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SummaryBackgroundThe role of metastasis-directed therapy (MDT) in castration-resistant prostate cancer (CRPC) remains unclear. Prostate Cancer Study 9 (PCS-9) aimed to evaluate the benefits of stereotactic body radiotherapy (SBRT) in addition to standard systemic therapy in patients with oligometastatic CRPC. MethodsThis open-label, randomised, phase 2 trial was conducted across 13 Canadian academic and community oncology centres. Male patients aged 18 years or older, with an Eastern Cooperative Oncology Group performance status of 0–2, and histologically confirmed oligometastatic CRPC (≤5 metastases), who had progressed on androgen deprivation therapy (ADT), were randomly assigned (1:1) to ADT–enzalutamide (ENZA; 160 mg once daily) or ADT–ENZA–SBRT to all oligometastatic sites. Randomisation was completed by sequentially numbered, sealed opaque envelopes, and stratified by the location of the metastasis. The primary endpoint was radiographic progression-free survival. Analysis was performed on an intention-to-treat basis. This study is registered with ClinicalTrials.gov, NCT02685397, and was halted and completed at the phase 2 stage. FindingsBetween Oct 18, 2016, and July 31, 2023, 102 male patients were randomly assigned to ADT–ENZA (n=49) or ADT–ENZA–SBRT (n=53); after excluding one patient per treatment group due to early withdrawal and insufficient data, 48 patients in the ADT–ENZA group and 52 patients in the ADT–ENZA–SBRT group were included in the final analysis. Most patients were White (80 [80%]) and median age was 73·0 years (IQR 67·0–79·5). At a median follow-up of 4·8 years (IQR 3·4–5·0), ADT–ENZA–SBRT significantly improved radiographic progression-free survival compared with ADT–ENZA alone (median radiographic progression-free survival, 4·6 years [95% CI 3·7–not reached] vs 2·3 years [1·4–3·7]; hazard ratio 0·48 [95% CI 0·27–0·86]; p=0·014). The most common grade 3 treatment related adverse event was impotence (eight [57%] of 14 patients in the ADT–ENZA group and nine [75%] of 12 patients in the ADT–ENZA–SBRT group). There were no grade 4 toxicities and no treatment-related deaths. InterpretationThese results demonstrate that SBRT, when combined with ADT–ENZA, prolongs disease control in oligometastatic CRPC by doubling median radiographic progression-free survival, with similar toxicity profiles between the groups. These findings support integrating SBRT into the treatment paradigm for oligometastatic CRPC. FundingJewish General Hospital (Astellas Canada).

Among men with high-risk, nonmetastatic, castration-resistant prostate cancer, the addition of enzalutamide to androgen-deprivation therapy improved overall survival by nearly a year as compared with ADT alone: median survival was 67 months with enzalutamide plus ADT and 56 months with ADT alone.

In a randomized trial involving men with metastatic prostate cancer with a DNA-repair defect, rucaparib was associated with longer progression-free survival than a control medication (11.2 vs. 6.4 months).

Guiding the beta-emitting isotope lutetium-177 to prostate cancer lesions with the prostate-specific membrane antigen–targeted radioligand 177 Lu-PSMA-617 plus using standard care was compared with standard care in patients with metastatic castration-resistant prostate cancer. The radioligand therapy prolonged progression-free and overall survival. Adverse effects were more common, but quality of life was maintained.

Background Real-world treatment patterns and survival in metastatic castration-resistant prostate cancer (mCRPC) have not been characterized for the full fee-for-service Medicare population. Methods Men newly diagnosed with mCRPC were identified in Medicare fee-for-service claims during 1/1/2014–6/30/2019. Men had evidence of mCRPC and continuous insurance coverage ≥1 year before and ≥6 months after diagnosis unless patients died. Treatment patterns after diagnosis were described. Survival from mCRPC diagnosis and from start of first-line (1 L) therapy was modeled using Kaplan-Meier analysis. Results Among 14,780 men with mCRPC, mean age was 76 and median follow-up after mCRPC was 17.0 months. 22% received no life-prolonging therapy after mCRPC, 78% received ≥1 line of therapy (LOT), 42% underwent ≥2 LOTs, and 20% had ≥3 LOTs. Median time from start of 1 L to next LOT or end of follow-up was 13.7 months, 10.9 months from 2 L start, and 8.9 months from 3 L start. The most common 1 L to 2 L treatment sequences among men with ≥2 lines were NHT followed by a different NHT (33%), chemotherapy followed by NHT (14%), and NHT followed by chemotherapy (13%). For those initiating 1 L treatment with NHTs, only 28% received subsequent treatment with a different class of therapy. Median survival was 25.6 months after mCRPC and 23.4 months following treatment initiation. Conclusions More than 1 in 5 Medicare patients with mCRPC did not receive any life-prolonging therapy, and less than half received 2 L therapy. NHTs were the most common 1 L and 2 L therapies, with patients treated with NHT as 1 L followed by a different NHT for 2 L as the most common treatment sequence. Median survival from diagnosis for all patients was 25.6 months. These data highlight the dramatic undertreatment that occurs for mCRPC patients, particularly for therapies beyond NHTs as well as the common use of sequential NHTs in real-world data.

ProBio is the first outcome-adaptive platform trial in prostate cancer utilizing a Bayesian framework to evaluate efficacy within predefined biomarker signatures across systemic treatments. Prospective circulating tumor DNA and germline DNA analysis was performed in patients with metastatic castration-resistant prostate cancer before randomization to androgen receptor pathway inhibitors (ARPIs), taxanes or a physician’s choice control arm. The primary endpoint was the time to no longer clinically benefitting (NLCB). Secondary endpoints included overall survival and (serious) adverse events. Upon reaching the time to NLCB, patients could be re-randomized. The primary endpoint was met after 218 randomizations. ARPIs demonstrated ~50% longer time to NLCB compared to taxanes (median, 11.1 versus 6.9 months) and the physician’s choice arm (median, 11.1 versus 7.4 months) in the biomarker-unselected or ‘all’ patient population. ARPIs demonstrated longer overall survival (median, 38.7 versus 21.7 and 21.8 months for taxanes and physician’s choice, respectively). Biomarker signature findings suggest that the largest increase in time to NLCB was observed in AR (single-nucleotide variant/genomic structural rearrangement)-negative and TP53 wild-type patients and TMPRSS2–ERG fusion-positive patients, whereas no difference between ARPIs and taxanes was observed in TP53 -altered patients. In summary, ARPIs outperform taxanes and physician’s choice treatment in patients with metastatic castration-resistant prostate cancer with detectable circulating tumor DNA. ClinicalTrials.gov registration: NCT03903835 . In a biomarker-driven, outcome-adaptive platform trial for patients with metastatic castration-resistant prostate cancer, androgen receptor pathway inhibitors showed longer survival with respect to taxanes and physician’s choice treatment.

Background: The aim of the present study is to evaluate the impact of metastases-directed stereotactic body radiotherapy in two groups of oligometastatic prostate cancer (PC) patients: oligorecurrent PC and oligoprogressive castration-resistant PC (oligo-CRPC). Methods: Inclusion criteria of the present multicentre retrospective analysis were: (1) oligorecurrent PC, defined as the presence of 1–3 lesions (bone or nodes) detected with choline positron emission tomography or CT plus bone scan following biochemical recurrence; (2) oligo-CRPC, defined as metastases (bone or nodes) detected after a prostatic-specific antigen rise during androgen deprivation therapy (ADT). Primary end points were: distant progression-free survival (DPFS) and ADT-free survival in oligorecurrent PC patients; DPFS and second-line systemic treatment-free survival in oligo-CRPC patients. Results: About 100 patients with oligorecurrent PC (139 lesions) and 41 with oligo-CRPC (70 lesions), treated between March 2010 and April 2016, were analysed. After a median follow-up of 20.4 months, in the oligorecurrent group 1- and 2-year DPFS were 64.4 and 43%. The rate of LC was 92.8% at 2 years. At a median follow-up of 23.4 months, in the oligo-CRPC group 1- and 2-year DPFS were 43.2 and 21.6%. Limitations include the retrospective design. Conclusions: Stereotactic body radiotherapy seems to be a useful treatment both for oligorecurrent and oligo-CRPC.

Lutetium-177 [177Lu]Lu-PSMA-617 is a radiolabelled small molecule that delivers β radiation to cells expressing prostate-specific membrane antigen (PSMA), with activity and safety in patients with metastatic castration-resistant prostate cancer. We aimed to compare [177Lu]Lu-PSMA-617 with cabazitaxel in patients with metastatic castration-resistant prostate cancer. We did this multicentre, unblinded, randomised phase 2 trial at 11 centres in Australia. We recruited men with metastatic castration-resistant prostate cancer for whom cabazitaxel was considered the next appropriate standard treatment. Participants were required to have adequate renal, haematological, and liver function, and an Eastern Cooperative Oncology Group performance status of 0–2. Previous treatment with androgen receptor-directed therapy was allowed. Men underwent gallium-68 [68Ga]Ga-PSMA-11 and 2-flourine-18[18F]fluoro-2-deoxy-D-glucose (FDG) PET-CT scans. PET eligibility criteria for the trial were PSMA-positive disease, and no sites of metastatic disease with discordant FDG-positive and PSMA-negative findings. Men were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (6·0–8·5 GBq intravenously every 6 weeks for up to six cycles) or cabazitaxel (20 mg/m2 intravenously every 3 weeks for up to ten cycles). The primary endpoint was prostate-specific antigen (PSA) response defined by a reduction of at least 50% from baseline. This trial is registered with ClinicalTrials.gov, NCT03392428. Between Feb 6, 2018, and Sept 3, 2019, we screened 291 men, of whom 200 were eligible on PET imaging. Study treatment was received by 98 (99%) of 99 men randomly assigned to [177Lu]Lu-PSMA-617 versus 85 (84%) of 101 randomly assigned to cabazitaxel. PSA responses were more frequent among men in the [177Lu]Lu-PSMA-617 group than in the cabazitaxel group (65 vs 37 PSA responses; 66% vs 37% by intention to treat; difference 29% (95% CI 16–42; p<0·0001; and 66% vs 44% by treatment received; difference 23% [9–37]; p=0·0016). Grade 3–4 adverse events occurred in 32 (33%) of 98 men in the [177Lu]Lu-PSMA-617 group versus 45 (53%) of 85 men in the cabazitaxel group. No deaths were attributed to [177Lu]Lu-PSMA-617. [177Lu]Lu-PSMA-617 compared with cabazitaxel in men with metastatic castration-resistant prostate cancer led to a higher PSA response and fewer grade 3 or 4 adverse events. [177Lu]Lu-PSMA-617 is a new effective class of therapy and a potential alternative to cabazitaxel. Prostate Cancer Foundation of Australia, Endocyte (a Novartis company), Australian Nuclear Science and Technology Organization, Movember, The Distinguished Gentleman's Ride, It's a Bloke Thing, and CAN4CANCER.

Opinion statement The management of metastatic castrate-resistant prostate cancer (mCRPC) has evolved in the past decade due to substantial advances in understanding the genomic landscape and biology underpinning this form of prostate cancer. The implementation of various therapeutic agents has improved overall survival but despite the promising advances in therapeutic options, mCRPC remains incurable. The focus of treatment should be not only to improve survival but also to preserve the patient’s quality of life (QoL) and ameliorate cancer-related symptoms such as pain. The choice and sequence of therapy for mCRPC patients are complex and influenced by various factors, such as side effects, disease burden, treatment history, comorbidities, patient preference and, more recently, the presence of actionable genomic alterations or biomarkers. Docetaxel is the first-line treatment for chemo-naïve patients with good performance status and those who have yet to progress on docetaxel in the castration-sensitive setting. Novel androgen agents (NHAs), such as abiraterone and enzalutamide, are effective treatment options that are utilized as second-line options. These medications can be considered upfront in frail patients or patients who are NHA naïve. Current guidelines recommend genetic testing in mCRPC for mutations in DNA repair deficiency genes to inform treatment decisions, as for example in breast cancer gene mutation testing. Other potential biomarkers being investigated include phosphatase and tensin homologues and homologous recombination repair genes. Despite a growing number of studies incorporating biomarkers in their trial designs, to date, only olaparib in the PROFOUND study and lutetium-177 in the VISION trial have improved survival. This is an unmet need, and future trials should focus on biomarker-guided treatment strategies. The advent of novel noncytotoxic agents has enhanced targeted drug delivery and improved treatment responses with favourable toxicity profiling. Trials should continue to incorporate and report health-related QoL scores and functional assessments into their trial designs.

Castration-resistant prostate cancer (CRPC) represents an advanced stage of prostate cancer progression. Although the combination of androgen deprivation therapy (ADT) with chemotherapy and first generation hormone therapy is initially effective, patients ultimately develop resistance. In recent years, breakthroughs in targeted therapies and immunotherapies, along with the emergence of novel combination strategies, have provided new hope for patients with CRPC. This article systematically reviews the latest advancements in targeted and immunotherapeutic approaches for CRPC, integrating clinical data and mechanistic studies to analyze the efficacy and challenges of novel agents (e.g., second-generation AR inhibitors, PARP inhibitors, PSMA-targeted therapies) and combination regimens. It also provides insights for exploring future optimization directions.