Lutetium-177 PSMA radioligand therapy in taxan-naive first- and second-line metastatic castration resistant prostate cancer after first-line ARPI therapy.
Authors: Mandel Philipp , Hoeh Benedikt , Siech Carolin , Koll Florestan , Humke Clara , Groener Daniel , Steuber Thomas , Graefen Markus , Maurer Tobias , Banek Severine , Chun Felix , Wenzel Mike 
Published: February 2025

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Background:
Lutetium-177 Prostate-specific membrane antigen (Lu-PSMA) radioligand therapy is EMA-approved for metastatic castration resistant prostate cancer (mCRPC) after androgen receptor pathway inhibition (ARPI) and taxane-based chemotherapy. However, its effect in taxane-naïve patients is under current investigation.
Methods:
We relied on the FRAMCAP database to elaborate Lu-PSMA therapy outcomes of progression-free (PFS) and overall (OS) in taxane-naïve mCRPC patients after previous ARPI treatment. Comparison was made against current standard of care with ARPI or docetaxel.
Results:
Of 269 patients, 11% received Lu-PSMA in first/second-line mCRPC vs. 57% ARPI vs. 33% docetaxel. Mostly no significant baseline differences between Lu-PSMA and ARPI patients were observed, while Lu-PSMA patients were significantly older, received less systematic treatments and ECOG1-2 proportions were higher, relative to docetaxel patients. In PFS (13.3 vs. 8.2 months, hazard ratio [HR]: 0.70, p=0.16) and OS analyses (68.9 vs. 39.1 months, HR: 0.64, p=0.2), Lu-PSMA was numerically more favorable than ARPI. In additional multivariable Cox regression models, Lu-PSMA was significant better regarding PFS and OS, relative to ARPI (both p<0.05). Compared to docetaxel, also significant better PFS (13.3 vs. 8.1 months, HR: 0.46) and OS (68.9 vs. 27.3 months, HR: 0.34, both p<0.01) was observed for Lu-PSMA treatment. The OS advantage was also observed after multivariable adjustment (p<0.01).
Conclusions:
Real-world evidence suggests that Lu-PSMA therapy provides significantly better PFS and OS outcomes in taxane-naïve mCRPC patients after previous ARPI treatment, relative to ARPI or docetaxel treatment and should therefore considered as an early mCRPC treatment.

A
B

Characteristic

N

Overall

N = 269

1

Lu-PSMA,

N = 29 (11%)

1

ARPI,

N = 152 (57%)

1

p-value

2

Docetaxel,

N = 88 (33%)

1

p-value

2

Age at metastatic disease, years
256
71 (65, 77)
74 (69, 79)
72 (66, 77)
0.055
68 (62, 73)
<0.001

Age at mCRPC, years
167
72 (67, 79)
76 (73, 83)
74 (68, 79)
0.083
69 (64, 75)
<0.001

PSA at mCRPC, ng/ml
133
17 (6, 47)
23 (9, 82)
18 (5, 47)
0.2
12 (4, 40)
0.091

Systemic treatment lines for mCRPC
269
3 (2, 4)
2 (1, 2)
3 (2, 4)
<0.001
3 (3, 5)
<0.001

Received cycles
139
3 (2, 6)
3 (2, 5)

4 (2, 6)
0.2

PSA response, %
26
23 (4, 62)
20 (11, 30)
17 (0, 90)
0.9
41 (17, 62)
0.3

ECOG at mCRPC
87

0.13

0.017

0

40 (46%)
4 (24%)
17 (45%)

19 (59%)

1-2

47 (54%)
13 (76%)
21 (55%)

13 (41%)

Cardiovascular disease
171
64 (37%)
9 (50%)
33 (34%)
0.2
22 (39%)
0.4

Gleason score 8-10
234
165 (71%)
16 (62%)
89 (69%)
0.5
60 (76%)
0.2

Local therapy
269
112 (42%)
12 (41%)
52 (34%)
0.5
48 (55%)
0.2

De Novo metastatic disease
259
140 (54%)
15 (54%)
86 (59%)
0.6
39 (45%)
0.4

High volume mHSPC
104
55 (53%)
6 (67%)
35 (54%)
0.7
14 (47%)
0.5

Metastatic sites at mCRPC
110

0.8

0.4

M1a

13 (12%)
2 (11%)
5 (10%)

6 (15%)

M1b

91 (83%)
15 (79%)
42 (84%)

34 (83%)

M1c

6 (5.5%)
2 (11%)
3 (6.0%)

1 (2.4%)