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Metastatic Hormone-Sensitive Prostate Cancer (mHSPC): Advances and Treatment Strategies in the First-Line Setting.

ABSTRACT: The treatment landscape of metastatic hormone-sensitive prostate cancer (mHSPC) has changed radically in recent years. Androgen deprivation therapy (ADT) alone was for decades the standard of care for treating mHSPC. This changed when studies showed that the addition of docetaxel chemotherapy or abiraterone acetate to ADT significantly increases overall survival of patients with mHSPC, followed by more recent evidence showing the efficacy of androgen receptor antagonists, such as enzalutamide and apalutamide, in this setting. While this rapid therapeutic evolution is welcome, it presents clinicians with a crucial challenge: the choice of treatment selection and sequencing. In the first-line setting there are no comparative data currently available to guide treatment choice between the different available regimens, and no prospective data to guide clinical decision after progression. Decisions on treatment will now need to be personalised based on indirect comparison of the available efficacy data from multiple phase 3 studies, together with considerations of disease volume, comorbidities, treatment aims, toxicity profile and cost reimbursement within the healthcare setting. Here, we provide an overview of the clinical trial data to date and propose some biological and clinical insights which may be helpful in making decisions on treatment selection and sequencing.

SUBMITTER: Ng K

PROVIDER: S-EPMC7683690 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ImportanceThe effectiveness of triplet therapy compared with androgen pathway inhibitor (API) doublets in a heterogeneous patient population with metastatic castration-sensitive prostate cancer (mCSPC) is unknown.ObjectiveTo assess the comparative effectiveness of contemporary systemic treatment options for patients with mCSPC across clinically relevant subgroups.Data sourcesFor this systematic review and meta-analysis, Ovid MEDLINE and Embase were searched from each database's inception (MEDLINE, 1946; Embase, 1974) through June 16, 2021. Subsequently, a "living" auto search was created with weekly updates to identify new evidence as it became available.Study selectionPhase 3 randomized clinical trials (RCTs) assessing first-line treatment options for mCSPC.Data extraction and synthesisTwo independent reviewers extracted data from eligible RCTs. The comparative effectiveness of different treatment options was assessed with a fixed-effect network meta-analysis. Data were analyzed on July 10, 2022.Main outcomes and measuresOutcomes of interest included overall survival (OS), progression-free survival (PFS), grade 3 or higher adverse events, and health-related quality of life.ResultsThis report included 10 RCTs with 11 043 patients and 9 unique treatment groups. Median ages of the included population ranged from 63 to 70 years. Current evidence for the overall population suggests that the darolutamide (DARO) triplet (DARO + docetaxel [D] + androgen deprivation therapy [ADT]; hazard ratio [HR], 0.68; 95% CI, 0.57-0.81), as well as the abiraterone (AAP) triplet (AAP + D + ADT; HR, 0.75; 95% CI, 0.59-0.95), are associated with improved OS compared with D doublet (D + ADT) but not compared with API doublets. Among patients with high-volume disease, AAP + D + ADT may improve OS compared with D + ADT (HR, 0.72; 95% CI, 0.55-0.95) but not compared with AAP + ADT, enzalutamide (E) + ADT, and apalutamide (APA) + ADT. For patients with low-volume disease, AAP + D + ADT may not improve OS compared with APA + ADT, AAP + ADT, E + ADT, and D + ADT.Conclusions and relevanceThe potential benefit observed with triplet therapy must be interpreted with careful accounting for the volume of disease and the choice of doublet comparisons used in the clinical trials. These findings suggest an equipoise to how triplet regimens compare with API doublet combinations and provide direction for future clinical trials.

Project description:BackgroundDarolutamide is a potent androgen-receptor inhibitor that has been associated with increased overall survival among patients with nonmetastatic, castration-resistant prostate cancer. Whether a combination of darolutamide, androgen-deprivation therapy, and docetaxel would increase survival among patients with metastatic, hormone-sensitive prostate cancer is unknown.MethodsIn this international, phase 3 trial, we randomly assigned patients with metastatic, hormone-sensitive prostate cancer in a 1:1 ratio to receive darolutamide (at a dose of 600 mg [two 300-mg tablets] twice daily) or matching placebo, both in combination with androgen-deprivation therapy and docetaxel. The primary end point was overall survival.ResultsThe primary analysis involved 1306 patients (651 in the darolutamide group and 655 in the placebo group); 86.1% of the patients had disease that was metastatic at the time of the initial diagnosis. At the data cutoff date for the primary analysis (October 25, 2021), the risk of death was significantly lower, by 32.5%, in the darolutamide group than in the placebo group (hazard ratio 0.68; 95% confidence interval, 0.57 to 0.80; P<0.001). Darolutamide was also associated with consistent benefits with respect to the secondary end points and prespecified subgroups. Adverse events were similar in the two groups, and the incidences of the most common adverse events (occurring in ≥10% of the patients) were highest during the overlapping docetaxel treatment period in both groups. The frequency of grade 3 or 4 adverse events was 66.1% in the darolutamide group and 63.5% in the placebo group; neutropenia was the most common grade 3 or 4 adverse event (in 33.7% and 34.2%, respectively).ConclusionsIn this trial involving patients with metastatic, hormone-sensitive prostate cancer, overall survival was significantly longer with the combination of darolutamide, androgen-deprivation therapy, and docetaxel than with placebo plus androgen-deprivation therapy and docetaxel, and the addition of darolutamide led to improvement in key secondary end points. The frequency of adverse events was similar in the two groups. (Funded by Bayer and Orion Pharma; ARASENS ClinicalTrials.gov number, NCT02799602.).

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Metastatic Hormone-Sensitive Prostate Cancer (mHSPC): Advances and Treatment Strategies in the First-Line Setting.

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