PSMA Targeted radionuclide therapy in Prostate Cancer

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1 PSMA Targeted radionuclide therapy in Prostate Cancer Tawatchai Chaiwatanarat Division of Nuclear Medicine Department of Radiology Chulalongkorn University Bangkok, Thailand

2 * cell si ze ~20 µm Radionuclide therapy

3 Radionuclide therapy Li gand PSM A on tumor cell Antibody Inhibitor * cell si ze ~20 µm

4 Radionuclide therapy Radionuclide therapy radionuclide nucli de Li gand PSM A on tumor cell Nuclide Particle Mean beta energy (kev) Max tissue penetration (~number of cells)* Yttri um-90 Beta mm ( ~600) I odi ne-131 Beta, Gamma mm (~100) Luteti um-177 Beta, Gamma mm (~100) Actinium-225 Alpha µm ( 2-3 cells) * cell si ze ~20 µm

5 90Y J591 phase I trial, New York, USA (J Clin Oncol 2004;22: ) 29 patients: 2 PSA, 6 stabilized 177Lu J591 phase II study, New York, USA (Clin Cancer Res. 2013;19: ) 47 patients: 60% PSA

6 I-131 MIP-1095 Zechmann CM, et al. (2014), Heidelberg, Germany 28 pts mcrpc, 1 dose administration 75% any PSA 61% > 50% PSA Pt.1 Pt.2 Eur J Nucl Med Mol Imaging 2014;41:

7 Oncotarget. 2016;7: Lu PSMA617 Ahmadzadehfar H, et al. (2016), Bonn, Germany 24 pts with hormone and chemotherapy refractory Median PSA = 522 ng/ml

8 Oncotarget. 2016;7: PSA change from baseline at 8 weeks after the first cycle 79.1 %: any PSA decline 41.6 %: >50% PSA decline

9 Ga68 PSMA Oncotarget. 2016;7:

10 Before Rx After 2 doses Ga68 PSMA Oncotarget. 2016;7:

11 Hematotoxicity Nephrotoxicity Hepatotoxicity Oncotarget. 2016;7:

12 Clin Nucl Med. 2016;41: Lu PSMA617 Rahbar K, et al. (2016), Münster, Germany 28 pt with conventional therapy refractory Total 50 treatment After 2 nd dose 75% PSA 50% PSA >50% Median survival 29.4 wk better than historical best supportive care of 19.7 wk

13 Clin Nucl Med. 2016;41:

14 Clin Nucl Med. 2016;41:

15 J Nucl Med 2016; 57: Lu PSMA617 Baum RP, et al. (2016), Bad Berka, Germany 56 patients up to 5 treatments Median PFS 13.7 months. Survival after 28 months was 78.6%.

16 70 yrs. mcrpc with l.n. metastasis Before Rx 1 st Lu nd Lu-177 J Nucl Med 2016; 57:

17 J Nucl Med 2016; 57: yrs. mcrpc with bone and l.n. metastasis Before Rx Lu-177 Ga-68 After Rx

18 EJNM 2017;14: Lu PSMA617, Münster, Germany 59 pt with end-stage mcrpc Total 159 treatments (median 3, range 1-7) 91% PSA 53% PSA > 50% Median PSA progression-free survival 18 wk. Median overall survival 32 wk.

19 EJNM 2017;14: Predictor of longer OS PSA decline after 1 st treatment (56 vs 29 wk. p=0.04) Baseline ALP < 220 U/L (56 vs 28 wk. p<0.01)

J Nucl Med 2017; 58: 312 9 Predictors of Response: 177Lu PSMA617 Ferdinandus J, et al.

20 J Nucl Med 2017; 58: Predictors of Response: 177Lu PSMA617 Ferdinandus J, et al. (2017), Bonn, Germany 40 patients Parameters effect PSA response 2 mo after RLT univariate analysis: parameter with negative impact younger age (<65 yr) regular need for pain medication high GSC, high GGT, high CRP, high LDH, low Hb, high platelets multivariate analysis: number of platelets Regular need for pain medication

21 Clin Nucl Med 2017;42: yrs. with mcrpc Before Rx After 2 cycles

22 Lancet Oncol Jun;19(6): Lu PSMA617 Hofman MS, et al. (2018), Melbourne, Australia 1 st prospective study, phase II, single-arm, single-centre 30 pt with metastatic castration resistant who progressed after standard treatments

23 Lancet Oncol Jun;19(6): Lu PSMA617 Hofman MS, et al. (2018), Melbourne, Australia Up to 4 cycles of treatment best PSA response: 97% PSA 70% PSA > 30% 57% PSA > 50% 37% > 10 points improve in health score (EORTC-Q30) after 2nd cycle

24 Lancet Oncol Jun;19(6): PSA response after 12 wk. Best PSA response from baseline

25 Lancet Oncol Jun;19(6): months after last treatment 82%

26 Lancet Oncol Jun;19(6): Lu PSMA617 Hofman MS, et al. (2018), Australia Up to 4 cycles of treatment : PSA progression-free survival of 7 months Median overall survival was 13.5 months

27 Lancet Oncol Jun;19(6):

28 Chula case: Lu-177 PSMA 1 st dose PSA (before) 117 -> 83 (7 wk after) 2 nd dose PSA (before) 83 -> 177 (8 wk after)

29 Chula case: Lu-177 PSMA 1 st dose PSA (before) 545->946 (8 wk after) 2 nd dose

30 Lu-177 PSMA Conclusion for 177Lu-PSMA-617 Convincing therapeutic response, both PSA level and radiologic findings % PSA 30-50% PSA > 50% PFS wks OS wks ~30% short / non-responders dose escalation was limited by hematological toxicity

31 Radiation β-beta particle mass = electron e.g. Lu-177 low LET (linear energy transfer) α-alpha particle mass = 2 neutrons + 2 protons e.g. Ac-225, Bi-213 high LET

32 J Nucl Med. 2016;57: Ac-PSMA617: Heidelberg, Germany

33 225Ac-PSMA617 Kratochwil et al., Heidelberg, Germany J Nucl Med 2018 May;59:

34 225Ac-PSMA617 Results: 40 pts. 2 died before 8 wk after 1 st treatment Of 38 pts. Only 1 dose in 9: 5 non-response, 4 severe xerostomia 33 (87%) PSA 24 (63%) PSA > 50% J Nucl Med 2018 May;59:

J Nucl Med 2018 May;59:795 802 225Ac-PSMA617 Duration of Tumor Control (not time to PSA progression ) 225Ac PSMA: new clinical

35 J Nucl Med 2018 May;59: Ac-PSMA617 Duration of Tumor Control (not time to PSA progression ) 225Ac PSMA: new clinical tumor-related symptoms or PSA relapse to baseline Other medication: first administration of a drug to initiation of the next treatment line 4 mo. 1 yr.

36 225Ac-PSMA617 Results: 40 pts. Of 38 pts. median time tumor control 9.0 mo (5 pts. > 2 yrs.) 1st-line: 8 mo. Abiraterone: 10.0 mo 2nd-line: 7 mo. Docetaxel: 6.5 mo 3rd-line: 6 mo. Enzalutamide: 6.5 mo 4th-line: 4 mo. Cabazitaxel: 6.0 mo J Nucl Med 2018 May;59:

37 J Nucl Med 2018 May;59:

38 J Nucl Med 2018 May;59:

39 Eur J Nucl Med Mol Imaging Sep Ac-PSMA617 Pretoria, South Africa & Karlsruhe, Germany 17 advanced metastatic CA prostate (>10 metastatic foci), chemotherapy-naïve 8 bone-only metastases 3 l.n.-only metastases 6 l.n. + bone metastases 2 visceral metastases; 1 lung metastases, 1 brain + liver metastases.

40 Eur J Nucl Med Mol Imaging Sep 19 Treatment was repeated every 8 weeks 3/17 received only 2 cycles due to excellent response Negative PSA and Ga-68 PSMA 9/17 received 3 cycles 5/17 received > 3 cycles at least 1 year follow up

41 Eur J Nucl Med Mol Imaging Sep 19 PSA response after 1 st cycle 12/17 80% 1/17 50% 1/17 <50% 3/17 increased 2/3 at end of treatment 1/3 not response after 3 rd cycle After 1 st cycle Best response

42 Eur J Nucl Med Mol Imaging Sep 19 At the end of treatment 14/17 PSA 90% 11/17 complete resolution by 68Ga-PSMA11 treatment-naïve tend to respond better Follow-up median follow-up period of 13 months 14/17 alive at the time of the analysis 7/14 remission (undetectable serum PSA) 7/14 stable disease (serum PSA and 68Ga-PSMA11 PET/CT)

43 Eur J Nucl Med Mol Imaging Sep 19 progressed while on Zoladex symptom-free on 11-month follow-up

44 Eur J Nucl Med Mol Imaging Sep 19 treatment-naïve Decreased pain symptom-free on 10-month follow-up

45 Sx, EBT, ADT improve But new lesions -> Chemo then die after 4 mo. Eur J Nucl Med Mol Imaging Sep 19

46 Eur J Nucl Med Mol Imaging Sep 19

47 Am J Nucl Med Mol Imaging Aug 20;8(4):

48 J Nucl Med :

49 J Nucl Med :

50 Nuklearmedizin. 2016;55:123 8 Essential inclusion criteria (German Society of Nuclear Medicine) non-resectable metastases progression under guidelines therapy detected PSMA expression of the tumor reasonable hematological function Leukocyte count > 2000/mm3 thrombocyte > 75,000/mm3; creatinine < 2 x upper standard limit AST or ALT < 5 x upper standard limit six-week interval with myelosuppressive therapy

51 Thank You for Your Attention

Session 4 Chemotherapy for castration refractory prostate cancer First and second- line chemotherapy

$Session 4 Chemotherapy for castration refractory prostate cancer First and second- line chemotherapy$ Session 4 Chemotherapy for castration refractory prostate cancer First and second- line chemotherapy October- 2015 ESMO 2004 October- 2015 Fyraftensmøde 2 2010 October- 2015 Fyraftensmøde 3 SWOG 9916 OS