Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Clinical Studies

Safety and efficacy of avelumab plus carboplatin in patients with metastatic castration-resistant prostate cancer in an open-label Phase Ib study



Single-agent PD-1/PD-L1 inhibitors have shown limited efficacy in unselected mCRPC. The evidence of a survival benefit with sipuleucel-T and ipilimumab, provides a rationale to study further increasing immunogenicity in mCRPC through combinations.


Safety and efficacy avelumab plus carboplatin was investigated in a single-arm Phase Ib study in mCRPC, progressing to at least one taxane and one androgen-receptor inhibitor. The primary endpoint was safety. Secondary endpoints included PSA/radiographic responses, progression-free survival (PFS) and overall survival (OS). Germline/somatic mutation analysis was performed.


In total, 26 patients were included. Patients were heavily pretreated: 76.9% received ≥3 and 42.3% ≥4 prior lines. A DNA damage repair (DDR) alteration was found in three patients (11.5%). The safety profile was acceptable with 73% Grade 3–4 treatment-related adverse events. PSA response rate ≥50% was seen in 7.7% of patients. The objective response rate was 17.6%, including one complete response (5.9%). Two of these responders had a known DDR alteration (one BRCA2, one ATM). The median response duration was 6 months. Median radiographic PFS was 6.6 months (95% CI 4.28–9.01), and median OS 10.6 months (95% CI 6.68–NR).


Avelumab plus carboplatin has an acceptable safety profile and was associated with a prolonged OS given the heavily pretreated population.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Trial schema.
Fig. 2: Prostate-specific antigen and radiographic responses waterfall plots.
Fig. 3: Kaplan–Meier curves for overall survival and progression-free survival.

Data availability

The datasets generated and/or analysed during this study are available from the corresponding author upon reasonable request.


  1. Bray F, Lortet-Tieulent J, Ferlay J, Forman D, Auvinen A. Prostate cancer incidence and mortality trends in 37 European countries: an overview. Eur J Cancer. 2010;46:3040–52.

    Article  CAS  Google Scholar 

  2. Sweeney CJ, Chen YH, Carducci M, Liu G, Jarrard DF, Eisenberger M, et al. Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 2015;373:737–46.

    Article  CAS  Google Scholar 

  3. Fizazi K, Tran N, Fein L, Matsubara N, Rodriguez-Antolin A, Alekseev BY, et al. Abiraterone plus prednisone in metastatic, castration-sensitive prostate cancer. N Engl J Med. 2017;377:352–60.

    Article  CAS  Google Scholar 

  4. Davis ID, Martin AJ, Stockler MR, Begbie S, Chi KN, Chowdhury S, et al. Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med. 2019;381:121–31.

    Article  CAS  Google Scholar 

  5. Chi KN, Agarwal N, Bjartell A, Chung BH, Pereira de Santana Gomes AJ, Given R, et al. Apalutamide for metastatic, castration-sensitive prostate cancer. N Engl J Med. 2019;381:13–24.

    Article  CAS  Google Scholar 

  6. de Bono JS, Oudard S, Ozguroglu M, Hansen S, Machiels JP, Kocak I, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147–54.

    Article  Google Scholar 

  7. Petrylak DP, Tangen CM, Hussain MH, Lara PN, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. 2004;351:1513–20.

    Article  CAS  Google Scholar 

  8. Tannock IF, de Wit R, Berry WR, Horti J, Pluzanska A, Chi KN, et al. Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer. N Engl J Med. 2004;351:1502–12.

    Article  CAS  Google Scholar 

  9. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med. 2011;364:1995–2005.

    Article  Google Scholar 

  10. Ryan CJ, Smith MR, de Bono JS, Molina A, Logothetis CJ, de Souza P, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. 2013;368:138–48.

    Article  CAS  Google Scholar 

  11. Scher HI, Fizazi K, Saad F, Taplin ME, Sternberg CN, Miller K, et al. Increased survival with enzalutamide in prostate cancer after chemotherapy. N Engl J Med. 2012;367:1187–97.

    Article  CAS  Google Scholar 

  12. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. 2014;371:424–33.

    Article  Google Scholar 

  13. Parker C, Nilsson S, Heinrich D, Helle SI, O’Sullivan JM, Fosså SD, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369:213–23.

    Article  CAS  Google Scholar 

  14. Sartor O, de Bono J, Chi KN, Fizazi K, Herrmann K, Rahbar K, et al. Lutetium-177-PSMA-617 for metastatic castration-resistant prostate cancer. N Engl J Med. 2021;385:1091–103.

    Article  CAS  Google Scholar 

  15. Petrylak DP, Loriot Y, Shaffer DR, Braiteh F, Powderly J, Harshman LC, et al. Safety and clinical activity of atezolizumab in patients with metastatic castration-resistant prostate cancer: a phase I study. Clin Cancer Res. 2021;27:3360–9.

    Article  CAS  Google Scholar 

  16. Hansen AR, Massard C, Ott PA, Haas NB, Lopez JS, Ejadi S, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018;29:1807–13.

    Article  CAS  Google Scholar 

  17. Antonarakis ES, Piulats JM, Gross-Goupil M, Goh J, Ojamaa K, Hoimes CJ, et al. Pembrolizumab for treatment-refractory metastatic castration-resistant prostate cancer: multicohort, open-label phase II KEYNOTE-199 study. J Clin Oncol. 2020;38:395–405.

    Article  CAS  Google Scholar 

  18. Palicelli A, Croci S, Bisagni A, Zanetti E, De Biase D, Melli B, et al. What do we have to know about PD-L1 expression in prostate cancer? A systematic literature review. Part 3: PD-L1, intracellular signaling pathways and tumor microenvironment. Int J Mol Sci. 2021;22:12297.

  19. Kantoff PW, Higano CS, Shore ND, Berger ER, Small EJ, Penson DF, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411–22.

    Article  CAS  Google Scholar 

  20. Fizazi K, Drake CG, Beer TM, Kwon ED, Scher HI, Gerritsen WR, et al. Final analysis of the ipilimumab versus placebo following radiotherapy phase III trial in postdocetaxel metastatic castration-resistant prostate cancer identifies an excess of long-term survivors. Eur Urol. 2020;78:822–30.

    Article  CAS  Google Scholar 

  21. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21:15–25.

    Article  CAS  Google Scholar 

  22. Rodríguez-Abreu D, Powell SF, Hochmair MJ, Gadgeel S, Esteban E, Felip E, et al. Pemetrexed plus platinum with or without pembrolizumab in patients with previously untreated metastatic nonsquamous NSCLC: protocol-specified final analysis from KEYNOTE-189. Ann Oncol. 2021;32:881–95.

    Article  Google Scholar 

  23. Doki Y, Ajani JA, Kato K, Xu J, Wyrwicz L, Motoyama S, et al. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386:449–62.

    Article  CAS  Google Scholar 

  24. Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the prostate cancer clinical trials working group 3. J Clin Oncol. 2016;34:1402–18.

    Article  Google Scholar 

  25. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45:228–47.

    Article  CAS  Google Scholar 

  26. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0. (v4.03: June 14, 2010). Accessed February 2022.

  27. Fizazi K, González Mella P, Castellano D, Minatta JN, Rezazadeh Kalebasty A, Shaffer D, et al. Nivolumab plus docetaxel in patients with chemotherapy-naïve metastatic castration-resistant prostate cancer: results from the phase II CheckMate 9KD trial. Eur J Cancer. 2022;160:61–71.

    Article  CAS  Google Scholar 

  28. Fizazi K, González Mella P, Castellano D, Minatta JN, Rezazadeh A, Shaffer DR, et al. CheckMate 9KD arm B final analysis: efficacy and safety of nivolumab plus docetaxel for chemotherapy-naïve metastatic castration-resistant prostate cancer. J Clin Oncol. 2021;39.6(suppl):12.

  29. Powles T, Yuen KC, Gillessen S, Kadel EE, Rathkopf D, Matsubara N, et al. Atezolizumab with enzalutamide versus enzalutamide alone in metastatic castration-resistant prostate cancer: a randomized phase 3 trial. Nat Med. 2022;28:144–53.

    Article  CAS  Google Scholar 

  30. Graff JN, Beer TM, Alumkal JJ, Slottke RE, Redmond WL, Thomas GV, et al. A phase II single-arm study of pembrolizumab with enzalutamide in men with metastatic castration-resistant prostate cancer progressing on enzalutamide alone. J Immunother Cancer. 2020;8.

  31. Hoimes CJ, Graff JN, Tagawa ST, Hwang C, Kilari D, Tije AJT, et al. KEYNOTE-199 cohorts 4 and 5: Phase II study of pembrolizumab plus enzalutamide for Enza-resistant metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(15_suppl):5543.

  32. Shenderov E, Boudadi K, Fu W, Wang H, Sullivan R, Jordan A, et al. Nivolumab plus ipilimumab, with or without enzalutamide, in AR-V7-expressing metastatic castration-resistant prostate cancer: a phase-2 nonrandomized clinical trial. Prostate. 2021;81:326–38.

    Article  CAS  Google Scholar 

  33. Sharma P, Pachynski RK, Narayan V, Fléchon A, Gravis G, Galsky MD, et al. Nivolumab plus ipilimumab for metastatic castration-resistant prostate cancer: preliminary analysis of patients in the CheckMate 650 trial. Cancer Cell. 2020;38:489–99.e3.

    Article  CAS  Google Scholar 

  34. Agarwal N, McGregor BA, Maughan BL, Dorff T, Kelly W, Fang B, et al. Cabozantinib in combination with atezolizumab in patients with metastatic castration resistant prostate cancer mCRPC): results of expanded cohort 6 of the COSMIC 021 study. Ann Oncol. 2021;32:S1283–346.

  35. Karzai F, VanderWeele D, Madan RA, Owens H, Cordes LM, Hankin A, et al. Activity of durvalumab plus olaparib in metastatic castration-resistant prostate cancer in men with and without DNA damage repair mutations. J Immunother Cancer. 2018;6:141.

    Article  Google Scholar 

  36. Yu E, Piulats JM, Gravis G, Fong PC, Todenhöfer T, Laguerre B, et al. Pembrolizumab plus olaparib in patients with docetaxel-pretreated metastatic castration-resistant prostate cancer: update of KEYNOTE-365 cohort a with a minimum of 11 months of follow-up for all patients. Ann Oncol. 2021;32:S652–3.

    Article  Google Scholar 

  37. Petrylak DP, Perez-Gracia JL, Lacombe L, Bastos DA, Mahammedi H, Kwan EM, et al. CheckMate 9KD cohort A2 final analysis: nivolumab plus rucaparib for chemotherapy naïve metastatic castration resistant prostate cancer. Ann Oncol. 2021;32:S626–77.

    Article  Google Scholar 

  38. Fong L, Morris MJ, Sartor O, Higano CS, Pagliaro L, Alva A, et al. A phase Ib study of atezolizumab with radium-223 dichloride in men with metastatic castration-resistant prostate cancer. Clin Cancer Res. 2021;27:4746–56.

    Article  CAS  Google Scholar 

  39. Flieswasser T, Van Loenhout J, Freire Boullosa L, Van den Eynde A, De Waele J, Van Audenaerde J, et al. Clinically relevant chemotherapeutics have the ability to induce immunogenic cell death in non-small cell lung cancer. Cells. 2020;9:1474.

  40. De Bono JS, Joshua AM, Shore ND, Kramer G, Tong Li X, Poehlein CH, et al. KEYNOTE-365 cohort I: phase 1b/2 study of pembrolizumab combined with platinum-containing chemotherapy and chemotherapy alone for treatment-emergent neuroendocrine prostate carcinoma (t-NE). J Clin Oncol. 2022;(suppl 6; abstr TPS218):40.

  41. Zhang J, Shih DJH, Lin SY. Role of DNA repair defects in predicting immunotherapy response. Biomark Res. 2020;8:23.

    Article  Google Scholar 

  42. Mota JM, Barnett E, Nauseef JT, Nguyen B, Stopsack KH, Wibmer A, et al. Platinum-based chemotherapy in metastatic prostate cancer with DNA repair gene alterations. JCO Precis Oncol. 2020;4:355–66.

    Article  Google Scholar 

  43. Mateo J, Porta N, Bianchini D, McGovern U, Elliott T, Jones R, et al. Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2020;21:162–74.

    Article  CAS  Google Scholar 

  44. Wu YM, Cieślik M, Lonigro RJ, Vats P, Reimers MA, Cao X, et al. Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate. Cancer Cell. 2018;173:1770–82.e14.

    CAS  Google Scholar 

  45. Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science. 2017;357:409–13.

    Article  CAS  Google Scholar 

  46. Narayan V, Barber-Rotenberg J, Fraietta J, Hwang WT, Lacey SF, Plesa G, et al. A phase I clinical trial of PSMA-directed/TGFβ-insensitive CAR-T cells in metastatic castration-resistant prostate cancer. J Clin Oncol. 2021;39:125–125.

    Article  Google Scholar 

  47. De Bono JS, Fong L, Beer TM, Gao X, Geynisman DM, Burris HA, et al. Results of an ongoing phase 1/2a dose escalation study of HPN424, a tri-specific half-life extended PSMA-targeting T-cell engager, in patients with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2021;(suppl 15; abstr 5013):39.

Download references


Study was carried out by Pivotal CRO. Statistical analyses were performed by Tania San José. The Sponsor of the study was APRO (Associació per la recerca oncològica, Spanish Oncology Research Group).


Funding for this study was jointly provided through an unrestricted educational grant from Pfizer, Inc, New York, NY, USA and Merck KGaA, Darmstadt, Germany, as part of an alliance between Merck (CrossRef Funder ID: 10.13039/100009945) and Pfizer. Pfizer and Merck reviewed the manuscript for medical accuracy only before journal submission. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors.

Author information

Authors and Affiliations



All authors conceived and/or designed the work that led to the submission, acquired data and/or played an important role in interpreting the results; drafted or revised the manuscript; approved the final version and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Corresponding author

Correspondence to Joaquim Bellmunt.

Ethics declarations

Ethics approval and consent to participate

The study was carried out with the approval of the Institutional Ethics committee of all participating institutions. The study was conducted in accordance with the ethical principles pronounced in the Declaration of Helsinki (Amendment 64th of the World Medical Association General Assembly, Fortaleza, Brazil, October 2013). This study was registered at the European Union Drug Regulating Authorities Clinical Trials Database as EudraCT Number 2017-004552-39.

Consent to publish

A signed informed consent was obtained from each participant prior to any study procedure.

Competing interests

Dr. JB reports serving in an advisory role to Genentech, MSD, Pfizer, GSK, BMS, AstraZeneca, Pierre-Fabre, Sanofi Aventis, Astellas, OncoGenex, and Janssen; receiving honoraria or travel expenses from Pfizer, MSD, GSK, Novartis, Pierre-Fabre, Astellas, and BMS; and receiving research funding from Takeda, Pfizer, Novartis, and Sanofi Aventis. Dr. AR-V reports serving in an advisory role for MSD, Pfizer, BMS, Astellas, Janssen, Bayer, Clovis and Roche; receiving honoraria or travel expenses from Pfizer, MSD, Astellas, BMS, Janssen, AstraZeneca, Roche, Bayer, and Sanofi Aventis; and receiving research funding from Takeda, Pfizer, and Merck. Dr. PM reports serving in advisory board for Pfizer, Ipsen, and BMS. Dr. AF reports serving in an advisory role to Janssen, Astellas, Sanofi, Eusa; and receiving research funding from AstraZeneca. Dr. BM has received consulting fees from Pfizer, Roche, AstraZeneca, Bayer, Astellas Pharma, and Janssen, support for attending meetings or travel from Janssen-Cilag; and other financial or non-financial interests from Roche, Janssen, and Bayer. Dr. AT reports personal fees and non-financial support from Roche, BMS, MSD, GSK, AstraZeneca and Pfizer. Dr. AC reports receiving honoraria or travel expenses from Astellas, BMS, Janssen, and Merck. Dr. RQ repots Personal fees and non-financial support from Merck, Sanofi Aventis, Roche, Pfizer, Jansen, Amgen and Astellas. Dr. OJ declares being an employee of Pivotal SLU. Dr. MM-G reports serving in an advisory role for Roche, Seagen and Pierre-Fabre; receiving honoraria or travel expenses from Roche and Pfizer. Dr. NJ reports serving in an advisory role for AstraZeneca; and receiving honoraria or travel expenses from Roche and MSD. Dr. Oscar Reig, Dr. AR-H, Dr. MO and Dr. CM report no competing interests.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Rodriguez-Vida, A., Maroto, P., Font, A. et al. Safety and efficacy of avelumab plus carboplatin in patients with metastatic castration-resistant prostate cancer in an open-label Phase Ib study. Br J Cancer 128, 21–29 (2023).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


Quick links