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study, though a groundbreaking new drug remains elusive. CVGBM represents the first of its kind and could pave the way for treatments utilizing comparable therapeutic strategies, either as standalone interventions or in combination of regimens.
Efficacy and safety of ponsegromab in patients with cancer cachexia Ponsegromab, a monoclonal antibody, inhibits growth differentiation factor 15, a driving factor for cancer cachexia. A phase 2 randomized, placebo-controlled trial evaluated Ponsegromab's efficacy and safety in 187 patients with cachexia, elevated GDF-15 levels (>1500 pg/ml) and various cancers (NSCLC, Pancreatic cancer, Colorectal Cancer), regardless of tumor stage (2). Patients were randomly assigned to receive Ponsegromab (100 mg, 200 mg, or 400 mg) or placebo, administered subcutaneously every four weeks for 12 weeks. The primary endpoint was change in body weight, while notable secondary endpoints included improvement in cachexia symptoms, physical activity, and increase in lumbar skeletal muscle index. After 12 weeks, patients receiving 400 mg Ponsegromab experienced a significant, placebo-adjusted median weight increase of 3.00 kg. This weight response was observed across all subgroups. Similarly, the 200 mg and 100 mg cohorts saw weight gains of 2.08 kg and 1.33 kg, respectively. Furthermore, the 400 mg group demonstrated a significant 4.11 point improvement in the FAACT-Anorexia Cachexia Subscale score, indicating enhanced appetite, and a significant increase in physical activity of 50 minutes of non-sedentary time per day. The side-effect profile was similar to placebo For me, Ponsegromab represents a very hopeful new class of drugs for an important unmet need of our patients. It has the potential to substantially improve the quality of life of patients in a difficult period of the cancer journey. I hope further studies will confirm these promising early results.
Author: Dr. med. Dennis Hoch, Inselspital Bern Mentor: Prof. Dr. med. Miklos Pless, Kantonsspital Winterthur
References: 1. Annals of Oncology (2024) 35 (suppl_2): S406-S427. 10.1016/annonc/
annonc1587 2. Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623

Prostate cancer
Many interesting studies in the field of prostate cancer (PC) were presented at ESMO 2024. In my opinion three studies deserve to be highlighted: one in the localized setting, one in the metastatic hormone-sensitive setting (mHSPC) and one in the metastatic castration resistant setting (mCRPC).
A large randomized study in patients with localized PC planned to undergo androgen deprivation therapy (ADT) evaluated the use of transdermal oestradiol (te2) compared with LHRH analogue (LHRHa) (1). It is known that LHRHa cause hot flushes which negatively affect patients’ quality of life (2). LHRHa also cause long-term side effects such osteoporosis, metabolic syndrome and cardiovascular events (3). The rationale of using te2 to achieve castration is to reduce these side effects compared to LHRHa. This phase 3 non-inferiority study showed that te2 is noninferior to LHRHa regarding metastasis free survival (MFS) and overall survival (OS) and it achieved a similar castration rate. In terms of side effects, a reduction in hot flushes (44% vs 89%) was seen on te2, but it had a greater risk of developing gynecomastia (85% vs 42%). No data on cardiovascular events, bone health or metabolic syndrome were presented. Transdermal estrogen appears to be an interesting option but many questions remain especially regarding prophylaxis of gynecomastia and patient compliance (need to change 4 patches twice per week). Finally, only data from non-metastatic patients were presented so we do not know the effect of this therapy in patients with metstatic disease who should receive an ARPI.
ARANOTE study The ARANOTE study was done in the mHSPC setting. This is a phase 3 study evaluating the benefit of the addition of darolutamide to ADT (4). It demonstrated a statistically significant reduction (-46%) in the risk of radiographic progression (rPFS) compared to ADT alone (primary endpoint). Although the overall survival (OS) is still immature, I think that darolutamide could become a new therapeutic option in addition to ADT in patients with mHSPC. It is important to emphasize the very favorable toxicity profile of darolutamide, almost similar to placebo. The only side effect that seems to increase with darolutamide is bone fractures highlighting the importance to evaluate bone health in all patients with mHSPC. Overall this is a potentially practicechanging study altough we have to wait final OS data.
PEACE-3 study Finally, in the mCRPC setting, the PEACE-3 study was presented by Prof. Silke Gillessen at the plenary session (5). This study demonstrated that the combination of enzalutamide + radium-223 improved radiographic progression-free survival (rPFS) compared to enzalutamide monotherapy in patients with mCRPC and bone metastases. A combination therapy between radium-223 and an androgen receptor pa-

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thway inhibitor (ARPI) had already been evaluated in the ERA-223 study (abiraterone + radium-223) (6). However, this trial was unblinded early after more fractures and deaths were observed in the experimental arm. Analyzing the fractures, it was found that in the majority of cases they were osteoporotic and non-pathological. Following the release of the ERA-223 data, the PEACE-3 study was amended with an urgent safety letter to investigators: bone protecting therapy with either zoledronic acid or denosumab became mandatory at the monthly dose. The introduction of bone potecting agents (BPA) achieved a massive reduction in the risk of fractures in both treatment arms, further underlining the importance of BPA in this setting (7). In view of the changed landsacpe where the vast majority of patients receive an ARPI-based therapy (8) in the mHSPC setting the impact of the findings of PEACE-3 is difficult to estimate since only 2-3% of the patients received an ARPI (abiraterone) in this trial. However, for patients with mCRPC and bone metastases who received ADT or ADT + docetaxel in mHSPC setting, enzalutamide + radium-223 represents a new standard of care.
Author: Dr. Fabio Turco, EOC Ente Ospedaliero Cantonale, Bellinzona Mentor: Prof. Dr. med. Richard Cathomas, Kantonsspital Graubünden
References: 1. Langley RE et al.: LBA69 Prostate cancer efficacy results from a randomised
phase III evaluation of transdermal oestradiol (tE2) versus luteinising hormone releasing hormone agonists (LHRHa) for androgen suppression in non-metastatic (M0) prostate cancer. Ann Oncol. 2024;35:S1258. 2. Nishiyama T et al.: Influence of hot flashes on quality of life in patients with prostate cancer treated with androgen deprivation therapy. Int J Urol. 2004;11(9):735-741. 3. Kokorovic A et al.: Canadian Urological Association guideline on androgen deprivation therapy: Adverse events and management strategies. Can Urol Assoc J. 2021;15(6):E307-E322. 4. Saad F et al.: Darolutamide in Combination With Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial. J Clin Oncol. 2024;42(36):4271-4281. 5. Gillessen S et al.: LBA1 A randomized multicenter open label phase III trial comparing enzalutamide vs a combination of Radium-223 (Ra223) and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer (mCRPC): First results of EORTC-GUCG 1333/PEACE-3. Ann Oncol. 2024;35(2):S1254. 6. Smith M et al.: Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):408-419. 7. Gillessen S et al.: Decrease in Fracture Rate with Mandatory Bone-protecting Agents in the EORTC 1333/PEACE-3 Trial Comparing Radium-223 Combined with Enzalutamide Versus Enzalutamide Alone: A Safety Analysis. Eur Urol. 2025;87(3):285-288. 8. Tilki D et al.: EAU-EANM-ESTRO-ESUR-ISUP-SIOG Guidelines on Prostate Cancer. Part II-2024 Update: Treatment of Relapsing and Metastatic Prostate Cancer. Eur Urol. 2024;86(2):164-182.
Pembrolizumab dose reduction in metastatic NSCLC – an opportunity for improving cost-effectiveness?
There were many new developments, including practice-changing clinical trials, presented at this year's European Society of Medical Oncology (ESMO) Congress in Barcelona. From the vast number of abstracts available in the rapidly evolving field of thoracic oncology, we ha-

ve selected one abstract that was of particular interest to us: Low-dose versus standard dose pembrolizumab for treatment of advanced-stage non-small cell lung cancer (NSCLC) – Results of the pre-planned interim analysis of the clinical trial NVALT-30.
Progress in the field of oncology over the past few decades has been impressive, with an increase in the number of people potentially cured after cancer treatment and an increase in response rates leading to improved overall survival in the metastatic disease setting. While innovation and scientific progress have been a great benefit for patients and their families, this progress was also accompanied by a significant increase in costs (1). With the expected increase of patients living with cancer as life expectancy rises (2), there is a need to improve cost-effectiveness of oncology therapies and thus make the distribution of drugs more equitable. The introduction of immunotherapy marked a turning point in the treatment of various tumor entities. Immunotherapy has become part of the standard first-line treatment for advanced or metastatic NSCLC without genomic alterations (3). While immunotherapies targeting programmed cell death-1 (PD-1) and its ligand (PD-L1), administered as monotherapy or in combination with chemotherapy, have improved the clinical outcomes of patients with advanced and metastatic NSCLC, they have also contributed to the increase of treatment costs (4). The trial DEDICATION-1/NVALT-30 is investigating the impact of dose reduction of the PD-1-targeting immune checkpoint inhibitor pembrolizumab on overall survival in advanced NSCLC (5). The authors compare the standard dose of 400 mg every 6 weeks or 200 mg every 3 weeks with a dose reduction to 200 mg every 6 weeks or 100 to 150 mg every 3 weeks. A strength of this study are the broad inclusion criteria: Patients should have an ECOG score of 0-2, no prior therapy and be scheduled for first-line treatment with pembrolizumab. A total of 750 patients are expected to be enrolled and being randomized in a 1:1 ratio. Stratification factors include treatment modality (pembrolizumab monotherapy vs. chemoimmunotherapy), PDL1 expression status (<50% vs. ≥50%), smoking status, ECOG performance score (0-1 vs. 2) as well gender. At ESMO, data from the pre-planned interim analysis after the enrolment of the first 250 patients, including 1-year follow-up were presented. There was no significant difference in 1-year overall survival (57.5% (95% CI: 49.5% 67.3%) in the standard dose group and 55.0% (95% CI: 47% - 64.4%) in the reduced dose group) or median progression-free survival (6.9 months (95% CI: 6-9.8) in the standard dose group vs. 7.6 months (95% CI: 5.8-11.3) in the reduced dose group). The rate of adverse events was also similar between the two groups, with 8% vs 10% in the standard dose and reduced dose groups, respectively. Based on the data from this interim analysis, with a one-year survival difference of 2.7%, the study has met the pre-spe- onkologie  1 | 2025 21