This document summarizes the results of the TheraP trial, which compared treatment with 177Lu-PSMA-617 versus cabazitaxel in men with metastatic castration-resistant prostate cancer. The trial found that 177Lu-PSMA-617 resulted in a higher PSA response rate and longer progression-free survival compared to cabazitaxel, with fewer grade 3-4 adverse events. Patient-reported outcomes also favored 177Lu-PSMA-617 over cabazitaxel.

1. Rian Hidayatullah
1
Supervisor:
Dr.YustiaTuti, SpKN-TM(K)
Dr. Ayu R. Dewi, SpKN-TM(K)

2. Introduction
Metastatic castration- resistant
prostate cancer is incurable
Treatment :
- docetaxel
- androgen receptor-directed
therapies : abiraterone, enzalutamide
Improves survival progressing after
previous treatment with docetaxel.
Cabazitaxel
Promising treatment for patient with
advanced prostate cancer.
177Lu-PSMA-617
177Lu-PSMA-617  high dose of
radiation  β- particulate : 0.7 mm
TheraP trial  aimed to compare the
activity and safety of 177Lu-PSMA-617
with cabazitaxel

3. Methods
■ Study design and participants
- TheraP  multicentre (11 centres), unblinded, randomized phase 2 trial  in Australia.
- Criteria : men with metastatic castration-resistant prostate cancer + previously treated by
docetaxel + rising PSA as per PCWG3.
- Eligible participants :
• adequate renal, haematological, and liver function
• ECOG performance = 0-2.
• Previous treatment with androgen receptor-directed therapy
• Previously  68Ga- PSMA- 11 and 18F- FDG PET/CT, criteria :
- PSMA positive  with SUVmax at least 20 (site of disease); >10 (metastatic disease).
- No site of metastatic disease  FDG positive and PSMA-negative.
3

4. Methods
Procedures
4
Control Group
 Treated with  cabazitaxel 20
mg/m2 intravenous
 Every 3 weeks (max. 10 cycles).
Experimental Group
 Treated with  177Lu –PSMA-617 intravenous
 Every 6 weeks (max. 6 cycles)
 Administered doses  8.5 GBq  decreased by
0.5 GBq per cycle.
 1,5 L oral hydration
 Planar and SPECT-CT : 24 hours.
 Treatment suspended  if SPECT-CT showed very
low or no PSMA uptake at site of metastatic
disease.
 During study treatment : blood test (routine
haematology, biochemistry, serum PSA) 
reviewed every 3 weeks.
 Chest CT, abdomen and pelvis CT, also bone scan
(99mTc-phosphate)  done every 12 weeks 
until radiological progression.

5. Methods
Procedures
Measurement of patient-reported outcomes :
■ Present pain intensity (PPI)  McGill-Melzack scale
■ Quality of life measurement  European Organization for Research andTreatment of
Cancer (EORTC)  every 3 weeks until end of study treatment.
■ Patient Disease andTreatment Assessment Form (DATA)  every 4 weeks until
radiographic progression.
■ A safety assessment  done at 30 days and 12 weeks  after last dose of study
treatment.
– Follow up  every 12 weeks
5

6. Methods Outcome
Primary
Endpoint
PSA response rate
 PSA reduction
of 50% or more
from baseline
Progression-free survival
• 1st evidence of PSA progression defined
by increase of at least 25% or 2 ng/mL
after 12 weeks
• Radiographic progression  Locally
reported CT and bone scanning (RECIST)
and PCWG3 criteria for bone lesions.
• Commencement of non-protocol
anticancer treatment
• Death from any cause

7. Methods Outcomes
Defined according RECIST 1.1
Objective response rate :
Reported according the Common Terminology
Criteria for Adverse Events version 4.03.
Adverse events :
Men with PPI score at baseline of 2 or more; and
defined as a reduction from baseline of 2 or more
points.
Pain response :
Related to prognostic and predictive biomarkers
await analysis and results will be published
separately.
Exploratory endpoints :

8. RESULTS
8

9. - Between Feb 6 2018 to Sept 3 2019.
- 291 partisipants  underwent 68Ga-
PSMA-11 and 18F-FDG PET/CT.
- 91 men ineligible  29 low uptake + 51
discordant + 11 other.
- 98 men treated with 177Lu-PSMA-617 
45 (46%) complete protocol therapy.
- Among 85 men treated with cabaxitazel
 31 (36%) received 10 cycles.
Data cutoff  July 20, 2020 : reaching the
prespecified target of 170 PSA progression-
free survival event after median follow-up of
18.4 months.

10. - 91 (91%) men in each group  previous
treatment with enzalutamide or
abiraterone.

11. RESULTS
- PSA reduction of 50% or
more from baseline 
more frequent in 177Lu-
PSMA-617 than
cabazitaxel.
- 65 of 99 men (66%) in
177Lu-PSMA-617 compared
with 37 of 101 men (37%) in
cabaxitazel.

12. Results
■ Progression events :
- 173 men (90 in Lu177 group; and 83 in
cabazitaxel group)  Lu177 group had
delayed progression compared with
cabazitaxel group (HR 0,63).
- Similar benefits in radiographic progression
(0.64; p=0,0070) and PSA progression-free
survival (0,60; p=0,0017).
- These 3 progression events  not constant
with respect to time  Lu-177 more apparent
after 6 months compared to cabazitaxel.
12

13. Results
■ Progression-free survival at 12 months :
- 19% in 177Lu-PSMA-617 group : 3% in cabazitaxel group.
■ Median progression-free survival :
- 5.1 months in 177Lu-PSMA-617 group : 5.1 months in cabazitaxel group.
■ RECIST criteria : 78 men at baseline with objective response rate :
- 49% in 177Lu-PSMA-617 group : 24% cabazitaxel group.
■ Analysis of overall survival  is planned to occur after 170 deaths and results will be
published when ready. At this time 90 deaths were documented.
13

14. ■ 183 partisipants (85 men 177Lu-PSMA-617
group + 98 cabazitaxel group) 
included in safety analysis.
■ Grade 3-4 adversed event occurred in 32
(33%) 177Lu-PSMA-617 group VS 45 (53%)
cabazitaxel group.
■ Grade 3-4 thrombocytopenia was more
common : 11 (11%) 177Lu-PSMA-617
group VS 0 cabazitaxel group.
■ Grade 3-4 neutrophenia was less
common : 4 (4%) 177Lu-PSMA-617 group
VS 11 (13%) cabazitaxel group.
14

15. Results
• 90 men with PPI score of 2 or more at baseline :
- a pain response occurred in : - 29 of 48 men (60%) in 177Lu-PSMA-617 group.
- 18 of 42 men (43%) in cabazitaxel group.
• PPI- progression-free survival favoured the 177Lu-PSMA-617 group (HR 0.72; p=0.033).
• Mean global health status  similar in 177Lu-PSMA-617 group and cabazitaxel group.

16. Discussion
■ TheraP  the first reported randomized trial comparing 177Lu-PSMA-617 with a standard of care
therapy.
■ The choice of cabazitaxel showing improved overall survival compared with a 2nd line novel anti-
androgen.
■ Toxicity of 177Lu-PSMA-617 showed  fewer grade 3-4 toxicities compared with cabazitaxel,
except thrombocytopenia.
■ The patient-reported outcomes  better with 177Lu-PSMA-617 than cabazitaxel.
■ The time to pain progression  favoured 177Lu-PSMA-617 over cabazitaxel.
■ Greater improvements in fatigue, social functioning, and insomnia with 177Lu-PSMA-617 than with
cabazitaxel.
■ Selection of patients on the basis of molecular imaging phenotype : using the combination of
PSMA and 18F-FDG PET/CT  to maximise the probability of observing benefit.
16

17. Discussion
■ Ability to select patients is a key advantage of the theranostic approach of combining
imaging and therapy modalities  our study : no inform patient with lower PSMA
expression or discordant 18F-FDG-avid disease  would also benefit from 177Lu-PSMA-
617.
■ We await the results of theVISION trial, a phase 3 randomized trial  comparing 177Lu-
PSMA-617 to best standard of care or best supportive care.
■ TheraP used  a quantitative PET parameter (ie: SUVmax) and 18F-FDG to assist 
identifying patients with discordant 18F-FDG-positive, PSMA-negative disease.
■ The promosing efficacy and safety profile of 177Lu-PSMA-617  seen in men with
mCRPC  after multiple lines of therapy.
■ Used of 177Lu-PSMA-617 in men with newly diagnosed metastatic hormone-sensitive
prostate cancer is also explored.
17

18. Limitation
18
 1st limitation : 15 men in cabazitaxel group
sought treatment with 177Lu-PSMA-617
(didn’t want chemotherapy)  withdrew
from the trial.
 2nd limitation : used a randomized phase 2
design, and sample size was focused on
biological activity (PSA response and
progression-free survival), rather than on
direct measures of patient benefit (overall
survival or quality of life).
 3rd limitation : partisipants with
concordant disease on imaging using
68Ga-PSMA-11 and 18F-FDG PET/CT 
findings might not be applicable to men
selected less carefully.

19. Conclusion
TheraP showed better activity, safety, and patient-reported
outcomes with 177Lu-PSMA-617 than with cabazitaxel in men
with mCRPC progressing after docetaxel.

20. 20

21. 21

22. 22

23. 23
• Studies have demonstrated PSMA expression in the small intestine, proximal
renal tubules, and salivary glands (Tasch et al., 2001).
• However, the expression levels in these tissues are much lower than in the
prostate gland (Sokoloff et al., 2000).
• Some minimal expression is also observed in the brain but most agents,
particularly antibodies, do not penetrate the brain because of the blood-brain
barrier.
• PSMA is expressed in the neovasculature of numerous other solid tumors,
including bladder, pancreas, lung, and kidney cancers, but not in normal
vasculature (Elsasser-Beile et al., 2009a).

24. The Power of PowerPoint | thepopp.com 24
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%

25. PSA= 9579 ng/mL
PSA= 35 ng/mL
6x cycles
177Lu-PSMA-617 RLT
4x cycles
177Lu-PSMA-617 RLT
PSA= 69 ng/mL PSA= 0.2 ng/mL
A
C
E
B
D
F
PSA= 69 ng/mL PSA= 0.2 ng/mL
E F
3x cycles
177Lu-PSMA-617 RLT
PSA= 231 ng/mL PSA= 0.2 ng/mL

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39. Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [177lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (lupsma trial): a single-centre, singlearm, phase 2 study. Lancet Oncol 2018; 19:825–833.

40. Hofman MS, Violet J, Hicks RJ, Ferdinandus J, Thang SP, Akhurst T, et al. [177lu]-PSMA-617 radionuclide treatment in patients with metastatic castration-resistant prostate cancer (lupsma trial): a single-centre, singlearm, phase 2 study. Lancet Oncol 2018; 19:825–833.

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Gambar 4.1. Rantai Peluruhan
Uranium-233 dan Uranium-
232/Thorium-232.

44. Gambar 4.15. LET tinggi memiliki probabilitas tinggi untuk menghasilkan kerusakan double
stranded DNA, sedangkan LET rendah memiliki probabilitas yang sama untuk menginduksi
kerusakan double stranded DNA jika menggunakan dosis lebih tinggi.
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45. Gambar 4.16. Ilustrasi partikel alfa melintas melewati parameter m, n, dan c. A:Tampak samping sel yang
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partikel alfa berpusat pada jarak 1,5 µm (LR 115) dari membran nukleus. B: Gambar sel dan jalur partikel alfa
yang sesuai (seperti yang diilustrasikan pada poin A).
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