ESMO 2023 Wrap-Up: highlights on mCRPC
ESMO Congress 2023: Highlights on metastatic castration-resistant prostate cancer
Emerging immunotherapy for mCRPC
By Simon van Rysewyk
What is STEAP1?
The tumour-associated antigen six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is expressed in many prostate tumours, and at increased levels in metastatic castration-resistant prostate cancer (mCRPC). A STEAP1-targeted monoclonal antibody (mAb) 2+1 T-cell engager (TCE) molecule, AMG 509 (xaluritamig), has been developed to redirect T cells to eliminate prostate cancer cells that express STEAP11.
At the European Society for Medical Oncology (ESMO) Congress 2023, William K Kelly (Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, USA) presented the first clinical report of xaluritamig, and described the monotherapy dose exploration from the first-in-human open-label, multicentre phase 1 study in patients with mCRPC from North America, Europe, Asia and Australia2.
Study methods
Eligible men aged ≥18 years had mCRPC resistant to prior hormonal therapy and 1–2 taxane regimens, satisfactory organ function and an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0–1. Xaluritamig was given intravenously (IV) weekly or every other week at various dose levels (DL). The primary endpoint was to assess efficacy and safety2.
Was xaluritamig efficacious?
- At higher DLs (DL8–15), prostate-specific antigen (PSA) responses were more frequent than in lower DLs (DL1–7)2
- PSA50 (≥50% PSA decline) responses occurred in 42patients (47.2%); PSA90, in 24 patients (27.0%)2
- Response Evaluation Criteria in Solid Tumours (RECIST) responses included 15 (22.7%) confirmed partial response (PR) and 30 (45.5%) stable disease (SD)2
- At higher DLs, 14patients (38.9%) had confirmed PR and 12 (33.3%) SD2
What were the safety results?
Treatment-emergent adverse events were reported for all patients. The most common adverse events (AEs) were cytokine release syndrome (CRS; 72.2%), fatigue (52.6%), anaemia (45.4%), pyrexia (40.2%) and myalgia (39.2%). CRS occurred mainly in cycle 1 and improved with premedication and step dosing2.
Conclusion
In this first-in-human dose exploration, xaluritamig showed encouraging efficacy (PSA, RECIST), low-grade CRS, and mostly grade 1 or 2 AEs that were clinically manageable.
This study offers proof of concept for STEAP1 as a target for TCEs and support for further investigation of xaluritamig as a potential treatment for mCRPC
Combination treatment synergies for mCRPC: New clinical trial data
By Simon van Rysewyk
Pembrolizumab plus enzalutamide for mCRPC
Current treatments for mCRPC are not curative, and median survival following progression to mCRPC is approximately 3 years. Accumulating evidence indicates synergism with enzalutamide and the PD-1 inhibitor pembrolizumab for mCRPC3,4.
Julie N Graff (Portland VA Research Foundation, Oregon, USA) presented outcome data from the phase 3 randomised KEYNOTE-641 clinical trial, which investigated the efficacy and safety of pembrolizumab plus enzalutamide for men with mCRPC who had not received chemotherapy, were abiraterone-naive, or intolerant to, or had progressed on, abiraterone acetate.
What were the study procedures and endpoints?
Eligible patients aged ≥18 years with confirmed mCRPC and no prior chemotherapy except docetaxel were randomised 1:1 to pembrolizumab 200 mg or intravenous placebo every 3 weeks for ≤35 cycles plus enzalutamide 160 mg orally daily.
Primary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS) per Prostate Cancer Working Group (PCWG)-modified Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1).
Did the trial support the study hypotheses?
The trial endpoints were not met:
- OS (median, 24.7months [pembrolizumab + enzalutamide] vs 27.3 months [placebo + enzalutamide]; HR, 1.04; 95% CI, 0.88−1.22; P=0.66)
- rPFS (median, 10.4months [pembrolizumab + enzalutamide] vs 9.0 months [placebo + enzalutamide]; HR, 0.98; 95% CI, 0.84−1.14; P=0.41)
The boundary for futility for OS was crossed and the trial was discontinued.
Any-grade and grade ≥3 treatment-related adverse events were reported in 77.9% and 31.2%, respectively, of 615 patients with ≥1 dose pembrolizumab and enzalutamide, and in 61.6% and 10.8% of 620 patients with ≥1 dose placebo and enzalutamide.
Conclusion
In KEYNOTE-641, pembrolizumab and enzalutamide did not benefit efficacy outcomes in men with mCRPC who had not received chemotherapy or abiraterone. The combination was associated with more treatment-related adverse events than placebo. Graff concluded:
A modest number of complete responses occurred; future studies should focus on patient selection and the identification of predictive markers of response
A randomised, phase 2 trial of enzalutamide plus
177Lutetium-PSMA-617 for mCRPC (ENZA-p)
Enzalutamide and lutetium-177-prostate-specific membrane antigen-617 (177Lu-PSMA-617) improve OS in mCRPC5,6. ENZA-p is an open-label, randomised phase 2 clinical trial that evaluates combining enzalutamide with adaptive dosing of 177Lu-PSMA-617 versus enzalutamide alone as first-line treatment for mCRPC. Louise Emmett (University of New South Wales, Sydney, Australia), primary investigator of ENZA-p, presented the results at ESMO 2023.
Endpoints of ENZA-p and trial procedure
- Primary: Prostate-specific antigen progression-free survival (PSA–PFS)
- Secondary: rPFS; PSA50% (≥50% PSA decline) and PSA90% response rates (PSA50RR, PSA90RR); adverse events (AEs); OS
Patients were randomised 1:1 to enzalutamide 160 mg daily or enzalutamide 160 mg daily plus adaptive dosing with 7.5 GBq 177Lu-PSMA-617 on days 15 and 57; two additional doses of 177Lu-PSMA-617 were given if persistent PSMA-positive disease was evident on interim 68Ga-PSMA positron emission tomography (PET; day 92).
Primary endpoint results
- PSA–PFS was longer with enzalutamide + 177Lu-PSMA-617 versus enzalutamide alone (median 13 months vs 7.8 months; HR, 0.43; 95% CI, 0.29−63; P<0.001)
- PSA50RR and PSA90RR were higher with enzalutamide + 177Lu-PSMA-617 versus enzalutamide alone: 93% (77/83) versus 68% (54/79) (P<0.001) and 78% (65/83) versus 37% (29/79)
(P<0.001)
Conclusion
Adaptive dosing with 177Lu-PSMA-617 in addition to enzalutamide can benefit efficacy outcomes in the mCRPC setting. This trial therefore supports this combination as a potential first-line treatment for mCRPC. Emmett made this closing prediction:
I think this is going to become more important as we move this radiation treatment earlier in the disease paradigm to hormone-sensitive prostate cancer. It [has] the potential to reduce toxicity by only administering if persistent PSMA-avid disease is present on the PSMA–PET or SPECT [single-photon emission computerised tomography] images.
MAGNITUDE update: Niraparib with abiraterone acetate plus prednisone for mCRPC
In the phase 3 MAGNITUDE trial, niraparib and abiraterone acetate plus prednisone (NIRA + AAP) significantly improved rPFS in people with BRCA+ mCRPC7.
Primary investigator Kim Nguyen N Chi (Vancouver Prostate Cancer, Canada) presented the final analysis of MAGNITUDE.
What the final analysis incudes
- Secondary endpoints of OS and time to cytotoxic chemotherapy (TCC)
- Time to symptomatic progression (TSP) and patient-reported outcomes
Final analysis results
In the final analysis, 113 patients received NIRA + AAP. The results showed:
- OS benefit favouring NIRA + AAP over placebo + AAP (HR, 0.79; 95% CI, 0.55–12; P=0.18)
- Improvement in TSP (HR, 0.56; 95% CI, 0.37–85; P=0.01)
- Clinically meaningful improvement in TCC (HR, 0.60; 95% CI, 0.39–92; P=0.02)
- Time to worst pain progression and time to pain interference progression favoured NIRA + AAP
Conclusions
NIRA + AAP could emerge as a standard of care for this subgroup of patients with mCRPC.
Pain and analgesic use in men with mCRPC initiating first-line treatment
By Simon van Rysewyk
What is this presentation about?
Oncology nurse Ulrika Rönningås (Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden) presented data from the prospective study PROCEED (N=143), which evaluated three dimensions of pain (frequency, severity, distress) measured using the Memorial System Assessment Scale (MSAS). Analgesic use was collected from medical records. Seventy-two men starting first-line treatment for mCRPC were included.
What did the study find for men with mCRPC on analgesics?
- 9% (n=46) used analgesics
- 8 % had pain ‘frequently’ or ‘almost constantly’
- 51% reported ‘quite a bit’ or ‘very much’ distress
- 5% reported ‘severe’ or ‘very severe’ pain
What did the study find for men with mCRPC not on analgesics?
- 1% (n=26) did not use analgesics
- 44% had pain ‘frequently’ or ‘almost constantly’
- 19% had ‘severe’ pain; no participant not using analgesics reported ‘very severe’ pain
- 38% reported ‘quite a bit’ or ‘very much’ distress
What do the study data mean?
According to Rönningås, pain experience in men with mCRPC differs between those using analgesics from those who do not. Pain management was not effective for more than half of the participants with mCRPC, even for those using analgesics.
Rönningås recommends that “men with mCRPC starting life-prolonging treatment may benefit from a structured multidimensional assessment. When the disease has progressed to an mCRPC phase, an early integrated palliative approach with thorough symptom management may be essential in order to obtain the best possible quality of life”.
References
- Nolan-Stevaux O, Li C, Liang L, Zhan J, Estrada J, Osgood T, et al. AMG 509 (Xaluritamig), an Anti-STEAP1 XmAb 2+1 T-cell Redirecting Immune Therapy with Avidity-Dependent Activity Against Prostate Cancer. Cancer Discov. Epub October 20, 2023.
- Kelly WK, Danila DC, Lin CC, Lee JL, Matsubara N, Ward PJ, et al. Xaluritamig, a STEAP1 × CD3 XmAb 2+1 Immune Therapy for Metastatic Castration-Resistant Prostate Cancer: Results from Dose Exploration in a First-in-Human Study. Cancer Discov. 2023:OF1–OF14.
- Graff JN, Liang LW, Kim J, Stenzl A. KEYNOTE-641: A Phase III study of pembrolizumab plus enzalutamide for metastatic castration-resistant prostate cancer. Future Oncol. 2021;17(23):3017–3026.
- Graff JN, Tagawa ST, Hoimes CJ, Gerritsen WR, Vaishampayan UN, Elliott T, et al. Pembrolizumab plus enzalutamide for enzalutamide-resistant metastatic castration-resistant prostate cancer (mCRPC): Updated analyses after one additional year of follow-up from cohorts 4 and 5 of the KEYNOTE-199 study. J Clin Oncol. 2021;39:5042.
- Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. New Eng J Med. 2014;371(5):424–433.
- Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahba RK, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. New Eng J Med. 2021;385(12):1091–1103.
- Chi KN, Rathkopf DE, Smith MR, Efstathiou E, Attard G, Olmos D. Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. J Clin Oncol. 2022;40:12.
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