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Earning Platinum Status – Revisiting the Role of Carboplatin in the Genomic Era of Prostate Cancer

Carboplatin is a second-generation platinum-based chemotherapeutic agent developed to retain the antitumor efficacy of cisplatin while substantially reducing renal, neurologic, and gastrointestinal toxicity.1 Its antineoplastic activity derives from the formation of DNA inter- and intra-strand cross-links that disrupt DNA replication and transcription, leading to cell cycle arrest and apoptosis, particularly in tumors with impaired DNA repair capacity.2 Although platinum agents have demonstrated broad activity across solid tumors, their role in prostate cancer historically remained limited, in part because early clinical studies were conducted in unselected, heavily pretreated populations.

Early clinical experience with carboplatin in prostate cancer occurred prior to the widespread adoption of taxanes and modern androgen receptor–targeted therapies. Phase II trials and retrospective series evaluating carboplatin, most commonly in combination with paclitaxel, docetaxel, or estramustine, demonstrated modest antitumor activity in metastatic castration-resistant prostate cancer (mCRPC).3,4 Responses were heterogeneous and not durable, limiting enthusiasm for carboplatin as a standard therapy in unselected patient populations.

The clinical relevance of platinum chemotherapy in prostate cancer was substantially reframed with advances in tumor genomic profiling. Large-scale sequencing studies demonstrated that approximately 23% of metastatic prostate cancers harbor deleterious alterations in DNA damage response (DDR) genes, including BRCA1, BRCA2, and other homologous recombination repair (HRR) pathway components.5,6 Because platinum-induced DNA cross-links require intact HRR mechanisms for repair, tumors with HRR deficiency represent a biologically enriched population for platinum sensitivity.

Retrospective multi-institutional analyses evaluating platinum chemotherapy in genomically characterized mCRPC cohorts demonstrated exceptional responses among patients with biallelic inactivation of BRCA2.7 In parallel, interest has emerged in the use of carboplatin for prostate cancers characterized by combined loss of key tumor suppressor genes, including RB1, TP53, and PTEN. Tumors harboring these alterations often exhibit lineage plasticity, reduced androgen receptor dependence, and aggressive clinical behavior, features commonly described as aggressive-variant prostate cancer.8,9 Although these tumors are not uniformly HRR-deficient, they frequently display genomic instability and sensitivity to cytotoxic chemotherapy. Platinum-based regimens, including carboplatin-containing combinations, have therefore been explored in this biologically distinct subset, particularly in patients with rapidly progressive disease or neuroendocrine features. While prospective validation remains limited, these observations provide an additional biological rationale for carboplatin use beyond canonical HRR alterations.

These molecular insights parallel and complement the clinical success of PARP inhibitors in HRR-deficient mCRPC and provide a strong mechanistic rationale for revisiting carboplatin in contemporary treatment paradigms. Platinum agents and PARP inhibitors exploit overlapping vulnerabilities in DNA repair, and emerging clinical data suggest that platinum chemotherapy may retain activity following PARP inhibitor exposure, as well as vice versa, raising important questions regarding optimal sequencing and combination strategies.10

Beyond direct cytotoxic effects, platinum chemotherapy may also modulate the tumor microenvironment. DNA damage induced by platinum agents can promote genomic instability, increase neoantigen burden, and activate innate immune signaling pathways, potentially enhancing tumor immunogenicity.11 These effects provide a rationale for investigating carboplatin in combination with immunotherapeutic or cellular approaches, although clinical validation in prostate cancer remains limited.

In summary, while carboplatin demonstrated only modest and inconsistent activity in early, unselected prostate cancer studies, contemporary genomic insights have substantially clarified its therapeutic potential. Identification of HRR-deficient tumors and aggressive molecular subtypes defined by tumor suppressor loss has transformed carboplatin from a largely historical therapy into a biologically rational option for selected patients. This evolving understanding has catalyzed renewed clinical investigation of carboplatin, both as monotherapy and in combination with targeted and immune-based approaches.

The following section provides a framework to outline ongoing and recent clinical trials evaluating carboplatin-based therapies in prostate cancer.

Select Clinical Trials Actively Accruing Patients with Prostate Cancer to Therapeutic Regimens Containing Carboplatin

  • OPTION-DDR – Randomized phase 3 trial of Carboplatin and Docetaxel in mCRPC patients with Alterations in DNA Damage Response Genes (NCT06439225)
  • COBRA – Phase 2 trial of Carboplatin or Olaparib for BRcA Deficient Prostate Cancer (NCT04038502)
  • Phase 2 neoadjuvant Carboplatin before Surgery for Inherited BRCA1 or BRCA2 mutated prostate cancer (NCT05806515)
  • Phase I/II study of PEGylated Arginine Deiminase (ADI-PEG20) with Carboplatin and Cabazitaxel for aggressive variant prostate cancers (NCT06085729)
  • Phase 2 trial of carboplatin, cabazitaxel and pembrolizumab for aggressive variant prostate cancer (NCT05563558)
  • SWOG 2312 – Randomized phase 3 study of Cabazitaxel with or without Carboplatin for mCRPC stratified for aggressive variant signature (NCT06470243)
  • HiTeCH – Phase 2 trial of Bipolar Androgen Therapy plus Carboplatin in mCRPC (NCT03522064)
  • SPECTRA – Phase 2 trial of Supraphysiological Androgen therapy to enhance DNA damaging agents in mCRPC, including Carboplatin (NCT06039371)
  • LuCarbo – Phase 1 trial of 177Lu-PSMA-617 plus Carboplatin in mCRPC (NCT06303713)
  • CATCH-177 - Cabazitaxel +/- Carboplatin vs 177Lu-PSMA-617 in mCRPC (NCT06738303)
  • KEYNOTE-365 – Randomized phase 2 trial of Etoposide plus Carboplatin plus Pembrolizumab for small cell, large cell or mixed Neuroendocrine prostate cancer (NCT02861573)
Written by: Evan Yu, MD, Section Head of Cancer Medicine in the Clinical Research Division at Fred Hutchinson Cancer Center. He also serves as the Medical Director of Clinical Research Support at the Fred Hutchinson Cancer Research Consortium and is a Professor of Medicine in the Division of Oncology and Department of Medicine at the University of Washington School of Medicine in Seattle, WA

References:

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  2. Kelland L. The resurgence of platinum-based cancer chemotherapy. Nat Rev Cancer. 2007;7(8):573–584.
  3. Cabrespine A, Guy L, Khenifar E, et al. Randomized phase II study comparing paclitaxel and carboplatin versus mitoxantrone in patients with hormone-refractory prostate cancer. Urology 2006;67(2):354-359.
  4. Oh WK, Halabi S, Kelly WK, et al. A phase II study of estramustine, docetaxel, and carboplatin with granulocyte-colony-stimulating factor support in patients with hormone-refractory prostate carcinoma: Cancer and Leukemia Group B 99813. Cancer 2003;98(12):2592-2598.
  5. Robinson D, Van Allen EM, Wu YM, et al. Integrative clinical genomics of advanced prostate cancer. Cell. 2015;161(5):1215–1228.
  6. Pritchard CC, Mateo J, Walsh MF, et al. Inherited DNA-repair gene mutations in men with metastatic prostate cancer. N Engl J Med. 2016;375(5):443–453.
  7. Cheng HH, Pritchard CC, Boyd T, et al. Biallelic inactivation of BRCA2 in platinum-sensitive metastatic prostate cancer. Eur Urol. 2016;69(6):992–995.
  8. Aparicio AM, Harzstark AL, Corn PG, et al. Platinum-based chemotherapy for variant castrate-resistant prostate cancer. Clin Cancer Res. 2013;19(13):3621–3630.
  9. Beltran H, Prandi D, Mosquera JM, et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat Med. 2016;22(3):298–305.
  10. Slootbeek PHJ, Kloots ISH, van Oort IM, et al. Cross-resistance between platinum-based chemotherapy and PARP inhibitors in castration-resistant prostate cancer. Cancers (Basel). 2023;15(10):2814.
  11. Galluzzi L, Buqué A, Kepp O, Zitvogel L, Kroemer G. Immunogenic cell death in cancer and infectious disease. Nat Rev Immunol. 2017;17(2):97–111.