Latest developments in prostate cancer treatment

Favorable complementary mechanisms: 223RaCl2 followed by 177Lu-PSMA (RALU)

The positive efficacy and safety data of 177Lu-PSMA-617 in the treatment of mCRPC patients from the Lu-PSMA and VISION trials led to its FDA approval and designation as a breakthrough therapy for later lines of mCRPC treatment [1,2]. 223Ra-dichloride (223RaCl2) is a targeted α-therapy and prolongs OS in patients with bone-predominant mCRPC [3].

RALU is a retrospective study investigating the safety and clinical effectiveness of 177Lu-PSMA radioligand therapy (177Lu-PSMA-617 or 177Lu-PSMA-I&T) in mCRPC patients who already received 223RaCl2 in routine clinical practice [4]. Data were analyzed from 133 patients who received either 177Lu-PSMA-617 (65 %) or 177Lu-PSMA-I&T (35 %) after 223RaCl2.

The median PSA and alkaline phosphatase (ALP) among enrolled patients were 285.5 ng/ml and 146.0 U/L, respectively, with 56 % receiving ≥4 therapies before starting 177Lu-PSMA. All patients received prior 223RaCl2; other prior treatments included abiraterone (71 %), enzalutamide (70 %), docetaxel    (74 %), and cabazitaxel (23 %). All patients had bone metastases, and 27 % had visceral metastases at baseline. Overall, 73 % of patients received 1-4 cycles of 177Lu-PSMA, and 27 % received ≥5 cycles.

Any grade and grade 3/4 TEAEs occurred in 79 % and 28 % of patients, respectively, during and after 177Lu-PSMA till the end of a 30-day follow-up period. Overall, 10 % stopped, interrupted, or ­delayed 177Lu-PSMA treatment due to ­TEAEs. Grade 3/4 hematologic laboratory abnormalities up to 90 days post-177Lu-PSMA occurred in 30 %, 13 % and 2 % of patients for anemia, thrombocytopenia and neutropenia, respectively. The most common TEAEs of any grade, excluding lab abnormalities, were dry mouth (15 %), nausea (9 %), and fatigue (8 %). The median OS was 13.2 months (95 % CI 10.5-15.6) from the first dose of 177Lu-PSMA treatment, with the median OS extending to 33.4 months (95 % CI 31.2-37.4) from the first dose of 223RaCl2 (Figure 1). 177Lu-PSMA-617 and 177Lu-PSMA-I&T use had similar OS outcomes and similar toxicity profiles. During 177Lu-PSMA treatment, 42 % of patients had a PSA50 response, and 19 % had an ALP30 response (defined as a decrease of ≥30 % in ALP from ­baseline).

In a real-world setting, the earlier incorporation of 223RaCl2 in the treatment ­sequence with subsequent 177Lu-PSMA therapy was clinically feasible in heavily pretreated ­patients with mCRPC. These results are similar to those reported in previous phase III and real-world studies [5-7].

Figure 1: Overall survival with Lu-PSMA treatment since the first dose of Lu-PSMA (left) and the first dose of 223RaCl2 (right) in the RALU study

Figure 1: Overall survival with Lu-PSMA treatment since the first dose of Lu-PSMA (left) and the first dose of 223RaCl2 (right) in the RALU study

Benefit in patient-reported outcomes with 177Lu-PSMA-617: Updated VISION

In the phase 3 VISION study, 177Lu-PSMA-617 plus standard-of-care (SoC) showed a significant benefit in the radiographic progression-free survival (rPFS) (HR 0.40; 99.2 % CI 0.29-0.57) and OS (HR 0.62; 95 % CI 0.52-0.74) versus SoC (both p<0.001) [2]. Hermann et al. presented the VISION study’s secondary endpoints: health-related quality of life (HRQoL), pain, time to first symptomatic skeletal event (SSE), and updated safety data [8].

The VISION study is a randomized phase 3 trial in adults with PSMA-positive mCRPC previously treated with at least one androgen receptor pathway inhibitor (ARPI) and one or two taxane chemotherapy regimens. Eligible participants were randomized 2:1 to SoC therapy plus six cycles of 177Lu-PSMA-617 versus SoC alone.

The two patient-reported outcomes evaluated in the study were the FACT-P score and the BPI-SF pain intensity score. Time to worsening for both of these metrics favored the addition of 177Lu-PSMA-617 to SOC with a delay of 7.3 months (9.7 vs. 2.4 months (HR 0.46; p<0.001)) for the FACT-P score and 11.4 months (14.3 vs. 2.9 months (HR 0.45; p<0.001)) for the BPI-SF pain intensity score (Figure 2).

Moreover, the time to first SSE or death was delayed from 6.8 months to 11.5 months by 177Lu-PSMA-617 addition to SoC (HR 0.50; 95 % CI 0.40-0.62; p<0.001) regardless of bone-targeted therapy being part of SoC. Spinal cord compression, the most deleterious SSE, was less frequent in the 177Lu-PSMA-617 arm compared to SoC alone (1.3 % vs. 5.6 %).

An updated assessment of TEAEs confirmed that the addition of 177Lu-PSMA-617 was generally well-tolerated. However, a higher incidence of grade 3-5 TEAEs occurred in patients treated with 177Lu-PSMA-617 related to bone marrow suppression, dry mouth, nausea/vomiting, and renal effects. A low incidence of grade 3/4 creatinine abnormalities was observed in both arms, with creatinine levels being stable throughout the entire duration of the study.

The updated results from the secondary endpoints of the VISION study ­support the use of 177Lu-PSMA-617 as a ­subsequent treatment option in mCRPC patients who have received at least one ARPI or taxane-containing regimen.

Figure 2: Kaplan-Meier estimates of time to worsening in FACT-P total score (A) and BPI-SF pain intensity (B) in the rPFS analysis set of the VISION study

Figure 2: Kaplan-Meier estimates of time to worsening in FACT-P total score (A) and BPI-SF pain intensity (B) in the rPFS analysis set of the VISION study

177Lu-PSMA I&T efficacious with good safety profile: data from prospective Swiss-registry study

177Lu-ITG-PSMA-1, also known as 177Lu-PSMA I&T, is a DOTAGA-chelated urea-based PSMA inhibitor currently being tested in a prospective, randomized phase 3 trial in patients with progressive mCRPC (ECLIPSE, NCT05204927). At EANM, Nicolas and Chirindel et al. presented data regarding the safety and efficacy of 177Lu-PSMA I&T implemented in daily clinical practice in Switzerland [9].

Patients with mCRPC, who were PSMA+ and unfit for chemotherapy, who progressed on androgen receptor-­axis-targeted therapies (ARAT), received 177Lu-PSMA I&T (6-8 GBq, 4-6 cycles ­every 6 weeks). The primary endpoint was safety, and key secondary endpoints included PSA response and OS.

Of the 107 registered patients, 93 were included based on sufficient follow-up data for the preliminary two-year analysis. Compared to the VISION trial, a higher proportion of patients with lymph node (78 %) or soft tissue metastases (30 %) were enrolled in the study [2]. On the other hand, the proportion of ­patients who received prior chemotherapy was lower in this study than in the ­VISION trial (64 % vs. 97 %), with patients receiving fewer Lu-PSMA treatment ­cycles (median 3 vs. 5).

The preliminary safety analysis showed a high incidence of grade ≥3 lymphopenia (20 %) and anemia (13 %) with 177Lu-PSMA I&T treatment. No grade ≥3 xerostomia event was observed, with low incidences of grade ≥3 thrombocytopenia (3 %) reported. The preliminary efficacy results of 177Lu-PSMA I&T treatment regarding biochemical response (any PSA-response: 71 %; PSA50-response: 47 %) and median OS (15 months) were similar to those reported with 177Lu-PSMA-617 treatment in the VISION trial.

This preliminary analysis from a ­real-world setting adds to the tolerable safety profile and efficacy of Lu-PSMA radioligand therapies in the treatment of mCRPC patients.

177Lu-PSMA-617 impacts QoL in mCRPC patients in a palliative setting

Improving the patient’s quality of life (QoL) while providing disease control is the ultimate goal of palliative care. Scheer et al. evaluated the impact on QoL of 177Lu-PSMA-617 in patients with advanced mCRPC treated in a palliative setting [10]. QoL was prospectively assessed in 44 patients (age 58-84 years) at the beginning of every treatment cycle, using the QLQ-c30 score. Before every 177Lu-PSMA-617 treatment cycle, serum PSA levels were analyzed as an indicator of tumor burden, and renal and salivary gland function, as an indicator of safety. Patients were treated at an 8-to-10-week interval and divided into three groups based on the number of treatment cycles received (≥2; ≥3; ≥4).

Treatment discontinuations occurred with an increasing number of treatment cycles. In this context, deterioration of the general condition, progressive disease, and renal failure were the main reasons for discontinuations. Interestingly, symptom burden decreased from the first to the third treatment cycle but increased in the fourth. Excretion from salivary glands decreased continuously, particularly after the fourth treatment. Effect on blood serum PSA reached nadir before the third treatment cycle, with ~50 % of patients experiencing a decrease of serum PSA levels of >90 % from the first to fourth treatment cycle.

The results indicated that palliative treatment with 177Lu-PSMA-617 had a positive effect on patients’ QoL, especially if the patients were able to receive multiple cycles of treatment. Of note, the tumor burden of the patients increased slightly during therapy. So far, no relevant therapy-associated side effects concerning bone marrow suppression, salivary gland, and kidney function were reported in the study.

225Ac-PSMA in mCRPC patients progressing after androgenic treatment

Radioligand therapy using alpha emitters, such as 225Ac-PSMA (both PSMA-617 & PSMA‑I&T), have gained importance in recent years as a last-resort treatment option in mCRPC patients when all others have been exhausted [11,12]. The successful results were attributed to their short-range, high linear energy transfer causing double-strand breaks in DNA. In a retrospective study, 23 progressive mCRPC patients, who relapsed after new-generation anti-androgenic treatment and could not receive further systemic treatments, received 225Ac-PSMA treatment at a single center [13]. Further inclusion criteria were having received two or more cycles of 177Lu-PSMA therapy and discontinuation of treatment due to progression or unresponsiveness.

Enrolled patients received 1-4 cycles of 225Ac-PSMA with a mean dose of 7.63 MBq (6.2-10 MBq) per cycle. The mean interval time between two doses of 225Ac-PSMA was 116 days. One case of grade 3 hematological- and nephro-toxicity each was reported. Xerostomia grade 1-2 was observed in 40 % of patients.

Treatment response was evaluated in 16 patients whose 68Ga-PSMA PET/CT images were available before and after the first course of 225Ac-PSMA treatment. Partial responses and stable disease were observed in 5 patients (31 %) each, whereas 6 patients (38 %) showed disease progression, resulting in a disease control rate of 62 %. Around 32 % of patients had ≥50 % PSA decline, and 58 % had any PSA decline after the first cycle of 225Ac-PSMA treatment. The mean PFS and OS were 3.1 and 7.3 months, respectively, comparatively shorter than pre­viously reported pooled data from a ­meta-analysis of 9 studies [14].

In conclusion, 225Ac-PSMA showed promise with its high disease control rate and favorable toxicity profile in advanced mCRPC patients for whom all treatment options were exhausted. Future randomized, controlled, and prospective trials are needed to further evaluate the therapeutic effects and survival benefits compared with existing clinical treatments.

Reduced dose of 177Lu-PSMA might lead to OS benefits among elderly and heavily pretreated mCRPC patients

In the randomized TheraP trial, a high proportion of mCRPC patients had an excellent response to 177Lu-PSMA-617 treatment even though they did not receive all six planned treatment cycles [15]. Thus, a prospective phase II trial was conducted to test two different therapeutic schemes of 177Lu-PSMA-617 according to age and previous therapies [16].

Patients aged over 75 years or who had received docetaxel were given 3.7-4.4 GBq every 8-12 weeks for 4-6 cycles. Patients under 75 years or who had not received docetaxel were given 5.5 GBq every 8-12 weeks for 4-6 cycles. Infusion with mannitol and external cooling plus polyglutamate folate tablets were given during and after each treatment cycle to reduce kidney and salivary gland uptake. The main objective was to evaluate the PSA response rate from baseline. The secondary endpoints included acute and late toxicity, PFS, and OS.

A total of 80 patients with a median age of 71 years were evaluated. The median Gleason Score at diagnosis was 8 and the median PSA level was 50.7 ng/ml among the enrolled study population. More than one-third (36 %) had already received three lines of treatment. A high proportion of patients showed a PSA decrease of more than 30 % (53.7 %) and more than 50 % (41.3 %) from baseline. No grade 3 or 4 adverse events or toxicity on parotid glands occurred. The median PFS was approximately 7 months in both groups, but OS was better in the high-dose group, with 94.6 % vs. 79.4 % at 6 months and 83.7 vs. 55.9 % at 12 months, respectively (Figure 3). Potential confounders were not corrected prior to survival analysis, such as the age difference and prior treatment between the two dose groups. The median OS for the entire patient population was 19.8 months.

Overall, a lower dose of 3.7-4.4 GBq/cycle of 177Lu-PSMA-617 in selected patients was well tolerated and could thus be considered the minimum effective dosage. However, a 5.5 GBq/cycle dose for 4-6 cycles led to a higher biochemical response in advanced mCRPC patients.

Figure 3: Overall survival curves in mCRPC patients based on the dose of 177Lu-PSMA-617 received

Figure 3: Overall survival curves in mCRPC patients based on the dose of 177Lu-PSMA-617 received


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