Treatment of metastatic castration-resistant prostate cancer: review of current evidence and synthesis of expert opinions on radioligand therapy

Abstract

Background: Despite the boom in the development of cancer management in the last decade, most patients with metastatic prostate cancer (PCa) eventually progress to metastatic castration-resistant PCa (mCRPC) and often require multiple lines of treatment. The treatment landscape of mCRPC has evolved rapidly in recent years, introducing various types of systemic therapies, including taxane-based chemotherapy, androgen receptor pathway inhibitors, bone-targeted radionuclides (e.g., radium-223), immune checkpoint inhibitors, poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) inhibitors, and radioligand therapies (RLTs) [e.g., a prostate-specific membrane antigen (PSMA) ligand labelled with ¹⁷⁷Lu].

Methods: To help clinicians navigate the increasingly complex treatment landscape of mCRPC, this article reviews the evidence on different therapeutic regimens from pivotal trials. In addition, it reports on the results of a questionnaire developed and distributed by the Hong Kong Society of Uro-Oncology (HKSUO), with the aim of collecting the perspectives of specialists experienced in the treatment of advanced PCa in Hong Kong with regard to the clinical application of RLT, primarily [¹⁷⁷Lu]Lu-PSMA-617/analogue therapy.

Results: A total of 43 questionnaire respondents (including clinical oncologists, urologists, nuclear medicine specialists, and medical oncologists) voted on 27 consensus questions divided into eight sections. Consensus or strong consensus (correspondingly ≥75% or ≥90% acceptance for an answer option) was reached for 10 questions. Subsequently, a panel of 13 local and overseas experts coordinated by the HKSUO discussed the voting results and provided further insights into certain questions.

Conclusion: The literature review, the voting results of the questionnaire, and the expert opinions are expected to facilitate better understanding of recent therapeutic advancements and the role of novel RLTs in the treatment of mCRPC among clinicians.

Keywords: [177Lu]Lu-PSMA-617; genitourinary oncology; metastatic castration-resistant prostate cancer; prostate-specific membrane antigen; radioligand therapy.

Figure 1

Consensus-based treatment algorithm for patients who received one line of androgen receptor pathway inhibitor (ARPI) therapy for metastatic castration-resistant prostate cancer (mCRPC). Chemo, chemotherapy; dMMR, mismatch repair-deficient; FDG, fluorodeoxyglucose; HRR, homologous recombination repair; MSI, microsatellite instability; PARP, poly (adenosine diphosphate [ADP]-ribose) polymerase; PET, positron emission tomography; PSMA, prostate-specific membrane antigen; TMB, tumour mutational burden. Asterisk denotes that an answer option with ≥75% or ≥90% agreement was considered to reach consensus or strong consensus, respectively. Dagger indicates that the item is defined as one or more PSMA-positive metastatic lesion ([⁶⁸Ga]Ga-PSMA-11 uptake greater than that of the liver parenchyma in one or more metastatic lesions of any size in any organ system) and no PSMA-negative lesions that meet the following criteria: PSMA uptake equal to or lower than that of the liver parenchyma in any lymph node with a short axis of ≥2.5 cm, in any metastatic solid-organ lesions with a short axis of ≥1.0 cm, or in any metastatic bone lesion with a soft tissue component of ≥1.0 cm in the short axis.