Abstract

INTRODUCTION

Prostate-specific membrane antigen (PSMA) is a promising target for the diagnosis and therapy of metastatic castration-resistant prostate cancer (mCRPC) [1–5]. Several studies have demonstrated the safety and low toxicity profile of [¹⁷⁷Lu] Lu-PSMA-617 (Lu-PSMA) for the therapy of mCRPC patients [6–12]. Prolongation of overall survival (OS) is one the most important parameters in the evaluation of efficacy of a therapeutic agent. Although, there are still no prospective studies on the OS of mCRPC patients who have undergone Lu-PSMA therapy, results from the first retrospective studies were very promising. These studies showed a positive effect of Lu-PSMA therapy on OS in patients in advanced stages of mCRPC [13–15]. Abiraterone and enzalutamide are both the approved hormone therapies for mCRPC patients [16–18]. Papers published to date on OS in mCRPC patients treated with Lu-PSMA therapy included small numbers of patients and inhomogeneous patient groups. The primary aim of this study was to measure OS in mCRPC patients who received at least abiraterone or enzalutamide as antitumor therapy prior to radioligand therapy (RLT). The second aim of this study was to analyse the predictive value of different pre-therapeutic parameters and the prostate-specific antigen (PSA) level response to the first cycle on OS.

RESULTS

Survival analysis and prognostic factors

Survival was calculated from the day of the first RLT cycle. The median OS was 60 weeks in all patients, irrespective of response to treatment (95% CI: 47.3–72.7). The univariate analysis showed that low levels of aspartate transaminase (AST ≤ 24 U/l), gamma-glutamyl transferase (GGT ≤ 31 U/l), CRP ≤ 16 mg/l, lactate dehydrogenase (LDH < 225 U/l) and ALP ≤ 140 U/l; high pre-therapeutic haemoglobin (Hb ≥ 10.4 g/dl); high albumin (albumin ≥ 38.6 g/l); lower number of bone metastases; absence of liver metastases; an ECOG status of 0/1; no history of prior blood transfusion; no regular intake of analgesics; any decline in PSA levels and a decline in PSA levels of ≥ 50% were significant predictors of OS (Table ​(Table4).4). Analyzing the percentage of PSA decline after the first cycle determined a PSA decline ≥ 14 % as best cut-off point with a median OS of 88 weeks vs. 29 weeks.

Table 4

Univariate and multivariate analyses of different pre-therapeutic parameters and their impact on overall survival (only the significant parameters are shown)

Parameters	p-value	Median OS reported in weeks (95 % CI)	Multivariate analysis p-value
Number of bone metastases 29 patients ≤ 20 met 45 patients > 20 met 24 patients : super scan or diffuse bone/bone marrow met	0.02	94 (60.7–127.3) 55 (38.8–71.2) 37 (12.7–61.3)	ns
Existence of liver metastases 13 patients: yes 87 patients: no	0.04	28 (18.6–37.4) 60 (47.3–72.7)	0.02 HR: 3.2 (95% CI: 1.5–7.1)
ECOG performance status (0/1 vs 2/3) 77patients: 0–1 23 patients: 2–3	< 0.0001	71 (43.7–98.3) 33 (24.7–41.3)	ns
Blood transfusion prior to the first cycle 16 patients: yes 84 patients: no	0.04	36 (28.3–43.7) 63 (49.5–76.5)	ns
Albumin (cut-off: 38.6 g/l) 49 patients ≤ 38.6 51 patients > 38.6	0.0003	38 (26.0–50.0) 95 (47.3–142.7)	0.01 HR: 0.9 (95% CI: 0.8 – 0.95)
AST (cut-off: 24 U/l)) 56 patients ≤ 24 44 patients > 24	0.0002	88 (61.1–114.9) 36 (16.8–55.2)	0.04 HR: 2.5 (95% CI: 1.3 –4.8)
GGT (cut-off: 31 U/l) 42 patients ≤ 31 58 patients > 31	0.0001	88 (63.4–112.6) 47 (31.5–62.5)	ns
ALP (cut-off: 140 U/l) 52 patients ≤ 140 48 patients > 140	0.0003	71 (45.9–96.0) 42 (24.0–60.0)	ns
ALP (cut-off: 220 U/l) 65 patients ≤ 220 35 patients > 220	0.019	70 (56.9–83.1) 37 (17.7–56.2)	ns
LDH (cut-off: 225 U/l) 36 patients < 225 64 patients ≥ 225	< 0.0001	not reached 46 (29.6–62.4)	ns
Hb (cut-off: 10.4 g/dl) 33 patients <10.4 67 patients ≥10.4	0.0001	36 (24.5–47.5) 88 (60.7–115.3)	< 0.0001 HR: 0.5 (95% CI: 0.2–0.9)
CRP (cut-off: 16 mg/l) 65 patients ≤ 16 35 patients > 16	0.0001	71 (46.8–95.2) 33 (25.2–40.8)	ns
Regular need for analgesics 39 patients: yes 61 patients: no	0.007	36 (24.7–47.3) 70 (56.1–83.9)	ns
Regular need for opioids 35 patients: yes 65 patients: no	0.0002	33 ( 24.9–41.1) 88 (48.0–127.9)	ns
PSA percent change (cut-off: –14%) 62 patients: decline > 14 % 38: no PSA decline or decline ≤ 14%	< 0.0001	88 (58.3–117.7) 29 (20.1–37.8)	< 0.0001 HR: 6.9 (95% CI: 3.6 - 13.3)
PSA any decline 69 patients: yes 31 patients: no	< 0.0001	71 (45.4–96.6) 29 (20.5–37.5)	ns
PSA decline ≥ 50% 38 patients: yes 62 patients: no	0.009	70 (39.5–100.5) 49 (30.2–67.8)	ns

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Abbreviations: ALP, alkaline phosphatase; ALT, alanine transaminase; AST, aspartate transaminase; CRP, C-reactive protein; GGT, gamma-glutamyl transferase; Hb, haemoglobin; HR, hazard ratio; LDH, lactate dehydrogenase; ns, not significant; Plt, platelets; PSA, prostate-specific antigen; WBC, white blood cells.

In the multivariate analysis, only albumin, AST and Hb levels, existence of liver metastases and a PSA decline ≥ 14% remained significant (Table ​(Table4)4) (Figure ​(Figure1).1). The other pre-therapeutic parameters were not significant with regard to OS.

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Figure 1

Kaplan-Meier survival curves of prostate cancer patients treated with Lu-PSMA stratified by various prognostic variables in the multivariate analysis

(A) a prostate-specific antigen (PSA) decline more than 14%. (B) Hb level prior to the first cycle. (C) AST level prior to the first cycle. (D) albumin level prior to the first cycle.

Prior chemotherapy was not a significant predictor of OS. In the current study, 70 patients had been treated previously with chemotherapy; of those, 21 patients also had second-line chemotherapy with cabazitaxel. The patients with prior chemotherapy had a median OS of 57 weeks (90% CI: 40.2–73.8) compared to 63 weeks (95% CI: 49.1–76.9) in patients without chemotherapy (p = 0.40) (Figure ​(Figure2A2A).

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Figure 2

Kaplan-Meier survival curves of patients according to prior chemotherapy

(A) no impact of prior chemotherapy on overall survival. (B) Overall survival considering the number of lines of chemotherapy. Although patients with the history of both docetaxel and cabazitaxel show longer median overall survival, this difference was not significant.

Forty-nine patients received only docetaxel; those patients had a median OS of 53 weeks (90% CI: 34.5–71.5). The median OS in the 21 patients underwent both docetaxel and cabazitaxel had not yet been reached (p = 0.07) (Figure ​(Figure2B2B).

DISCUSSION

According to several retrospective studies, there is a high response rate to Lu-PSMA therapy [6–9, 19, 20] and a very low probability of high-grade hematotoxicity [8, 12] or nephrotoxicity [8, 11, 21]. However, apart from a good response and a low-toxicity profile, prolongation of overall survival is the most important factor for the evaluation of the efficacy of a new therapeutic agent.

Rahbar et al. [14] compared 28 patients who were treated with a total of 50 cycles of RLT (one to two cycles per patient) with a historical patient cohort treated with the best supportive care prior to the availability of Lu-PSMA [14]. The estimated median OS in their study was 29.4 weeks, which was significantly longer than the OS of 19.7 weeks (p = 0.031) that was observed in the historical best supportive care group. Rahbar et al. did not compare the median OS between responders and non-responders, and the majority of patients in this study underwent further cycles of Lu-PSMA therapy after the data had been published.

In a recently published study from our group, 52 patients who received a total of 190 cycles of RLT (three to six cycles per patient) were analysed. In 80.8% of patients, a decline in PSA levels two months after the first cycle was observed, with 44.2% showing a PSA decline of ≥ 50%. The median OS was 60 weeks for all patients. The median OS was significantly longer for patients who showed any PSA decline after the first cycle compared to patients without a PSA decline (68 vs 33 weeks). These results were very promising because they showed that Lu-PSMA induces a good response, and in responders it induces a significantly longer OS. In that study, a majority of patients had a history of therapy with abiraterone and/or enzalutamide, and 55.8% and 44.0% of patients received chemotherapy and a therapy with Ra-223, respectively.

Bräuer et al. [13] confirmed the results of our published study. They investigated a group of 59 patients who underwent a total of 159 cycles of RLT (median: three cycles). They reported that patients with any decline in PSA levels in response to the first cycle of RLT had a significantly longer median OS (56 weeks) compared to OS of patients with PSA progression (29 weeks). All of the patients in their study had had at least abiraterone or enzalutamide; 80% and 10% of the patients had been given chemotherapy and/or therapy with ²²³Ra, respectively.

In both studies [13, 15], patients with a decline in PSA levels of ≥ 50% after the first RLT did not have a significantly longer OS than those with a PSA decline of < 50%. Both studies were limited by a small number of patients, and there was a need to investigate these results in a larger cohort.

Currently, abiraterone and enzalutamide are among the first line of therapies used to treat mCRPC [18]. In this study patients who received at least one of these therapies were included. Of the 100 patients included in the current study, 70% had been given at least a first line chemotherapy with docetaxel. 36% had been given ²²³Ra therapy. All of the patients suffered from very advanced disease, with 98% having bone involvement, 70% more than 20 lesions up to super scan, and13% having hepatic metastases.

Despite their advanced disease and history of various therapies, the median OS was 60 weeks in all patients. The median OS of patients in the study of Bräuer et al. [13] was 32 weeks, which was shorter than the median OS of the patients in our study. This may be because of 48% of the patients in their study had an ECOG of 2 or 3 compared to only 23 % of the patients in our study. In the current study, patients with an ECOG of 0 or 1 showed significantly longer median OS compared to patients with an ECOG of 2/3 (77 weeks vs. 33 weeks; p < 0.0001). Ferdinandus et al. evaluated the prognostic value of various pre-therapeutic parameters on therapy response, based on changes in PSA after the first cycle of RLT [22]. Their multivariate analysis of these parameters showed that patients with a high platelet count or a regular need for analgesics had a significantly worse response to the first RLT cycle, considering any PSA decline after two months. When a PSA decline of ≥ 50% was considered, patients with a regular need for analgesics showed a worse response in the multivariate analysis; other pre-therapeutic parameters had no impact on the response to RLT [22].

Based on the study of Ferdinandus et al., we evaluated the impact of numerous pre-therapeutic parameters on OS (Tables ​(Tables11–3). In the univariate analysis, some of these parameters as well as response to the RLT as measured by PSA were significant (Table ​(Table4).4). In contrast to previously published results from our team and the University Hospital Muenster [13, 15], patients with a decline in PSA levels of ≥ 50 % showed a significantly longer median OS (70 weeks; 95% CI: 39.5–100.5) than those patients with decline in PSA of < 50 % (49 weeks; 95% CI: 30.2–67.8).

According to various guidelines and trials, response to a therapy is defined as a ≥ 50% decline in the PSA levels [16, 17, 23, 24]; however, patients treated with RLT are typically in a very aggressive phase of their disease with a rapidly rising PSA level prior to RLT. Thus, a PSA level that was unchanged two months after the first cycle of RLT could be considered as a response to treatment. In the current study, as with the other two studies mentioned above, patients with any decline in PSA levels showed a significantly longer OS. A decline in PSA of 14% was a significant cut-off point in both the univariate and the multivariate analysis. Patients with a PSA decline of > 14% had a median OS of 88 weeks (95% CI: 58.3–117.7) compared with 29 weeks in patients with PSA decline of ≤ 14% (95% CI: 20.1–37.8) (p < 0.0001).

Thirty-nine patients (39%) required analgesics regularly. The need for pain killers was a negative predictor of OS (p = 0.005), which was in concordance to the results of Ferdinandus et al. who reported a worse response in these patients [22]. A majority of these patients (35/39) took an opioid and had a significantly shorter OS of 33 weeks vs 88 weeks for those not on opioids (p = 0.0002).

The baseline level of PSA was not significant predictor of OS. However, ALP, LDH and CRP (which could be used as tumour-burden parameters) each was a significant predictor of OS in the univariate analysis. In concordance with other studies [13, 25], we found that an ALP cut-off level of 220 U/l was significant in the univariate analysis. In addition, we found that a cut-off level of 140 U/l was more significant than a cut-off level of 220 U/l (Table ​(Table44).

The Hb level was significant in both univariate and multivariate analyses (Table ​(Table4).4). Patients with a Hb level ≥ 10.4 g/dl had a longer OS (p < 0.0001) than those with Hb < 10.4 g/dl. AST, GGT and albumin each was a significant predictor of OS (Table ​(Table4).Of4).Of these parameters, AST and albumin were also significant in the multivariate analysis. The extent of bone metastases and the existence of liver metastases were significant predictors of OS, with hepatic involvement being significant in the multivariate analysis.

Prior chemotherapy did not have an impact on OS. Of the 70 patients who had received chemotherapy, the median OS in patients with a history of both docetaxel and cabazitaxel treatment was longer than patients treated with docetaxel alone, but the difference was not significant in this study. This may be because the majority of patients with a history of treatment with only docetaxel were not fit enough for therapy with cabazitaxel at the time of the RLT; however, this aspect should be evaluated in a larger cohort of patients.

The median OS in mCRPC patients receiving RLT in advanced stages of disease is 60 weeks. The median OS is significantly longer in patients without hepatic involvement, with high levels of albumin and Hb and low levels of AST. A decline in PSA levels of more than 14% measured two months after the first cycle of RLT was the most important response parameter with regard to OS.

MATERIALS AND METHODS

All patients who underwent Lu-PSMA therapy in our department from Dec 2014 to March 2017 were evaluated for inclusion in this study. Eligible patients were selected according to following inclusion criteria: (1) patients with mCRPC and PSMA positive metastases in the PSMA imaging; (2) patients with a history of therapy with either abiraterone or enzalutamide or both; (3) patients treated with at least three cycles of RLT, or patients with 1–2 cycles of RLT who died before the third cycle, did not receive the third cycle because of significant worsening of their general condition or because of an excellent response to the first or second cycle; (4) patient follow-up of at least two months after the last cycle or the patient died; and (5) complete documentation.

Acknowledgments

Footnotes

REFERENCES