A Review of Selected Presentations From the ESMO Congress 2024
September 13-17, 2024 • Barcelona, Spain
Efficacy and Safety of Darolutamide Plus Androgen-Deprivation Therapy in Patients With Metastatic Hormone-Sensitive Prostate Cancer From the Phase III ARANOTE Trial
In recent years, several phase III trials have been undertaken to assess the optimal combination of androgen-deprivation therapy (ADT), docetaxel, and an androgen receptor pathway inhibitor (ARPI) in patients with metastatic hormone-sensitive prostate cancer (mHSPC). The ARASENS trial demonstrated a significant overall survival (OS) benefit with darolutamide, ADT, and docetaxel vs placebo, ADT, and docetaxel (hazard ratio [HR], 0.68; 95% CI, 0.57-0.80; P<.0001).1
At ESMO 2024, Fred Saad, MD, presented results from the ARANOTE trial comparing darolutamide plus ADT vs placebo plus ADT, without docetaxel, in patients with mHSPC (Figures 1 and 2).2 The global, randomized, double-blind, phase III ARANOTE trial enrolled 669 patients with mHSPC who were assigned 2:1 to darolutamide 600 mg twice daily plus ADT (n=446) or placebo plus ADT (n=223). Patients were stratified based on the presence of visceral metastases and use of prior local therapy. The primary endpoint was radiological progression-free survival (rPFS) by central blinded review.
The median age of enrolled patients was 70 years; the trial enrolled patients in Asia (30%), Latin America (29%), and Europe and the rest of the world (41%). Metastases were present in 72% of patients, 71% had high-volume disease, and 12% had visceral metastases.
After a median follow-up of 25 months, darolutamide plus ADT was associated with a significant improvement in rPFS over placebo plus ADT (median rPFS, not reached vs 25.0 months; HR, 0.54; 95% CI, 0.41-0.71; P<.0001); 24-month rPFS rates were 70.3% and 52.1%, respectively. The rPFS benefit observed with darolutamide was consistent across key subgroups. Darolutamide plus ADT also showed a benefit over placebo plus ADT in secondary endpoints including time to metastatic castration-resistant prostate cancer (mCRPC; stratified HR, 0.40; 95% CI, 0.32-0.51), time to prostate-specific antigen (PSA) progression (stratified HR, 0.31; 95% CI, 0.23-0.41), time to initiation of subsequent therapy (stratified HR, 0.40; 95% CI, 0.29-0.56), and time to pain progression (stratified HR, 0.72; 95% CI, 0.54-0.96). OS data were immature at the time of analysis.
The incidence of grade 3/4 treatment-emergent adverse events (TEAEs) was similar with darolutamide plus ADT and placebo plus ADT (30.8% and 30.3%), as was the rate of grade 5 TEAEs (4.7% and 5.4%). The frequency of TEAEs as assessed by exposure-adjusted incidence rate (EAIR) was similar between arms. The most frequent TEAEs were vasodilation and flushing (EAIR, 5.6 per 100 person-years with darolutamide plus ADT vs 5.0 per 100 person-years with placebo plus ADT), hypertension (5.5 vs 6.7 per 100 person-years), and diabetes mellitus or hyperglycemia (5.3 vs 6.7 per 100 person-years).
Investigators concluded that the addition of darolutamide to ADT was associated with a significant improvement in rPFS, benefits in secondary endpoints, and a favorable safety profile in patients with mHSPC, suggesting that darolutamide plus ADT without docetaxel should be an additional standard of care for these patients.
References
1. Smith MR, Hussain M, Saad F, et al. Darolutamide and survival in metastatic, hormone-sensitive prostate cancer. N Engl J Med. 2022;386(12):1132-1142.
2. Saad F, Vjaters E, Share N, et al. Efficacy and safety of darolutamide plus androgen-deprivation therapy (ADT) in patients with metastatic hormone-sensitive prostate cancer (mHSPC) from the phase III ARANOTE trial. LBA68: Mini Oral Session. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain.
A Randomized, Multicenter, Open-Label, Phase III Trial Comparing Enzalutamide Versus a Combination of Radium-223 and Enzalutamide in Asymptomatic or Mildly Symptomatic Patients With Bone Metastatic Castration-Resistant Prostate Cancer: First Results of EORTC-GUCG 1333/PEACE-3
The novel hormonal therapies (NHTs), abiraterone and enzalutamide, are standard first-line treatment options for patients with mCRPC with progression on ADT.1 Thus far, no first-line combination approach has demonstrated an improvement in rPFS and OS over single-agent therapy.
In the randomized, phase III ALSYMPCA trial, conducted prior to the introduction of NHT, the α-emitter radium-223 demonstrated an OS improvement over placebo in patients with CRPC with bone metastases.2 In the randomized, phase III ERA-223 trial, the addition of radium-223 to abiraterone and prednisone or prednisolone in patients with CRPC with bone metastases did not improve symptomatic skeletal event (SSE)–free survival or OS and increased the frequency of bone fractures.3 As a result, this combination was not evaluated further.
At ESMO 2024, Silke Gillessen, MD, presented results from the randomized, open-label, phase III EORTC-GUCG 1333/PEACE-3 trial evaluating the addition of radium-223 to enzalutamide in patients with mCRPC and bone metastases (Figure 3 and Table 1).4 Enrolled patients had asymptomatic or mildly symptomatic disease with no known visceral metastases. A total of 446 patients were randomly assigned to enzalutamide 160 mg once daily with or without radium-223 55 kBq/kg intravenously (IV) every 4 weeks for 6 cycles. Use of bone-protecting agents was required after the first 119 patients.
The median age of enrolled patients was 70 years; 30% of patients had received prior docetaxel for mHSPC and 2% had received prior abiraterone. The trial met its primary endpoint, demonstrating a significant improvement in rPFS with radium-223 plus enzalutamide vs enzalutamide alone (median rPFS, 19.4 vs 16.4 months; HR, 0.69; P=.0009). Median OS was 42.3 months and 35.0 months, respectively (HR, 0.69; 95% CI, 0.52-0.90; P=.0031). The difference in OS met prespecified levels of significance and thus the study analysis will continue to a final OS analysis.
Time to next systemic treatment was also significantly improved with radium-223 plus enzalutamide vs enzalutamide alone (HR, 0.57; 95% CI, 0.44-0.75; P<.0001). There was no significant difference in time to pain progression or time to SSE. The incidence of grade 3 or higher treatment-related AEs (TRAEs) was higher with radium-223 plus enzalutamide vs enzalutamide alone (28% vs 19%). The most common grade 3 or higher TRAEs were hypertension (11.5% vs 12.1%), fatigue (4.1% vs 1.3%), anemia (2.8% vs 0%), and neutropenia (3.2% vs 0%).
Investigators concluded that the PEACE-3 results support use of enzalutamide plus radium-223 plus a bone-protecting agent as a potential first-line treatment option for patients with prostate cancer with bone metastases who have not previously received an ARPI.
References
1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: prostate cancer. Version 4.2024. May 17, 2024.
2. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
3. Smith M, Parker C, Saad F, 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 III trial [published correction appears in Lancet Oncol. 2019;20(10):e559.]. Lancet Oncol. 2019;20(3):408-419.
4. Gillessen S, Choudhury A, Saad F, et al. A randomized, multicenter, open-label, phase III trial comparing enzalutamide versus a combination of radium-223 and enzalutamide in asymptomatic or mildly symptomatic patients with bone metastatic castration-resistant prostate cancer: first results of EORTC-GUCG 1333/PEACE-3. LBA1: Proffered Paper Session. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain.
Cabozantinib Plus Atezolizumab Versus 2nd Novel Hormonal Therapy in Patients with Metastatic Castration-Resistant Prostate Cancer: Final Overall Survival Results of the Phase III, Randomized, CONTACT-02 Study
Currently, patients with mCRPC who develop disease progression on NHT, particularly those with visceral metastases, have limited treatment options and a poor prognosis. Among the options are a second NHT, which is used more frequently in real-world practice, or chemotherapy.1 There is a need for more effective therapies for these patients. One strategy being evaluated in clinical trials is the combination of the multitargeted tyrosine kinase inhibitor (TKI) cabozantinib and the programmed death-ligand 1 (PD-L1) inhibitor atezolizumab.
At ESMO 2024, Neeraj Agarwal, MD, presented final OS results from the phase III CONTACT-02 trial, which evaluated cabozantinib plus atezolizumab against a second NHT in patients with mCRPC with progression on a first NHT and with measurable extrapelvic soft tissue metastases (Table 2).2 The combination of cabozantinib and atezolizumab was initially evaluated in the phase 1b COSMIC-021 trial, demonstrating an objective response rate (ORR) of 23% in 132 patients with mCRPC with progression after enzalutamide, abiraterone, or both, supporting further evaluation of the regimen.3
The randomized, phase III CONTACT-02 trial was undertaken to compare the efficacy and safety of cabozantinib plus atezolizumab vs a second NHT in patients with mCRPC with progression on 1 prior NHT and with measurable extrapelvic (visceral or lymph node) soft tissue metastasis.2 Prior docetaxel for locally advanced or metastatic castration-sensitive prostate cancer (mCSPC) was allowed.
A total of 575 patients were randomly assigned to cabozantinib 40 mg orally each day plus atezolizumab 1200 mg IV every 3 weeks or a second NHT consisting of abiraterone 1000 mg orally daily plus prednisone 5 mg orally twice daily or enzalutamide 160 mg orally daily.
The median age of enrolled patients was 71 years; 59% to 60% had a Gleason score of 8 or greater at diagnosis, and 51% to 52% had metastatic disease at diagnosis. At baseline, visceral metastases were present in 38% to 41% of patients, liver metastases were present in 23%, and bone metastases were present in 76% to 79%. The median duration of first NHT was approximately 12 months.
As presented at the 2024 ASCO Genitourinary Cancers Symposium, the trial met one of its coprimary endpoints, demonstrating a significant improvement in PFS with cabozantinib plus atezolizumab over second NHT (median PFS, 6.3 vs 4.2 months; HR, 0.65; 95% CI, 0.50-0.84; P=.0007).4 The PFS benefit was also observed in the subset of patients with liver metastases (median PFS, 6.2 vs 2.1 months; HR, 0.43; 95% CI, 0.27-0.68) and in patients with bone metastases (median PFS, 6.3 vs 4.1 months; HR, 0.67; 95% CI, 0.50-0.88).
After a median follow-up of 24 months, the second coprimary endpoint of OS showed a nonsignificant trend toward improvement with cabozantinib plus atezolizumab over second NHT (median OS, 14.8 vs 15.0 months; HR, 0.89; 95% CI, 0.72-1.10; P=.30). The improvement in OS with cabozantinib plus atezolizumab over second NHT was more notable in patients with liver metastases (median OS, 12.2 vs 7.1 months; HR, 0.68; 95% CI, 0.47-1.00; P=.051) and bone metastases (median OS, 13.8 vs 11.6 months; HR, 0.79; 95% CI, 0.63-1.00; P=.046).
Investigators noted that the AE profile with cabozantinib plus atezolizumab was consistent with other TKI and checkpoint inhibitor combinations. The most frequent grade 3 or 4 AEs with cabozantinib plus atezolizumab were anemia (8%), hypertension (8%), fatigue (6%), and diarrhea (5%). The most frequent grade 3 or 4 AEs with NHT were anemia (6%), fatigue (2%), and hypertension (2%). TRAEs led to discontinuation in 5% of patients receiving cabozantinib plus atezolizumab and 2% receiving NHT.
Cabozantinib plus atezolizumab was similar to NHT in the median time to clinically meaningful deterioration of quality of life (QOL; HR, 1.19; 95% CI, 0.94-1.51), showed a trend toward improved median time to SSE (HR, 0.73; 95% CI, 0.44-1.20), and was superior to NHT in the median time to initiation of chemotherapy (HR, 0.59; 95% CI, 0.45-0.77).
The investigators concluded that cabozantinib plus atezolizumab could be useful for selected patients with mCRPC with disease progression on an NHT.
References
1. Swami U, Sinnott JA, Haaland B, et al. Treatment pattern and outcomes with systemic therapy in men with metastatic prostate cancer in the real-world patients in the United States. Cancers (Basel). 2021;13(19):4951.
2. Agarwal N, Azad A, Galceran JC, et al. Cabozantinib plus atezolizumab versus 2nd novel hormonal therapy in patients with metastatic castration-resistant prostate cancer: final overall survival results of the phase III, randomized, CONTACT-02 study. LBA67: Proffered Paper Session. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain.
3. Agarwal N, McGregor B, Maughan BL, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration-resistant prostate cancer: results from an expansion cohort of a multicentre, open-label, phase 1b trial (COSMIC-021). Lancet Oncol. 2022;23(7):899-909.
4. Agarwal N, Azad A, Carles J, et al. CONTACT-02: Phase III study of cabozantinib (C) plus atezolizumab (A) vs second novel hormonal therapy (NHT) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2024;42(4_suppl):18.
Adding Metformin to Androgen-Deprivation Therapy for Patients With Metastatic Hormone-Sensitive Prostate Cancer: Overall Survival Results From the Multi-Arm, Multi-Stage, Randomized Platform Trial STAMPEDE
Metformin has the potential to be beneficial when added to ADT in patients with advanced prostate cancer, as it could mitigate the metabolic adverse effects of ADT and it has demonstrated anticancer activity in preclinical studies.1
At ESMO 2024, Silke Gillessen, MD, presented results from 2 arms of the STAMPEDE trial evaluating the efficacy and safety of adding metformin to standard of care (SOC) in patients with mHSPC (Figure 4).2 The trial enrolled 1874 patients with mHSPC with an HbA1c less than 6.5% who were not receiving treatment for diabetes. Patients were randomly assigned to SOC (n=938) or SOC plus metformin 850 mg once daily as a starting dose, increasing to a target dose of 850 mg twice daily (n=936). The primary endpoint was OS; secondary endpoints included metabolic effects, toxicity, failure-free survival, PFS, and prostate cancer–specific survival.
The median age of enrolled patients was 69 years; 11% of patients had visceral metastases at baseline. SOC included ADT plus docetaxel (82%), ADT alone (15%), and ADT + ARPI (3%).
After a median follow-up of 60 months, the addition of metformin to SOC was not associated with a significant improvement in OS (median OS, 69.1 vs 63.1 months; HR, 0.91; 95% CI, 0.80-1.03; P=.142). The 5-year OS rates were 55% and 52%, respectively. There was some evidence of a benefit with the addition of metformin to SOC in the subgroup of patients with high-volume disease as assessed by OS (HR, 0.79; 95% CI, 0.66-0.93; P=.0059) and PFS (HR, 0.76; 95% CI, 0.64-0.89; P=.0010). However, the trial was not powered to detect differences in these subsets.
Multiple metabolic parameters improved significantly with the addition of metformin to SOC, including weight, glucose level, HbA1c, total cholesterol, and low-density lipoprotein cholesterol.
Regarding safety, gastrointestinal AEs of any grade occurred in 86% of patients receiving SOC plus metformin vs 67% of patients receiving SOC. Renal or urinary events occurred in 71% and 66% of patients, respectively.
The investigators concluded there was no clear evidence that adding metformin to SOC improves OS in unselected patients with mHSPC, although potential benefit in patients with high-volume disease requires further evaluation. Moreover, the improvement in metabolic parameters could translate to reduced cardiovascular deaths in the future. They added that further research is warranted regarding the potential role of metformin added to an ADT–ARPI doublet backbone.
References
1. Hua Y, Zheng Y, Yao Y, Jia R, Ge S, Zhuang A. Metformin and cancer hallmarks: shedding new lights on therapeutic repurposing. J Transl Med. 2023;21(1):403.
2. Gillessen S, Murphy L, James N, et al. Adding metformin to androgen-deprivation therapy for patients with metastatic hormone-sensitive prostate cancer: overall survival results from the multi-arm, multi-stage, randomized platform trial STAMPEDE. LBA70: Mini Oral Session. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain.
Decipher mRNA Score for Prediction of Survival Benefit From Docetaxel at Start of Androgen-Deprivation Therapy for Advanced Prostate Cancer: An Ancillary Study of the STAMPEDE Docetaxel Trials
For men with mHSPC, the standard of care is ADT plus an ARPI such as abiraterone or enzalutamide. The addition of docetaxel to an ARPI and ADT may also be considered.1 Adding docetaxel to ADT is associated with an improvement in OS but also an increase in AEs and a reduction in QOL.2,3 Accordingly, it would be useful to be able to identify which patients are most likely to benefit from treatment intensification and which cancers are most likely to be sensitive to docetaxel.
At ESMO 2024, Emily Grist, MBBS, MRCP, PhD, presented results of an analysis of the STAMPEDE trials, which evaluated the prognostic and predictive value of the Decipher 22-gene messenger RNA (mRNA) score (DS) for selecting patients most likely to benefit from the addition of docetaxel to ADT plus ARPI (Figure 5).4
The DS was generated based on whole transcription profiling using the Veracyte test on tumor index cores from 895 patients enrolled in the STAMPEDE trial. OS outcomes were assessed in patients dichotomized by DS (≤0.8 vs >0.8) after adjusting for age, World Health Organization performance status, pre-ADT PSA, Gleason score, T stage, N stage, and metastatic volume.
DS was significantly lower among patients with M0N0 disease (adjusted P<.001), then showed a similar distribution across M0N1, M1 low-volume, and M1 high-volume disease. DS was prognostic, with each 0.1 increment increasing the risk of death by 11% in M1 disease (HR, 1.11; P<.001) and by 9% in M0 disease (HR, 1.10; P=.012).
In patients with M1 disease in the docetaxel trial, DS was significantly predictive of an efficacy benefit with docetaxel. The hazard ratio for OS with docetaxel plus ADT vs ADT alone was 0.64 (95% CI, 0.48-0.86) in patients with a high DS vs 0.96 (95% CI, 0.71-1.30) in patients with a low DS. The interaction between DS and OS benefit with docetaxel was statistically significant (P=.039). Moreover, the predictive value of DS was consistent whether patients had high-volume or low-volume disease. In contrast, there was no interaction between DS and outcomes in patients with M0 disease.
In the STAMPEDE abiraterone trial, DS was significantly prognostic but there was no statistically or clinically significant biomarker-treatment interaction predicting a benefit with the addition of abiraterone to ADT.
Investigators concluded that the DS can identify patients treated with ADT plus abiraterone with M1 prostate cancer who have a poor prognosis, and it can also identify docetaxel-sensitive tumors. They suggested that the DS provides a rational biomarker for selecting patients to receive ADT plus ARPI plus docetaxel.
References
1. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: prostate cancer. Version 4.2024. May 17, 2024.
2. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multi-arm, multi-stage, platform randomised controlled trial. Lancet. 2016;387(10024):1163-1177.
3. Rush HL, Murphy L, Morgans AK, et al. Quality of life in men with prostate cancer randomly allocated to receive docetaxel or abiraterone in the STAMPEDE Trial. J Clin Oncol. 2022;40(8):825-836.
4. Grist E, Dutey-Magni P, Mendes L, et al. Decipher mRNA score for prediction of survival benefit from docetaxel at start of androgen-deprivation therapy for advanced prostate cancer: an ancillary study of the STAMPEDE docetaxel trials. 1596O: Proffered Paper Session. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain.
Phenotypic and Genomic Characterization of De Novo Metastatic Prostate Cancer: An Ancillary Study of the PEACE-1 Phase III Trial
The randomized, open-label, phase III PEACE-1 trial resulted in a paradigm shift in the treatment of first-line mCSPC, demonstrating an OS benefit with the addition of abiraterone to docetaxel and ADT.1 At ESMO 2024, Cédric Pobel, MD, presented results of an ancillary study of PEACE-1 evaluating prognostic and predictive biomarkers associated with rPFS and OS outcomes, with the aim of detecting aggressive or neuroendocrine-like variants at diagnosis.2
The analysis was conducted on paraffin-embedded tumor samples from 595 of the 1173 patients initially randomized in the PEACE-1 trial. The distribution of phenotypic and genomic characteristics was similar to that in the overall trial population.
Immunohistochemistry (IHC) analyses assessed for luminal components, neuroendocrine (NE) features, tumor suppressor proteins, Ki67, and ERG. Approximately 26% of patients had tumors with NE features, which were associated with poor prognosis.
Investigators found that by combining androgen receptor (AR) and NE marker expression, patients could be divided into 5 phenotypes with varying prognosis: AR-high luminal (42.9%), AR-low luminal (27.7%), amphicrine (27.1%), double-negative (0.8%), and NE prostate cancer (1.4%). Among the 5 phenotypes, median OS was longest in patients with AR-high luminal (5.7 years), followed by double-negative (5.5 years), AR-low luminal (4.8 years), amphicrine (4.0 years), and NE prostate cancer (1.1 years).
The genomic analysis found that having alterations in at least 2 of the 3 genes TP53, PTEN, and RB1 predicted poor outcomes, with a median OS of 2.2 years compared with 5.4 years for patients with less than 2 alterations (HR, 2.63; 95% CI, 1.10-6.30; P=.03). No biomarkers to predict benefit with abiraterone were found.
References
1. Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to androgen-deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase III study with a 2 × 2 factorial design. Lancet. 2022;399(10336):1695-1707.
2. Pobel C, Bargain C, Scoazec J, et al. Phenotypic and genomic characterization of de novo metastatic prostate cancer: an ancillary study of the PEACE-1 phase III trial. 1595MO: Mini Oral Session. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain.
Open-Label, Multicenter Randomized Trial of Radium-223–Docetaxel Versus Docetaxel–Radium-223 Sequence in Metastatic Castration-Resistant Prostate Cancer With Prospective Biomarker Evaluation (RAPSON Study)
At ESMO 2024, Vincenza Conteduca, MD, PhD, presented results from the RAPSON trial, which evaluated the optimal sequence of radium-223 and docetaxel in patients with symptomatic bone-dominant mCRPC with progression after ADT with or without abiraterone and enzalutamide.1
The multicenter, randomized, phase II trial conducted in 70 patients compared radium-223 followed by docetaxel at progression to docetaxel followed by radium-223 at progression. The primary endpoint was the effect of treatment sequence on health-related QOL (HRQOL), which was measured by changes in the Functional Assessment of Cancer Therapy–Prostate (FACT-P) questionnaire and the Brief Pain Inventory–Short Form questionnaire (BPI-SF) for bone pain intensity, from baseline to week 12.
To define meaningful improvements or worsening of symptoms, the upper limit of the minimally important difference range was calculated for each subscale. Patients with an increase of at least a minimally important difference in the FACT-P questionnaire were considered to be responders and patients with a decrease of at least a minimally important difference were considered nonresponders. Secondary endpoints included PFS, OS, safety, and biomarker studies.
In the primary analysis, radium-223 was associated with HRQOL benefits over docetaxel, including less deterioration of HRQOL from baseline to week 12 and a higher likelihood of a response as assessed by pain intensity and its interference with daily activities.
Rates of treatment reductions and discontinuations owing to AEs were reported for the first assigned treatment period. During this time, the rate of treatment reductions owing to toxicity was lower with radium-223 vs docetaxel (1/34 vs 9/36), as was the rate of treatment discontinuations owing to TRAEs (2/23 vs 7/36).
There was no significant difference between starting with radium-223 or docetaxel in median PFS (7.3 vs 9.7 months; P=.074) or in median OS (17.4 months in both arms; P=.964).
Investigators concluded that in patients with bone-dominant symptomatic mCRPC, radium-223 followed by docetaxel was associated with improvements in QOL and tolerability compared with docetaxel followed by radium-223. Additional follow-up and studies are needed to further individualize sequential therapy for these patients.
Reference
1. Conteduca V, Brighi N, Gurioli G, et al. Open-label, multicentre randomized trial of radium-223–docetaxel versus docetaxel–radium-223 sequence in metastatic castration-resistant prostate cancer (mCRPC) with prospective biomarker evaluation (RAPSON study). LBA71: Mini Oral Session. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain.
Nivolumab 3 mg/kg and Ipilimumab 1 mg/kg in Molecularly Selected Patients With Metastatic Castration-Resistant Prostate Cancer
Immune checkpoint inhibitors (ICI) have not demonstrated significant benefit when administered as monotherapy in patients with mCRPC, which has been attributed to a lack of tumor-infiltrating T cells.1 However, in the CheckMate 650 trial, the combination of the anti-CTLA-4 ipilimumab and the anti-PD-1 nivolumab demonstrated preliminary activity in a cohort of unselected patients with mCRPC, with particular activity noted in several groups of biomarker-selected patients: those with mismatch repair deficiency (MMRd)/microsatellite instability (MSI-H) tumors, those with a high tumor mutational burden (hTMB), and those with DNA damage repair alterations (CDK12 inactivation and BRCA mutations).
Based on this preliminary study, the phase II INSPIRE trial was undertaken to further evaluate the efficacy and safety of nivolumab plus ipilimumab in patients with mCRPC with biomarker-selected subtypes. Results were presented at ESMO 2024 by Niven Mehra, MD, PhD.2
The efficacy cohort included 65 patients with mCRPC receiving ongoing ADT who had MMRd/MSI-H (n=21), hTMB (n=8), CDK12 inactivation (n=16), and BRCA mutations (n=20). The safety cohort included an additional 4 patients who had received prior ICI monotherapy. Patients received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg IV every 3 weeks for up to 4 doses followed by nivolumab 480 mg IV every 4 weeks for up to 1 year.
The primary endpoint was disease control rate (DCR) for at least 6 months. Secondary endpoints included ORR, biochemical response rate, PFS, OS, and grade 3 or higher TRAEs.
Patients were a median of 69 years old (range, 51-82 years); 68% had received prior taxanes and 77% had received a prior ARPI. At baseline, metastases were detectable in the lymph nodes in 68% of patients, in the bone in 83%, in visceral sites in 17%, and in soft tissue in 11%.
The 6-month DCR rate was 38% overall; particular activity was noted in patients with MMRd, with a 6-month DCR rate of 81% and an ORR of 75%. The 6-month DCR rates in patients with hTMB, CDK12 inactivation, and BRCA mutations were 25%, 19%, and 15%, respectively, and corresponding ORR rates were 0%, 22%, and 23%, respectively. The median PFS in the MMRd subset was 32.7 months, and the earliest 90% or greater reduction in PSA relative to baseline was 86%.
In the safety cohort, grade 3 or greater TRAEs occurred in 48% of patients, with the most common events including diarrhea (10%), γ-glutamyl transferase increase (10%), lymphocyte count decrease (10%), alanine aminotransferase increase (9%), aspartate aminotransferase increase (9%), and colitis (9%). TRAEs led to discontinuation of ipilimumab and nivolumab in 19% of patients each.
Based on the reported findings, investigators concluded that there is a need for early testing for MMRd in patients with mCRPC to inform treatment with dual ICIs. They also noted the need for additional precision medicine approaches for patients with MMRd, who comprise approximately 5% of the metastatic prostate cancer population.3
References
1. Sharma P, Pachynski RK, Narayan V, et al. Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell. 2020;38(4):489-499.e3.
2. Mehra N, Van Wilpe S, Westdorp H, et al. Nivolumab 3 mg/kg and ipilimumab 1 mg/kg (nivo3/ipi1) in molecularly selected patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). LBA72: Mini Oral Session. Presented at: ESMO Congress 2024; September 13-17, 2024; Barcelona, Spain.
3. Graham LS, Schweizer MT. Mismatch repair deficiency and clinical implications in prostate cancer. Prostate. 2022;82 Suppl 1:S37-S44.