Elsevier

The Lancet

Volume 398, Issue 10305, 18–24 September 2021, Pages 1075-1090
The Lancet

Seminar
Prostate cancer

https://doi.org/10.1016/S0140-6736(21)00950-8Get rights and content

Summary

The management of prostate cancer continues to evolve rapidly, with substantial advances being made in understanding the genomic landscape and biology underpinning both primary and metastatic prostate cancer. Similarly, the emergence of more sensitive imaging methods has improved diagnostic and staging accuracy and refined surveillance strategies. These advances have introduced personalised therapeutics to clinical practice, with treatments targeting genomic alterations in DNA repair pathways now clinically validated. An important shift in the therapeutic framework for metastatic disease has taken place, with metastatic-directed therapies being evaluated for oligometastatic disease, aggressive management of the primary lesion shown to benefit patients with low-volume metastatic disease, and with several novel androgen pathway inhibitors significantly improving survival when used as a first-line therapy for metastatic disease. Research into the molecular characterisation of localised, recurrent, and progressive disease will undoubtedly have an impact on clinical management. Similarly, emerging research into novel therapeutics, such as targeted radioisotopes and immunotherapy, holds much promise for improving the lives of patients with prostate cancer.

Introduction

Prostate cancer is a major health issue, with approximately 1·3 million new cases diagnosed worldwide every year. About 10 million men are presently living with a diagnosis of prostate cancer, and approximately 700 000 of these are living with metastatic disease.1, 2 Metastatic prostate cancer accounts for more than 400 000 deaths annually, and this mortality is expected to more than double by 2040. A similar number of men are estimated to be living with treatment-related morbidity for more than 10 years after diagnosis.1, 2

Since the publication of the previous Seminar,3 research efforts have continued to expand our understanding of prostate cancer. Insights into initial development and underlying biology, the ability to diagnose primary and metastatic cancer, and treatment options have developed greatly. This Seminar will focus on the latest developments, how they relate to previous data, and their clinical implications, and should be read in the context of the wide variation in health-care resources available to patients with prostate cancer globally.4

Section snippets

The biology of prostate cancer

The oncogenesis of prostate cancer is associated with complex interactions between inherent germline susceptibility, acquired somatic gene alterations, and microenvironmental and macroenvironmental factors. Localised prostate cancer often contains multiple foci containing different genetic alterations with different capacity for metastatic seeding and inherent treatment resistance.

The adult human prostate is structurally divided into central, transition, and peripheral zones. The outermost

Prostate-specific antigen screening

Prostate-specific antigen (PSA) screening generally refers to an organised programme or policy under which men, usually between the ages of 50 years and 75 years, are invited to take a PSA test and potentially a digital rectal examination as part of a surveillance strategy to detect prostate cancer. This approach contrasts with an early-detection programme under which men can request a PSA test after discussion with their primary health-care provider, which is not widely offered worldwide. At

Management of primary prostate cancer

The intensity of treatment offered for the intrapelvic component of prostate cancer is based on key clinicopathological factors, including PSA concentrations, clinical tumour stage, and histological grade, in accordance with the reclassification of the Gleason score to the International Society of Urological Pathology Grade Group classification.64 The standard division into low-risk, intermediate-risk, and high-risk prostate cancer increasingly incorporates factors such as number of positive

Oligometastatic prostate cancer

The oligometastatic state is typically defined as prostate cancer with three to five metastatic lesions,99 and can be further subdivided by the interval between the appearance of deposits.100 Interest has surged in metastasis-directed therapy for oligometastatic disease with more sensitive molecular imaging, which reclassifies non-metastatic disease on conventional imaging to metastatic disease. Three randomised phase 2 trials (table 3) have shown that metastasis-directed therapy might prolong

Metastatic castration-sensitive prostate cancer

Although early detection and improved local treatments have resulted in a reduction in mortality, 20–40% of patients will develop recurrence (figure 2). Patients who present with metastatic disease at initial presentation typically have cancers with a more aggressive biology and have a shorter overall survival compared with patients who develop metastatic recurrence years after the initial diagnosis of primary prostate cancer.105, 106

Reduction of circulating testosterone via chemical or

Non-metastatic castration-resistant prostate cancer

Non-metastatic CRPC (nmCRPC) is defined by rising PSA and castrate levels of serum testosterone and no evidence of metastatic disease on conventional imaging (bone scintigraphy and CT scan), and is a consequence of androgen deprivation therapy being used at the time of biochemical relapse after definitive therapy for localised prostate cancer. Patients with nmCRPC are often asymptomatic and have variable PSA doubling times and life expectancy. Clinical interest in nmCRPC has been driven by

AR-targeted therapy

Novel AR-targeted therapies for the treatment of mCRPC are well established. The phase 3 COU-AA-301121, 124 and COU-AA-302119, 125 trials showed an approximate 4 month survival advantage with abiraterone plus prednisone over placebo in both the pre-docetaxel and post-docetaxel disease state (table 5). Abiraterone also improved quality of life, pain control, and reduced skeletal-related events. The potent AR antagonist enzalutamide, which impairs AR nuclear translocation and binding to androgen

Conclusion

Enormous advances in the understanding of the biology of prostate cancer, imaging technology, and therapeutic approaches have been made in the last decade. The debate over PSA-based prostate cancer screening has benefited from the maturation of several large randomised controlled trials that have inspired a risk-based screening approach that, combined with MRI, can safely avoid a substantial number of biopsies. Similarly, the initial characterisation of prostate cancer after diagnosis has

Declarations of interests

SGW reports grant support from Bristol-Myers Squibb; consultancy fees and travel support from Astellas Pharma, Janssen, Bayer, Amgen, and Noxopharm paid to institution; and chaired the prostate cancer subcommittee of the Australia and New Zealand Urogenital and Prostate clinical trials group, during which time he received scientific grant support from Bayer and Astellas Pharma. SS reports advisory board fees paid to institution and grant support from AstraZeneca, Merck Sharp & Dohme, Amgen,

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