Prostate cancer continues to be one of the most commonly diagnosed cancers in men globally and a leading cause of male cancer deaths. The landscape of metastatic hormone-sensitive prostate cancer has significantly changed over the past decade. For many years, androgen deprivation therapy alone through surgical or chemical castration was the mainstay of treatment yielding limited 5-year survival rates. New treatment approaches using Docetaxel chemotherapy or androgen receptor pathway inhibitors to intensify upfront systemic therapy have resulted in significantly improved survival rates compared to androgen deprivation therapy alone. Clinicians are now equipped with an arsenal of drugs capable of prolonging life for metastatic hormone-sensitive prostate cancer patients. Furthermore, new treatment modalities are being tested in clinical trials making treatment of metastatic hormone-sensitive prostate cancer an extremely dynamic space. In this narrative review, we provide an overview of the key systemic treatments for metastatic hormone-sensitive prostate cancer, namely androgen deprivation therapy, novel androgen receptor pathway inhibitors and Docetaxel. We summarise a series of landmark trials that have led to the integration of novel androgen receptor pathway inhibitors and docetaxel into the treatment paradigm for metastatic hormonesensitive prostate cancer. Lastly, we discuss nursing, financial and side-effect considerations pertaining to the use of these drugs. This article aims to give its readers an understanding of the evidence and clinical aspects of novel therapies in metastatic hormone-sensitive prostate cancer as they become increasingly available for use around the world.

Recent clinical trials have revealed that Lutetium PSMA-617 (Lu-PSMA, a small molecular inhibitor of prostate-specific membrane antigen radiolabelled with the beta emitter 177-Lutetium) significantly improves clinical outcomes including overall survival for patients with metastatic castration resistant prostate cancer (mCRPC). Nevertheless, owing to the highly heterogeneous nature of mCRPC, responses to Lu-PSMA therapy can be variable, with resistance inevitable. Currently, there are no existing data on the genomic landscape of mCRPC in the context of this therapy, with the identification of biomarkers linked to outcomes with Lu-PSMA being a critical unmet need in order to select patients most likely to benefit from treatment and to dissect mechanisms of resistance. mCRPC patients with high PSMA expression on positron emission tomography scans and prior treatment with docetaxel chemotherapy and an androgen receptor pathway inhibitor were enrolled on a compassionate access prospective registry at Peter MacCallum Cancer Centre. Patients received Lu-PSMA every 6 weeks for 4-6 cycles and entered into follow-up. Peripheral blood samples were collected for plasma circulating tumour DNA (ctDNA) analysis at baseline and prior to cycle 2 of therapy. A highly-sensitive targeted next-generation sequencing assay was applied to patient plasma and matched leukocytes. Somatic mutations (single nucleotide variants/indels) and copy number alterations from 43 genes were reported, along with the estimated ctDNA fraction. Current patient numbers preclude formal statistical analysis of genomic aberrations, however dynamic changes in ctDNA were assessed in relation to prostate-specific antigen (PSA) response and clinical and/or radiographic progression. In total, 19 plasma samples were analysed from 13 mCRPC patients with a median age of 71. Patients had between one and four prior lines of therapy for mCRPC and had a median time on Lu-PSMA therapy of 3.7 months. ctDNA was detected in 17/19 plasma samples with a median fraction of 26% (range 0-89%). Overall, a PSA response rate of 54% was observed. Interestingly, patients with higher baseline ctDNA fractions were more likely to experience a PSA response to Lu-PSMA therapy (median ctDNA fraction of responders 49% vs 10% in non-responders, p=0.1). Additionally, no PSA responses were seen in patients who did not attain a reduction in plasma ctDNA from baseline to cycle 2. This is the first targeted assessment of serial plasma samples from patients receiving Lu-PSMA therapy. Using a highly sensitive liquid biopsy assay, ctDNA was detectable in almost all samples. In this preliminary analysis, both baseline ctDNA fraction and early dynamic changes in ctDNA fraction appear to have clinical importance in Lu-PSMA therapy. Recruitment to this registry is proceeding rapidly, with further data available by April 2022. Citation Format: Heidi Fettke, Nicole Ng, Christine Hauser, Patricia Bukczynska, Elizabeth Medhurst, Louise Kostos, James Buteau, Jason Steen, Tu Nguyen-Dumont, Michael Hofman, Arun A. Azad. Circulating tumor DNA and outcomes with lutetium-PSMA in advanced prostate cancer: Preliminary results from an Australian study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 532.

TPS281 Background: [177Lu]Lu-PSMA is an effective class of therapy for men with metastatic castration-resistant prostate cancer (mCRPC); however, progression is inevitable. The limited durability of response is partially explained by the presence of micrometastatic deposits. Single tumor cells and micrometastases are energy-sheltered deposits receiving low absorbed radiation, due to the ~0.7mm mean path-length of Lutetium-177 (177Lu). Terbium-161 (161Tb) has abundant emission of Auger electrons that deposit a higher concentration of radiation over a shorter path, particularly to single tumor cells and micrometastases. 161Tb has shown superior in-vitro and in-vivo results in comparison with 177Lu. We hypothesize that [161Tb]Tb-PSMA-I&T will deliver effective radiation to sites of metastatic prostate cancer with an acceptable safety profile. Methods: This single-center, single-arm, phase I/II trial will recruit 30 to 36 men with progressive mCRPC. The phase I dose-escalation is designed with a 3+3 model to establish the safest dose of [161Tb]Tb-PSMA-I&T (dose levels: 4.4, 5.5 and 7.4 GBq). The maximum tolerated dose (MTD) will be defined as the highest dose level at which a dose-limiting toxicity occurs in less than 1/3 or 2/6 participants. The phase II dose-expansion will include 24 participants at the MTD. Up to six cycles of [161Tb]Tb-PSMA-I&T will be administered intravenously every six weeks, with each subsequent dose for each patient reduced by 0.4GBq. Key eligibility criteria include a diagnosis of mCRPC with progression after at least one line of taxane chemotherapy and a second-generation anti-androgen, PSMA-positive disease on PSMA PET/CT (SUVmax ≥20), no sites of discordance on FDG PET/CT, adequate bone marrow, hepatic and renal function, ECOG performance status ≤2, and no prior treatment with another radioisotope. The co-primary objectives are to establish the MTD of [161Tb]Tb-PSMA-I&T, and safety profile [CTCAE v5.0]. Secondary objectives include measuring absorbed radiation dose [Gray], evaluating anti-tumour activity [PSA 50% response rate, radiographic and PSA progression-free survival, overall survival, objective response rate], and evaluation of pain [BPI-SF] and health-related quality of life [FACT-P and FACT-RNT] over the first 12 months after treatment commences. Exploratory objectives include ctDNA analysis at baseline, during treatment and at progression, and optional tissue biopsies, to determine biomarkers of treatment response and resistance. Patient enrolment began in October 2022, with recruitment expected to continue for 24 months. Clinical trial information: NCT05521412 .

[177Lu]Lu-PSMA-617 (LuPSMA) radionuclide therapy improves overall survival in mCRPC, and was recently approved by the FDA. Nevertheless, owing to the heterogeneous nature of mCRPC, responses to LuPSMA therapy can be variable, and resistance is inevitable. As a result, biomarkers linked to clinical outcome with LuPSMA are urgently required. Using plasma ctDNA, we present the first comprehensive genomic analysis of a prospective cohort of mCRPC patients treated with LuPSMA. Targeted sequencing of 78 genes was performed on baseline plasma and matched buffy coat samples from patients who received LuPSMA on a prospective registry (NCT04769817). Reportable alterations included pathogenic single-nucleotide and copy number variants. Association between alterations and clinical outcomes were assessed using log rank, cox proportional, and chi-squared analyses. Clinical data collected included PSA decline by ≥50% or ≥90% (PSA50-response rate, PSA50-RR; and PSA90-RR), and PSA progression free survival (PSA-PFS). In total, 100 patients (median age 74 years, range 52-90) received a median of 4 cycles of LuPSMA. 83 patients had detectable ctDNA (median fraction 17%, range 0-94%) with PSA50-RR 50%, PSA90-RR 22%, and a median PSA-PFS of 7.2 months. Patients with an AR or PTEN aberration had significantly shorter PSA-PFS (HR 0.50 and 0.59, respectively; Table), as did patients with any PI3K pathway aberration (HR 0.56). Additionally, patients with a high ctDNA burden had significantly worse PSA-PFS (HR 0.42, Table). There were no significant differences in PSA-RR based on deleterious genomic changes. Our data reveal that aberrations in the AR and PI3K pathways, along with pre-treatment ctDNA fraction, whilst not linked to PSA-RR, are prognostic for durability of response to LuPSMA. If validated in larger cohorts, these data will help to optimise the use of LuPSMA by improving patient selection and enhancing prognostication. Analysis of clinical endpoints based on deleterious genomic changes in ctDNA n PSA-PFS (months, wild type (wt) vs variant) PSA-PFS HR (95% CI, wt vs variant) PSA50-RR (wt vs variant) PSA90-RR (wt vs variant) Exonic AR variants 47 8.1 vs 6.0 p=0.005 0.50 (0.30-0.83) p=0.006 58% vs 40% p=0.09 23% vs 21% p=0.8 Any AR variant (intronic and upstream enhancer regions included) 49 8.1 vs 6.0 p=0.007 0.53 (0.31-0.83) p=0.008 60% vs 41% p=0.09 24% vs 20% p=0.7 RB1 variant 19 7.9 vs 5.5 p=0.2 0.67 (0.39-1.2) p=0.2 51% vs 42% p=0.5 23% vs 21% p=0.9 PTEN variant 25 7.8 vs 6.3 p=0.04 0.59 (0.36-1.00) p=0.045 50% vs 48% p=0.9 22% vs 24% p=0.8 TP53 variant 43 8.1 vs 6.7 p=0.1 0.67 (0.42-1.1) p=0.1 52% vs 47% p=0.6 20% vs 26% p=0.5 BRCA2 variant 10 7.7 vs 5.1 p=0.2 0.63 (0.29-1.30) p=0.2 51% vs 40% p=0.7 20% vs 40% p=0.1 PIK3CA variant 8 7.7 vs 4.1 p=0.08 0.48 (0.20-1.1) p=0.09 52% vs 13% p=0.06 23% vs 13% p=0.5 PI3K pathway variant 35 7.8 vs 5.5 p= 0.02 0.56 (0.34-0.91) p=0.02 55% vs 40% p=0.2 22% vs 23% p=0.9 ctDNA fraction ≥20% 43 9.0 vs 5.1 p=0.0002 0.42 (0.26-0.67) p<0.001 55% vs 42% p=0.2 21% vs 23% p=0.8 Citation Format: Heidi Fettke, Louise Kostos, James Buteau, Jason A. Steen, Elizabeth Medhurst, Mo B. Haskali, Declan Murphy, Maria Docanto, Patricia Bukczynska, Nicole Ng, Shahneen Sandhu, Siavash Foroughi, Luc Furic, Tu Nguyen-Dumont, Michael S. Hofman, Arun A. Azad. Genomic aberrations in circulating tumor DNA (ctDNA) and clinical outcomes from [177Lu]Lu-PSMA-617 in metastatic castration-resistant prostate cancer (mCRPC). [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5614.