Deescalated 225Ac-PSMA-617 Versus 177Lu/225Ac-PSMA-617 Cocktail Therapy: A Single-Center Retrospective Analysis of 233 Patients

Hendrik Rathke; Erik Winter; Frank Bruchertseifer; Manuel Röhrich; Frederik Lars Giesel; Uwe Haberkorn; Alfred Morgenstern; Clemens Kratochwil

doi:10.2967/jnumed.123.267206

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FIGURE 1.
Waterfall graphs of best PSA response. (A) Of 104 patients receiving AcPSMA monotherapy, 55 had PSA decline of >50% (green); 16 had stable disease, defined by PSA decrease of <50% up to PSA increase of <20% (blue); 17 had PSA progression (red); and 16 were follow-up losses (purple). (B) Of 129 cocktail group patients, 74 had PSA decline of >50% (green), 36 had stable disease (blue), 17 had PSA progression (red), and 12 were follow-up losses (purple).
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FIGURE 2.
(A–D) Patient with meningeal, adrenal, pulmonary, lymph nodal, and osseous metastases. (A) Baseline staging per ¹⁸F-PSMA-1007 PET/CT is demonstrated as maximum-intensity projection. (B and C) Two cycles of AcPSMA and LuPSMA cocktail therapy were documented per planar scan of 208-keV γ-line of ¹⁷⁷Lu. (D) PET/CT restaging presents partial remission. (E–H) Patient with adrenal, osseous, lymph nodal, and hepatic metastases. (E) Baseline imaging was done as planar ^99mTc-PSMA scintigraphy. (F and G) AcPSMA monotherapy was documented per planar emission scans using 26% 440-keV and 12% 218-keV γ-coemissions of ²¹³Bi and ²²¹Fr. (H) Restaging per planar ^99mTc-PSMA scintigraphy demonstrates near-total remission.
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FIGURE 3.
Kaplan–Meier curves for AcPSMA monotherapy group with mOS of 9 mo (95% CI, 7.18–10.82) (A) and for AcPSMA and LuPSMA cocktail group with mOS of 15 mo (95% CI, 10.93–19.02) (B).

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TABLE 1.

Patient Characteristics for AcPSMA Monotherapy Group and AcPSMA and LuPSMA Cocktail Group

Characteristic	AcPSMA	AcPSMA and LuPSMA
Patients (n)	104	129
Age (y)	62 (48–81)	62 (44–80)
ECOG score of 0–1 (%)	66.3	87.6
ECOG score ≥ 2 (%)	34.6	12.4
Time until PSMA therapy (mo)	85 (9–282)	76 (2–295)
Previous β-PSMA therapy (%)
1 cycle	11	7
≥2 cycles	26	25
Site of disease (%)
Lung	13	8
Liver	22	15
Lymph node	70	67
Bone	96	97
Bone marrow (superscan)	76	39
Brain	2	1
Other	21	15
PSA (ng/mL)	312 (0–4,843)	78 (0–6,557)
AP (IU/L)	203 (19–3,148)	128 (37–1,866)
LDH (IU/L)	403 (156–4,066)	245 (149–2,662)
Gleason score (%)
6–7	30	28
8–10	53	61
Unknown	17	11
Previous therapy (%)
Prostatectomy and lymph node dissection	53	51
Radiotherapy of primary tumor	32	19
Both local therapies	43	39
Previous NAAD therapy (%)	89	87
1 regimen	32	38
2 regimens	68	59
More than 2 regimens	0	3
No NAAD regimen	11	13
Previous taxane therapy (%)	70	71
1 regimen (%)	51	40
2 regimens (%)	32	41
3 regimens (%)	18	20
No chemotherapy regimen	30	29
PLT ≥ 100/nL (%)	84	95
PLT < 100/nL (%)	16	5
Hb ≥ 9 g/dL (%)	78	88
Hb < 9 g/dL (%)	22	12
Event death (%)	62.5	52
Event censored (%)	37.5	48

ECOG = Eastern Cooperative Oncology Group clinical performance status; AP = alkaline phosphatase (reference level, 40–130 U/L); LDH = lactate dehydrogenase (reference level, <342 U/L); NAAD = novel androgen axis drugs, i.e., abiraterone, enzalutamide, apalutamide, and darolutamide; PLT = platelet (reference level, 150–440/nL); Hb = hemoglobin.
Data are median and range.
Taxane retreatment with docetaxel and cabazitaxel in complete 6-cycle series was counted as additional treatment line.
Percentages may not total 100% because of rounding.

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TABLE 2.

Overview of Available Literature About AcPSMA Monotherapy or Combination Therapy

Source	Patients (n)	Treatment activity	Cycles (n)	Ligand	PSA response > 50% (%)	mOS (mo)	Previous LuPSMA (%)
(2)	14	50, 100, 150, or 200 kBq/kg	31 (1–4) in study	PSMA-617	44	>12	21
(3)	40	100 kBq/kg	3–5/patient	PSMA-617	60	>12	20
(23)	17	7.4 MBq	59 in study	PSMA-617	82	NR	88
(24)	73	8, 7, 6, or 4 MBq, with deescalation of responders	210 in study	PSMA-617	70	18	70
(21)	28	100 kBq/kg	85 in study	PSMA-617	39	17	54
(20)	11	100 kBq/kg	25 in study	PSMA-617	45	NR	46
(7)	20	5.3 (1.5–7.9) MBq + 6.9 (5–11.6) GBq of ¹⁷⁷Lu	1/patient	PSMA-617	65	12	100
(31)	73	7.8/cycle mean	34 in study	PSMA-I&T	50	NR	79
(8)	15	2.7 ± 1.1 MBq + 6.7 ± 1.8 GBq of ¹⁷⁷Lu	2 (1–6)/patient	PSMA-617	29	>20 PR; 8.3 SD, PD	100
(10)	13	8 MBq first cycle, 6 MBq subsequent cycles	3/patient	PSMA-617	69	8.5	15.4
(28)	12	7.4 MBq	25 in study	PSMA-617	50	10	58
(29)	38	100 kBq/kg	2 (2–5)/patient	PSMA-617	66	12	23.6
(30)	13	100 kBq/kg, 7.6 (6–8.5) MBq	31 in study	PSMA-I&T	14.3	10	77
(25)	106	8 MBq first and second cycles, 6 MBq, and 4 MBq, with deescalation of responders	4 (1–9)/patient	PSMA-617	80.2	15	6.6
(27)	23	7.6 (6.2–10) MBq mean	38 in study	PSMA-617	26	7.7	100
(22)	56	100–150 kBq/kg	204 in study	PSMA-617	67.8	15	48.2
This work	233		536 in study	PSMA-617
Monotherapy	104	6 MBq, with deescalation of responders			53	9	37
Combination therapy	129	4 MBq + 4 GBq of ¹⁷⁷Lu			57	14	32

NR = not reported; PR = partial remission; SD = stable disease; PD = progression of disease.
Continuous data are median and range unless indicated otherwise.