subject's treatment exposure in years.

[1065]

[1066] Dose of study treatment received (Safety set)

[1067] ARDT N=232

[1068] [177Lu]Lu- Abiraterone Enzalutamide All ARDT PSMA-617 Subjects N=226

[1069] Total number of 226 (100) 100 (43.1) 132 (56.9) 232 (100) subjects

[1070] receiving study

[1071] treatment -n (%)

[1072] Cumulative dose [1]

[1073] Mean (SD) 24.74 (12.187) 136767.50 21322.42 (15206.718)

[1074] (89809.023)

[1075] Median 22.05 127000.00 15440.00

[1076] Min-Max 7.0-45.0 1000.0-377000.0 160.0-64800.0

[1077] Dose intensity [2]

[1078] Mean (SD) 5.80 (2.136) 980.65 (76.541) 152.77 (17.649)

[1079] Median 5.20 1000.00 160.00

[1080] Min-Max 4.1-22.6 539.4-1000.0 40.0-161.4

[1081] Relative dose intensity (%)

[1082] Mean (SD) 96.13 (5.724) 98.07 (7.658) 95.67 (10.236) 96.70 (9.271) Median 97.60 100.00 100.00 100.00 Min-Max 59.2-103.1 53.9-100.0 25.0-100.0 25.0-100.0 Relative dose intensity categories -n (%)

[1083] <=75% 3 (1.3) 3 (1.3) 6 (2.6) 9 (3.9) >75-90% 19 (8.4) 3 (1.3) 17 (7.3) 20 (8.6) >90-110% 204 (90.3) 94 (40.5) 109 (47.0) 203 (87.5)

[1084]

[1085] PAT060004-PCT-SEC01

[1086] - 81 -

[1087] Dose intensity and relative dose intensity include days of zero dose in the calculation. Dose intensity is defined as cumulative dose of study treatment divided by duration of exposure to study treatment. Relative dose intensity is defined as dose intensity divided by planned dose intensity. Conversion factor for [177Lu]Lu-PSMA-617 - 1 mCi = 0.037 GBq; 1 MBq = 0.001 GBq. [1] Unit of cumulative dose for [177Lu]Lu-PSMA-617 is GBq and for treatments in ARDT is mg. [2] Unit of dose intensity for [177Lu]Lu-PSMA-617 is GBq / month and for treatments in ARDT is mg / day.

[1088]

[1089] Dose of [177Lu]Lu-PSMA-617 received (Lu-PSMA-617 safety set)

[1090] Randomized Crossover All

[1091] [177Lu]Lu-PSMA- [177Lu]Lu-PSMA- [177Lu]Lu-PSMA- 617 617 617

[1092] Subjects Subjects Subjects

[1093] N=226 N=52 N=278

[1094] Total number of 226 (100) 52 (100) 278 (100) subjects receiving

[1095] study treatment -n

[1096] (%)

[1097] Cumulative dose [GBq]

[1098] Mean (SD) 24.74 (12.187) 18.83 (9.759) 23.64 (11.979) Median 22.05 14.75 21.80

[1099] Min-Max 7.0-45.0 6.9-44.6 6.9-45.0

[1100] Dose intensity [GBq / month]

[1101] Mean (SD) 5.80 (2.136) 6.59 (2.972) 5.94 (2.330) Median 5.20 5.40 5.25

[1102] Min-Max 4.1-22.6 4.0-20.0 4.0-22.6

[1103] Relative dose intensity dose (%)

[1104] Mean (SD) 96.13 (5.724) 96.68 (6.137) 96.23 (5.796) Median 97.60 97.95 97.65

[1105] Min-Max 59.2-103.1 57.4-101.6 57.4-103.1 Relative dose intensity categories -n (%)

[1106] <=75% 3 (1.3) 1 (1.9) 4 (1.4)

[1107] >75-90% 19 (8.4) 1 (1.9) 20 (7.2)

[1108]

[1109] PAT060004-PCT-SEC01

[1110] - 82 -

[1111] >90-110% 204 (90.3) 50 (96.2) 254 (91.4)

[1112] Dose intensity and relative dose intensity include days of zero dose in the calculation.

[1113] Dose intensity is defined as cumulative dose of study treatment divided by duration of exposure to study treatment. Relative dose intensity is defined as dose intensity divided by planned dose intensity. Conversion factor for [177Lu]Lu-PSMA-617 - 1 mCi = 0.037 GBq; 1 MBq = 0.001 GBq.

[1114]

[1115] Summary of duration between randomization and cut-off date (Full analysis set)

[1116] [177Lu]Lu-PSMA- ARDT N=234 All Subjects N=467 617 N=233

[1117] Duration between randomization and cut-off date (months)

[1118] n 233 234 467

[1119] Mean (SD) 7.23 (3.890) 7.23 (3.915) 7.23 (3.898) Median 7.26 7.28 7.26

[1120] Q1-Q3 3.38 - 10.74 3.38 - 10.51 3.38 - 10.55

[1121] Min-Max 0.8 - 15.1 0.7 - 15.1 0.7 - 15.1 Subjects censored before the median (above) - n (%)

[1122] Adequate 12 (5.2) 12 (5.1) 24 (5.1) assessment no

[1123] longer available

[1124] Event documented 4 (1.7) 3 (1.3) 7 (1.5)

[1125] after two or more

[1126] missing tumor

[1127] assessments

[1128] Ongoing without 121 (51.9) 93 (39.7) 214 (45.8) event

[1129] Withdrew consent 3 (1.3) 3 (1.3) 6 (1.3)

[1130] Duration between randomization and data cut-off date = (Cut-off date - Date of randomization (enrollment) + 1) / 30.4375 (months).

[1131]

[1132] Further information and details of the results of this clinical trial has been published in the patent application WO 2024 / 121722 A1, published 13 June 2024, filed as PCT / IB2023 / 062204 on 4 Dec 2023, and the article published under the title “177Lu-PSMA-617 versus a change ofPAT060004-PCT-SEC01

[1133] - 83 -

[1134] androgen receptor pathway inhibitor therapy for taxane-naive patients with progressive metastatic castrati on- resista nt prostate cancer (PSM Afore): a phase 3, randomised, controlled trial” in Lancet 2024; 404: 1227–39, and the additional / supplemental information of said article for which the URL is indicated. The entire content of said patent application and the Lancet article, including its additional / supplemental information, is incorporated herein by reference.

[1135] EXAMPLE 2:

[1136] BIOMARKER ANALYSIS 1

[1137] Association of baseline and on-treatment ctDNA fraction with clinical outcomes in patients with mCRPC in the PSMAfore study of177Lu-PSMA-617

[1138] Background:

[1139] In PSMAfore (NCT04689828), [Lu]Lu-PSMA-617 (Lu-PSMA-617) prolonged rPFS versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive adults with PSMA-positive metastatic castration-resistant prostate cancer (mCRPC) progressing once on an ARPI. Baseline circulating tumor DNA (ctDNA) fraction was associated with rPFS at the second interim analysis(IA) of OS. Here, it is assessed the association of baseline and cycle 2 day 1 (C2D1)ctDNA fraction, and early ctDNA and prostate-specific antigen (PSA) dynamics, with rPFS andOS at the third IA of OS.

[1140] Methods:

[1141] Patients were randomized 1:1 to Lu-PSMA-617 (7.4 GBq Q6W; x6) or ARPI change.

[1142] Endpoints included rPFS (primary) and OS (key secondary). Plasma ctDNA fraction was analyzed at baseline and at C2D1 using an in-house custom panel. Cox regression (adjusted for 3 risk classes based on clustering of 17 baseline clinical features) and random forest (adjusted for 15 baseline clinical features) modeling were used to assess the association of ctDNA fraction and PSA with clinical outcomes at the Feb-27-2024 data cutoff.

[1143] Results:

[1144] Patients with plasma samples at baseline and C2D1 were included (Lu-PSMA-617, n / N =82 / 234; ARPI change, n / N = 91 / 234). Cox regression models adjusted for clinical features in the Lu-PSMA-617 arm showed that higher ctDNA fraction was associated with shorter rPFS and OS (Table below). These associations were stronger for C2D1 than baseline, both when comparing individual models and within a model including both timepoints (TablePAT060004-PCT-SEC01

[1145] - 84 -

[1146] below). In random forest models including clinical features and C2D1 ctDNA fraction, the total area under curves were not improved by addition of baseline ctDNA fraction (rPFS, 0.87; OS, 0.86). In the overall population, fractional decreases from baseline to C2D1 in ctDNA (p = 0.0015) and PSA (p < 0.0001) were strongly associated with longer rPFS, and were weakly correlated with one another (correlation coefficient, 0.26). In the Lu-PSMA-617 arm, fractional decrease in ctDNA (p = 0.002) was more strongly correlated with OS than was decrease in PSA (p = 0.12).

[1147] Conclusions:

[1148] This exploratory analysis suggested that C2D1 ctDNA fraction was more strongly associated than baseline ctDNA fraction with rPFS and OS. Early ctDNA fraction dynamics contributed additional information in the prediction of rPFS and OS beyond PSA dynamics alone.

[1149] Table: Cox regression models (HRs correspond to 1 unit change in ctDNA fraction)

[1150] rPFS OS

[1151] Baseline model,HR (95% 6.0 (1.6–23.0); 0.0095 12.0 (3.0–48.7); 0.00052 CI); p

[1152] C-index ± SE 0.69 ± 0.04 0.75 ± 0.04

[1153] C2D1 model, HR (95% Cl); 47.7 (10.1-226.0); < 0.0001 82.7 (16.4-417.0); < 0.0001 P

[1154] C-index ± SE 0.72 ± 0.03 0.77 ± 0.03

[1155] Baseline + C2D1 model

[1156] Baseline,HR (95% CI); p 3.1 (0.7–14.0); 0.14 2.1 (0.4–12.7); 0.41 C2D1. HR (95% Cl); p 35.9 (7.2-180.0); < 0.0001 52.5 (7.6-362.0); < 0.0001 C-index ± SE 0.72 ± 0.03 0.79 ± 0.03

[1157] In this exploratory analysis of patients with taxane-naive mCRPC who had experienced one disease progression on prior ARPI:

[1158] • ctDNA fraction at baseline and cycle 2 day 1 are associated with overall survival in multivariate models of patients treated with177Lu-PSMA-617

[1159] • Post-treatment changes in ctDNA fraction may have clinical utility as a response biomarkerPAT060004-PCT-SEC01

[1160] - 85 -

[1161] • Post-treatment changes in ctDNA fraction merit evaluation as an intermediate endpoint for clinical benefit

[1162] See FIG. 2 for the trial design of PSMAfore: Phase 3 trial of 177Lu-PSMA-617 versus ARPI change in taxane-naive mCRPC that met its primary endpoint.

[1163] PSMAfore exploratory analysis:

[1164] Based on the second interim OS analysis; data cut off, June 21, 2023:

[1165] Timepoints assessed: Baseline

[1166] Outcomes assessed: rPFS, PSA50, RECIST response

[1167] • Patients receiving177Lu-PSMA-617 versus ARPI change had longer rPFS, regardless of baseline ctDNA fraction

[1168] • Higher ctDNA fraction was associated with worse outcomes

[1169] • 8q amplifications, AR amplification and TP53 deleterious alterations were associated with worse outcomes

[1170] Details published in de Bono JS, Morris MJ, Sartor O et al. Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with 177Lu-PSMA-617 versus change of ARPI in PSMAfore. J Clin Oncol 2024;42 (16 suppl):5008, the entire content of this publication is incorporated herein by reference.

[1171] Based on third interim OS analysis: data cutoff, February 27, 2024:

[1172] Timepoints assessed: Baseline and C2D1

[1173] Outcomes assessed: rPFS, OS, PSA50, RECIST response

[1174] • An assessment of the association of cycle 1 day 1 (baseline) and cycle 2 day 1 (C2D1) ctDNA fraction, and early ctDNA and PSA dynamics, with rPFS and OS

[1175] • ctDNA fraction was assessed as a prognostic biomarker

[1176] • ctDNA fraction was assessed as a response biomarker

[1177] Statistical analyses

[1178] • Cox regression modelling assessed associations between ctDNA fraction and PSA with rPFS and OS

[1179] • All Cox regression models were adjusted for 17 baseline clinical variables using a model-based clustering approach (Marbac M and Sedki M. VarSelLCM: an R / C++PAT060004-PCT-SEC01

[1180] - 86 -

[1181] package for variable selection in model-based clustering of mixed-data with missing values. Bioinformatics 2019:35(7);1255–1257, the entire content of which is incorporated herein by reference):

[1182] Age Symptomatology (BPI-SF) ALP

[1183] ECOG Liver metastases Hemoglobin

[1184] Stage at initial diagnosis Bone involvement Lymphocyte count

[1185] Prior radiation PSA AST

[1186] Time since diagnosis Initial Gleason score Neutrophil count

[1187] Prior ARPI use LDH

[1188]

[1189] Individual Cox regression models included ctDNA fraction at baseline or at C2D1.

[1190] Combined Cox regression models included ctDNA fraction at baseline and at C2D1 in the same model.

[1191] ctDNA fraction as a prognostic biomarker in patients treated with177Lu-PSMA-617

[1192] Higher ctDNA fraction was associated with worse rPFS and OS in individual Cox regression models,177Lu-PSMA-617 arm

[1193] See FIG. 3

[1194] In combined Cox regression models including both timepoints, baseline ctDNA fraction did not improve model performances beyond C2D1 ctDNA fraction,177Lu-PSMA-617 arm

[1195] rPFS:

[1196] Baseline Cox regression HR (95% Cl); p 3.1 (0.7-14.0); 0.14

[1197] C2D1 Cox regression HR (95% Cl); p 35.9 (7.2-180.0); < 0.0001

[1198] Cox regression C-index (SE) 0.72 (0.03)

[1199]

[1200] OS:

[1201] Baseline Cox regression HR (95% Cl); p 2.1 (0.4-12.7); 0.41

[1202] C2D1 Cox regression HR (95% Cl); p 52.5 (7.6-362.0); < 0.0001

[1203] Cox regression C-index (SE) 0.79 (0.03)

[1204]

[1205] PAT060004-PCT-SEC01

[1206] - 87 -

[1207] Note: ctDNA fraction treated as continuous variable; HRs correspond to 1 unit change in ctDNA fraction.

[1208] All models were adjusted for baseline clinical risk variables.

[1209] • Trends were generally similar in the ARPI change arm for rPFS

[1210] • Similar results were observed when the data were analyzed using random forest modelling

[1211] Lower baseline and C2D1 ctDNA fraction was associated with higher frequency of RECIST response,177Lu-PSMA-617 arm

[1212] See FIG. 4

[1213] aDefined as per RECIST: persistence of one or more non-target lesion(s) and / or maintenance of tumor marker level above the normal limits (Eisenhauer EA et al. Eur J Cancer 2009;45: 228–47, the entire content of which is incorporated herein by reference).

[1214] PSA50 response was associated with lower baseline and C2D1 ctDNA fraction, with a stronger association for C2D1 ctDNA fraction,177Lu-PSMA-617 arm

[1215] See FIG. 5

[1216] ctDNA fraction as a response biomarker

[1217] ctDNA clearance from baseline to C2D1 and PSA50 response were associated with longer rPFS, Overall population

[1218] See FIG. 6

[1219] aMedian rPFS unstable because of small sample size

[1220] • A similar trend for OS was observed in the177Lu-PSMA-617 arm, however, the low number of events among PSA50 responders (12 / 43) precluded accurate calculation of median OS

[1221] In Cox regression models, fractional decrease in ctDNA provided additional information beyond PSA50 response

[1222] Overall population, rPFS:PAT060004-PCT-SEC01

[1223] - 88 -

[1224] ctDNA fractional PSA50b

[1225] decrease3

[1226] Patients, n 145

[1227] Cox regression HR (95% CI) 0.17 (0.05–0.56) 0.32 (0.2–0.53)

[1228] P 0.0035 < 0.0001

[1229]

[1230] 177Lu-PSMA-617 arm, OS:

[1231] ctDNA fractional PSA50b

[1232] decrease3

[1233] Patients, n 68

[1234] Cox regression HR (95% CI) 0.07 (0.01–0.59) 0.44 (0.17–1.1)

[1235] P 0.015 0.09

[1236]

[1237] All models were adjusted for baseline clinical risk variables

[1238] fractional decrease in ctDNA was measured from baseline to C2D1 (~6 weeks)bPSA50 response was defined as per the protocol, including PSA timepoints at 12 weeks and beyond

[1239] ctDNA clearance at C2D1 provided additional information to PSA50 in the rPFS model Overall population (patients with detectable ctDNA at baseline)

[1240] See FIG. 7

[1241] actDNA responder and non-responder data for the PSA50 responder group are combined because of low patient numbers

[1242] Conclusion:

[1243] In exploratory analyses of PSMAfore in patients with taxane-naive mCRPC who had experienced one disease progression on prior ARPI:

[1244] • Higher ctDNA fraction was associated with shorter rPFS and OS in patients treated with177Lu-PSMA-617

[1245] - The association was stronger with C2D1 than baseline ctDNA fraction

[1246] • Higher ctDNA fraction was associated with worse tumor response

[1247] • ctDNA clearance from baseline to C2D1 was associated with longer rPFS and OS • Early ctDNA fraction dynamics contributed additional information in models of rPFS and OS beyond PSAPAT060004-PCT-SEC01

[1248] - 89 -

[1249] • Post-treatment changes in ctDNA fraction merit evaluation as an intermediate endpoint for clinical benefit

[1250] - See also FDA recently released guidance on the use of ctDNA as a biomarker for response in clinical trials (US Food and Drug Administration. 2024.

[1251] Available from: https: / / www.fda.gov / media / 183874 / download, accessed on filing date of the present application, the content of this guidance is incorporated herein by reference)

[1252] EXAMPLE 3:

[1253] BIOMARKER ANALYSIS 2

[1254] Baseline ctDNA analyses and associations with outcomes in taxane-naïve patients with mCRPC treated with [177Lu]Lu-PSMA-617 versus change of ARPI in PSMAfore

[1255] KEY FINDINGS & CONCLUSIONS

[1256] In patients with taxane-naive mCRPC:

[1257] • Higher baseline ctDNA fraction was associated with shorter rPFS across both treatment arms • Patients receiving 177Lu-PSMA-617 had longer rPFS compared with ARPI change regardless of baseline ctDNA fraction

[1258] • Early ctDNA fraction dynamics informs on rPFS and tumor response

[1259] • 8q amplifications, AR amplification, and TP53 deleterious alterations are prognostic and putative predictive biomarkers that were associated with shorter rPFS and decreased tumor response in the177Lu-PSMA-617 arm

[1260] BACKGROUND

[1261] • [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) versus androgen receptor pathway inhibitor (ARPI) change in

[1262] taxane-naive patients with metastatic castration-resistant prostate cancer

[1263] (mCRPC) in the phase 3 PSMAfore trial (NCT04689828)

[1264] OBJECTIVE

[1265] • To assess associations between baseline circulating tumor DNA (ctDNA) and outcomes in an exploratory analysis of data from PSMAforePAT060004-PCT-SEC01

[1266] - 90 -

[1267] METHODS

[1268] Study Design and Patients

[1269] • Eligible patients had confirmed progressive PSMA-positive mCRPC that had progressed once on prior ARPI therapy; patients had no prior taxane therapy, were not eligible for treatment with an inhibitor of poly(adenosine diphosphate-ribose) polymerase, and had an Eastern Cooperative Oncology Group performance

[1270] status 0-1 (Figure 2)

[1271] • Patients were randomized 1:1 to 177Lu-PSMA-617 (7.4 GBq [200 mCi] ± 10% once every 6 weeks for 6 cycles) or ARPI change (abiraterone or enzalutamide)

[1272] • The primary endpoint was rPFS by blinded independent central review

[1273] See FIG. 2

[1274] Abbreviations:

[1275] ARPI, androgen receptor pathway inhibitor; BICR, blinded independent central review; CT, computed tomography; ECOG, Eastern Cooperative Oncology Group; Ga, gallium; GBq, gigabecquerel; mCi, millicurie; mCRPC, metastatic castration-resistant prostate cancer; OS, overall survival; PARP, poly(adenosine diphosphate-ribose) polymerase; PET, positron emission tomography; PSA50, ≥50% reduction in prostate-specific antigen; PSMA, prostatespecific membrane antigen; RECIST, Response Evaluation Criteria for Solid Tumors; rPFS, radiographic progression-free survival.

[1276] Biomarker Exploratory Analyses

[1277] • Plasma ctDNA was analyzed using a customized 585-gene sequencing assay at baseline (cycle 1, day 1 [C1D1]) and day 1 of cycle 2 [C2D1] (Figure 8)

[1278] ARPI, androgen receptor pathway inhibitor; C, cycle; ctDNA, circulating tumor DNA; D, day; Lu, lutetium; PSMA, prostate-specific membrane antigen; QC; quality control.

[1279] • Associations between ctDNA fraction and outcomes were assessed in all samples passing quality control

[1280] Association between alterations in key prostate cancer drivers (18 selected genomic features prevalent in >10% of patients) and outcomes was assessed in samples with ctDNA fraction >0.5%; the prognostic and predictive value of those known to influencePAT060004-PCT-SEC01

[1281] - 91 -

[1282] radiation sensitivity (chromosome 8q [8q] and MYC amplifications, AR amplifications, TP53 deleterious alterations, and PI3K pathway alterations) was assessed

[1283] • Univariate Cox regression (reference: ARPI change) was used to assess

[1284] associations between ctDNA fraction or alterations with the following outcomes as

[1285] of the second interim overall survival analysis (data cutoff June 21, 2023):

[1286] - rPFS

[1287] ->50% decline in prostate-specific antigen response (PSA50)

[1288] - Response rate (RR) per Response Evaluation Criteria in Solid Tumors (RECIST)

[1289] RESULTS

[1290] ctDNA analysis

[1291] • Of the 468 patients, 252 samples were collected at C1D1 and 260 at C2D1 (Figure 9) - Baseline patient characteristics were consistent with the overall PSMAfore

[1292] population

[1293] - Median baseline ctDNA fraction was 5.9% (10.0% 177Lu-PSMA-617, 3.7% ARPI change), which was consistent with profiles of patients with mCRPC receiving

[1294] first- or second-line therapy (approximately 5% for each group)2

[1295] • Higher baseline ctDNA fraction was associated with shorter rPFS in the overall population (Figure 10A) and each treatment arm (Figure 10B)

[1296] • 177Lu-PSMA-617 prolonged rPFS compared with ARPI change regardless of baseline ctDNA fraction (Figure 10B)

[1297] • Responders based on PSA50 or RR per RECIST generally had lower ctDNA fractions than non-responders in both treatment arms (Figure 11)

[1298] • Early ctDNA clearance (from detectable to not detectable) was associated with longer rPFS than partial or no reduction in ctDNA in both arms (Figure 12)

[1299] Figure 9. ctDNA fraction summary

[1300] ARPI, androgen receptor pathway inhibitor; C, cycle; ctDNA, circulating tumor DNA; D, day; Lu, lutetium; PSMA, prostate-specific membrane antigen.

[1301] Figure 10. Higher baseline ctDNA fraction was associated with shorter rPFS

[1302] in the overall population (A) and in each treatment arm (B)

[1303] ARPI, androgen receptor pathway inhibitor; ctDNA, circulating tumor DNA; Lu, lutetium; NE, not evaluable; PSMA, prostate-specific membrane antigen; rPFS, radiographic progression-free survival.PAT060004-PCT-SEC01

[1304] - 92 -

[1305] Figure 11. ctDNA fraction was lower in responders than non-responders

[1306] ARPI, androgen receptor pathway inhibitor; ctDNA, circulating tumor DNA; PSA50, ≥50% reduction in prostate-specific antigen; Lu, lutetium; PSMA, prostate-specific membrane antigen; RECIST, Response Evaluation Criteria for Solid Tumors.

[1307] Figure 12. Early ctDNA clearance was associated with longer rPFS

[1308] ARPI, androgen receptor pathway inhibitor; ctDNA, circulating tumor DNA; D, ctDNA detectable; ND, ctDNA not detectable; Lu, lutetium; NE, not evaluable; PSMA, prostatespecific membrane antigen; rPFS, radiographic progression-free survival.

[1309] Genomic analysis

[1310] • The presence of 8q amplification, AR amplification, or a TP53 deleterious alteration was associated with shorter rPFS

[1311] (Figure 13)

[1312] • These alterations remained associated with rPFS after adjusting for ctDNA fraction in the 177Lu-PSMA-617 arm (data not shown)

[1313] • In the 177Lu-PSMA-617 arm, the presence of 8q amplification, AR amplification, or a TP53 deleterious alteration was associated with lower probability of response (PSA50 or RR by RECIST) compared with patients without these alterations

[1314] (Table below)

[1315] Figure 13. 8q amplifications (A), AR amplifications (B), and TP53 deleterious alterations (C) were associated with shorter rPFS in a univariable model adjusted for treatment* *ln the 177Lu-PSMA-617 arm, the presence of these alterations remained associated with rPFS after adjusting for ctDNA fraction.

[1316] 8q, chromosome 8q; alt, alteration; amp, amplification; ARPI, androgen receptor pathway inhibitor; ctDNA, circulating tumorDNA; Lu, lutetium; PSMA, prostate-specificmembrane antigen; rPFS, radiographic progression-free survival.

[1317] Table: Presence of 8q amplification, AR amplification, or TP53 deleterious alteration was associated with lower response rates

[1318] RECSST response A:t6faswn prevateatre •ss sissspfes

[1319]

[1320] TP53 ciaietericu:. aiisrationsPAT060004-PCT-SEC01

[1321] - 93 -

[1322]

[1323] ARPI, androgen receptor pathway inhibitor; ctDNA, circulating tumor DNA; Lu, lutetium; PSA50, ≥50% reduction in prostate-specific antigen; PSMA, prostate-specific membrane antigen; RECIST, Response Evaluation Criteria for Solid Tumors.

[1324] References (the entire content is incorporated herein by reference):

[1325] 1. Morris MJ, et al. Lancet. 2024, doi: 10.1016 / S0140-6736(24)01653-2.

[1326] 2. Fonseca NM, et al. Nat Commun. 2024;15:1828.

[1327] Baseline ctDNA analyses and associations with outcomes in taxane-naive patients with mCRPC treated with177Lu-PSMA-617 versus change of ARPI in PSMAfore.

[1328] Background:

[1329] [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged radiographic progression-free survival (rPFS) versus androgen receptor pathway inhibitor (ARPI) change in taxane-naive patients with metastatic castration-resistant prostate cancer (mCRPC) in PSMAfore (NCT04689828). In this exploratory analysis, associations between baseline circulating tumor DNA (ctDNA) and outcomes were assessed.

[1330] Methods:

[1331] Patients were randomized 1:1 to177Lu-PSMA-617 (7.4 GBq Q6W; 6 cycles) or ARPI change (abiraterone / enzalutamide). Patients known to have actionable mutations (e.g. BRCA) were excluded. The primary endpoint was rPFS. Baseline plasma ctDNA was analyzed using a customized 585-gene sequencing assay. ctDNA fraction was assessed in all samples passing quality control. Alterations in key prostate cancer drivers (prevalent in >10% participants) were assessed in samples with ctDNA fraction >1%. Univariate Cox regression (reference: ARPI change) was used to assess association of ctDNA fraction or alterations with rPFS, prostatespecific antigen response (>50% decline; PSA50) and RECIST response (RR) at the June 21, 2023 data cutoff.

[1332] Results:

[1333] Of 360 samples from 468 patients, 255 passed quality control and 156 had ctDNA fraction >1% (median 5.85%; range 0-85). Detection of ctDNA alterations was comparable between arms and with published data. Median rPFS was shorter for patients with ctDNA fraction >PAT060004-PCT-SEC01

[1334] - 94 -

[1335] versus <1% (HR 2.753; 95% CI 1.957–3.872; p<0.0001) (Table below); ctDNA fraction >1% was also associated with worse RR and PSA50 response. Median rPFS was shorter for patients with detected versus undetected AR (HR 1.954; 95% CI 1.333–2.865; p<0.001), TP53(1.655; 1.13-2.426; p<0.01) and PTEN(1.62; 1.018-2.578; p<0.05) alterations.

[1336] Median rPFS was longer with177Lu-PSMA-617 versus ARPI change in patients with detected AR, TP53, PTEN (Table below), PI3K pathway and DNA repair pathway alterations. There was no significant association between ctDNA alterations and PSA50 or RR.

[1337] Conclusions:

[1338] ctDNA fraction >1% and AR, TP53 and PTEN alterations were associated with worse outcomes in PSMAfore regardless of treatment. Nonetheless, patients with these negative prognostic biomarkers did better with 177Lu-PSMA-617 than with ARPI change. Clinical trial information: NCT04689828 (see clinicaltrials.gov, the entire content is incorporated herein by reference).

[1339] Table:

[1340] 177La-PSMA- ARPImLu-PS A- ARPS“lu-P3MA- ARP 61? Chang® 617 Change 61? Chang® S SO

[1341] Non- Median Res:psnd®rs RR fetes («S6% de- H&n- (95% Cl) dine), n Responders, n ctDHA fraction & M28 fMSS 8*49 8*88 8*28 8«S2 > v si %

[1342] 7.9 (5.8–11.3) v 17.1 (11.5–NE) | 2.4 (2.3–4.2) v 6.0 (5.6–13.7) | 32 v 17 | 53 v 35 | 20 v 8 | 35 v 17

[1343] (5.6–13.7) Alteration detected v undetected AR N=74 N=82 N=32 N=53 N=20 N=35 5.0 (2.7–8.6) v 11.6 (6.2–NE) | 2.3 (2.1–5.6) v 2.7 (2.2–6.0) | 13 v 19 | 20 v 33 | 9 v 11 | 15 v 20

[1344] ' v ' (2J-5.61 11.6 (6.2-8B v 2.7 (2.2-6.0) FP63 6.1 (3.1-0.31 2.4 12 v 20 22 v 31 8 v 12 15 v 20 v ' (2.2-4.31 9.2 (6.2-HE) v 2.7 (2.3 “5.8) P7W 3.5 (2.5-HB 2T ' 7 v 25 10 v 43 4 ¥ 16 S v 27

[1345] ¥ ' (2.6“8E) 7.9 (6.1-11.6) v 3.1 (2.3-5.81

[1346]

[1347] DCO Jun 2023.

Claims

PAT060004-PCT-SEC01- 95 -Claims1. A method of treating cancer with radioligand therapy (RLT) in a patient in need thereof;wherein said method comprises the steps of:(1) Optionally, before starting with the RLT, taking a blood sample from said patient for determining the circulating tumor DNA fraction (ctDNA%) (i.e. baseline ctDNA%);(2) Administering to said patient a certain specified first dose of a radioligand therapeutic agent (RLT agent);(3) Taking a blood sample from said patient for determining the ctDNA% (i.e. on- treatment ctDNA%);(4) Optionally, administering to said patient a certain specified second dose of said RLT agent;(5) Continuing with the administration of further specified doses of the RLT agent in the “ctDNA response” cases of:(i) the on-treatment ctDNA% is non-detectable (ND) or not exceeding a certain threshold (e.g. <0.5%), and / or(ii) there is a fractional decrease in the ctDNA from baseline to on- treatment, preferably, the decrease is from dectectable (D) to ND or the decrease is from above a certain threshold to below said threshold (e.g. from >0.5% to <0.5%), or the ctDNA% is both, at baseline and on- treatment, ND or not exceeding a certain threshold (e.g. <0.5%); but discontinuing the administration of further amounts of the RLT agent and starting with an escalation therapy in the “ctDNA non-response” cases of: (iii) the on-treatment ctDNA% is detectable (D) or exceeding a certain threshold (e.g. >0.5%); and / or(iv) there is no fractional decrease in the ctDNA from baseline to on- treatment.

2. The method of claim 1, wherein the the interval between the first dose administration (step (2)) and the second dose administration ((step 4)) is (i.e. a cycle) of about 3 to about 12 weeks, about 4 to about 10 weeks, about 4 to about 8 weeks, about 6 to about 8 weeks, about 6 (±1) weeks, or about 6 weeks.PAT060004-PCT-SEC01- 96 -3. The method of any one of the preceding claims, wherein the blood samples are taken before the respective RLT agent administration (“pre-dose”), preferably about a week before, more preferably about one, two, or three days before, even more preferably before but on the same day of RLT agent administration [i.e. on day 1 of cycle 1 (C1D1) in step (1), on day 1 of cycle 2 (C2D1) in step (3)].

4. The method of any one of the preceding claims, wherein the threshold is about 2%, about 1%, or about 0.5%.

5. The method of any one of the preceding claims, wherein the ctDNA evaluation comprises also determining the specific cancer-related alterations, e.g. gene mutations and amplifications, in ctDNA, in particular wherein said the alterations are selected from the group consisting of chromosome 8q amplifications, AR amplification, TP53 deleterious alterations, PTEN alterations, and wherein said amplifications / alterations are indicative for a suboptimal response to the RLT, more particularly said amplification / alteration is a chromosome 8q amplification and is indicative for a suboptimal response to the RLT.

6. The method of any one of the preceding claims, wherein said cancer is a prostate cancer (PC); said PC may be an oligometastatic or metastatic prostate cancer (OMPC or mPC), preferably is a mPC; said mPC may be a metastatic hormone-sensitive or a metastatic castration-resistant prostate cancer (mHSPC or mCRPC), preferably is a mCRPC.

7. The method of any one of the preceding claims, wherein said cancer is a prostate cancer and is prostate-specific membrane antigen (PSMA)-positive (PSMA+).

8. The method of any one of the preceding claims, wherein said cancer is a prostate cancer and the patient has been treated with androgen receptor pathway inhibitor (ARPI) therapy (i.e. pior ARPI therapy), and prior to or after taxane-based chemotherapy; preferably the patient has been treated with ARPI therapy, and prior to taxane-based chemotherapy (i.e. taxane-naive); more preferably the patient progressed under ARPI therapy, and prior to taxane-based chemotherapy; even more preferably, the patient progressed once on prior ARPI therapy and prior to taxane-based chemotherapy.PAT060004-PCT-SEC01- 97 -9. The method of any one of the preceding claims, wherein the RLT agent is a radiolabeled PSMA targeting agent, preferably said targeting agent is a low molecular weight (LMW) agent and not an antibody of a fragment thereof, more preferably a peptide or peptidomimetic, even more preferably said agent is selected from the group consisting of PSMA-617 (vipivotide tetraxetan), and PSMA l& T (zadavotide guraxetan), even more preferably is PSMA-617.

10. The method of any one of the preceding claims, wherein the RLT agent is radiolabed with an alpha-particle, beta-minus particle, or Auger-electron emitting radionuclide, preferably a beta-minus particle emitting radionuclide, preferably selected from the group consisting of Lu-177, Tb-161, 1-131, and Cu-67; more preferably Lu-177 or Tb-161, even more preferably Lu-177.

11. The method of any one of the preceding claims, wherein the the RLT agent is a beta-minus-particle emitting radionuclide and the specified dose is from about 5 to about 25 GBq, from about 5 to about 10 GBq, from about 6 to about 8.5 GBq, from about 6.5 to about 7.5 GBq, about 7.4 ± 10% GBq, or 7.4 ± 10% GBq.

12. The method of any one of the preceding claims, wherein the escalation therapy is selected from the group of:(a) radioactive dose increase, e.g. from 7.4 GBq (200 mCi) to 9.25 GBq (250 mCi); (b) change to a radionuclide with higher emitting particle energies, e.g. from Lu-177 to Y-90;(c) change to radionuclide with higher LET (linear energy transfer), e.g. from beta-minus particle emitter to alpha-particle emitter or Auger-electron emitter, e.g. from Lu-177 to Ac-225 or Tb-161;(d) combination therapies, e.g. combining the RLT with immune checkpoint inhibitors, radiosensitizers, e.g. DNA damage increasing agents, e.g. alkylating agents, TOPi, antimetabolites, DNA damage repair inhibitors, e.g. DNA-PKi, PARPi, ATMi, ARTi, HSP90i, TOPi, in the case of prostate cancer: androgen receptor (AR) degraders;(e) chemotherapy, e.g. with taxanes.

13. Use of cell-free plasma ctDNA fraction of a blood sample taken on-treatment at day 1 of cycle 2 (C2D1), pre-dose, of a Radioligand therapy (RLT) as prognostic and / or predictive and / or response biomarker or as an (intermediate or final, primary or secondary or exploratory)PAT060004-PCT-SEC01- 98 -endpoint for clinical benefit or for a clinical trial, together with or without the baseline ctDNA fraction, preferably, without the baseline ctDNA fraction.

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