In the past five years, multiple studies have established docetaxel chemotherapy and androgen receptor-targeted therapies as alternate standard-of-care treatments for patients commencing continuous androgen deprivation therapy (ADT) for metastatic hormone-sensitive prostate cancer (mHSPC), demonstrating profound improvements in overall survival whilst delaying both disease related complications and the development of metastatic castration-resistant prostate cancer (mCRPC). Despite this, no prospective trials currently exist comparing chemotherapy to androgen receptor-targeted therapy, leaving clinicians with the dilemma of selecting between two distinct management pathways. Although administration of highly efficacious and well-tolerated androgen receptor pathway inhibitors represents an attractive option, we will argue that failure to administer upfront chemotherapy in select patients may represent a lost opportunity to capitalize on the patient and cost benefits of docetaxel for mHSPC.
BIOLOGY, NOT VOLUME, SHOULD DRIVE DOCETAXEL USE
Prostate cancer cells possess remarkable heterogeneity with regard to their reliance on androgen-driven growth pathways. Although reduction in serum PSA is observed in more than 90% of mHSPC patients upon ADT commencement, the longevity and depth of response are far less predictable. Early chemotherapy seeks to eliminate androgen-independent tumour clones before they acquire resistance mutations from the continued selection pressure of treatment exposure.
Subgroup analysis of the CHAARTED and GETUG-AFU15 studies suggests that docetaxel should be reserved only for patients with high-volume disease, defined by four or more bone metastases (one beyond the axial skeleton) or the presence of visceral metastases. Conversely, recent data from ARCHES (enzalutamide), ENZAMET (enzalutamide), and TITAN (apalutamide) support the use of androgen receptor-targeted therapies independent of disease volume . However, volumetric classification is at best arbitrary, and like other prognostic tools, was never intended be comprehensive. Such dichotomization invariably oversimplifies disease biology and overlooks the possibility that risk categorization more likely represents a continuum.
Other important clinicopathological factors may in fact play an equally prominent role in risk stratification and treatment selection. Coexistence of nonregional lymph node and bone metastases is associated with inferior survival, comparable to that of visceral disease . Biochemical measures such as elevated lactate dehydrogenase, low baseline PSA levels and abnormal alkaline phosphatase (from lytic bone metastases) may identify aggressive variants of mHSPC destined for poor outcomes . Furthermore, high-grade tumours , as well as uncommon histologic variants such as neuroendocrine or ductal disease (associated with germline BRCA2 mutation carriers ) are associated with intrinsic resistance to castration. Therefore, optimal treatment selection should consider both disease volume as well as other global indicators of disease biology when assessing the potential utility of chemohormonal therapy in mHSPC.
THE BEST CHANCE TO DELIVER DOCETAXEL IS EARLY IN THE DISEASE COURSE
Although upfront docetaxel is undoubtedly associated with significant toxicity and acute detriment to quality of life, this appears to largely return to baseline or improve over time . However, there may be greater value in delivering less-tolerable treatments earlier in the disease course, when patients are physically fitter and more resilient to adverse events. In fact, large registry-based real-world data suggests that reserving docetaxel till mCRPC may be ill-fated, with only 26% of patients receiving it during their disease course (1L – 12%, 2L – 8%, 3L – 6%) , speaking to the influence of frailty with progressive treatment lines. This pitfall was further exemplified in the LATITUDE study of upfront abiraterone, where subsequent exposure to life-prolonging therapy arguably fell short of desired expectations (57% in ADT monotherapy, 30% in combination). Concerningly, nonrandomized registry data suggest that benefit of docetaxel may even be augmented with prior exposure to androgen receptor-targeted therapies . Clearly, determining chemotherapy eligibility upfront, when patient performance status is least likely to be affected by disease and medical morbidity is critical to optimising outcomes for patients with metastatic prostate cancer.
DOCETAXEL MAINTAINS SUPERIOR COSTEFFECTIVENESS
Access to novel systemic therapies in advanced prostate cancer continues to be a major issue in many parts of the world. In a world of finite resources, healthcare jurisdictions face considerable ‘financial toxicity’ with reimbursing drug supply, as well as associated costs of extended monitoring and toxicity management. Although six cycles of docetaxel are completed within 18 weeks, androgen receptor-targeted therapies are administered till mCRPC development, with a median duration on treatment of 33 and 24 months in STAMPEDE and LATITUDE respectively. Unsurprisingly, a recent study modelling the cost-effectiveness of systemic therapies for mHSPC concluded that upfront docetaxel offered an overwhelming cost advantage over abiraterone . It is likely that subsequent analyses of enzalutamide and apalutamide will show similar trends. Without overall survival advantage over chemotherapy, the cost of androgen receptor-targeted treatments will need to fall substantially before it reaches parity with docetaxel in terms of cost-effectiveness.
IMPACT OF NOVEL IMAGING
Functional imaging using novel PET tracers such as 68Ga-prostate-specific membrane antigen have provided unprecedented ability to detect metastatic disease, with the full implications of this disruptive technology only beginning to be realized . With significant ‘stage migration’ expected, the temptation to extrapolate preexisting data from landmark studies that utilized conventional imaging remains high, particularly in relation to androgen receptor-targeted therapy trials. Not only is there no evidence to support commencing androgen receptor therapy in patients with metastatic disease on novel imaging alone, earlier use is likely to result in more extended treatment duration. The adverse event profile of such prolonged therapy remains unclear but may include concerns regarding cognitive loss, cardiovascular disease, cumulative seizure risk and predisposition to falls and nonpathological fractures. Extended therapy would also further contribute to an evergreater financial burden on our limited healthcare resources.
Although androgen receptor-targeted therapies have fundamentally transformed the treatment landscape for mHSPC, clinicians should think twice before deferring chemotherapy to the realms of mCRPC. Considering the recent ENZAMET results, there remains no compelling argument for triplet therapy (ADT + docetaxel + androgen receptor-targeted therapy), though ongoing studies (PEACE-1) may shed light on this matter. For now, decisions regarding upfront therapy must continue to be based around disease biology, patient fitness and cost-effectiveness considerations, until such time where molecular biomarkers can guide critical treatment decisions in the clinic.
Financial support and sponsorship
E.M.K. is supported by a National Health and Medical Research Council (NHMRC) Postgraduate Scholarship; A.A.A. is supported by a NHMRC project grant, Victorian Cancer Agency Clinical Research Fellowship and Astellas Investigator-initiated grant.
Conflicts of interest
E.M.K. has received honorarium from Janssen; research funding from Astellas Pharma and AstraZeneca; travel/accommodation from Astellas Pharma, Pfizer, and Ipsen. A.A.A. is a consultant for Astellas, Janssen and Novartis; is on the speakers bureau for Astellas, Janssen, Novartis and Amgen; has received honorarium from Astellas Pharma, Janssen, Novartis, Tolmar, Amgen, Pfizer and Telix; on the member of the scientific advisory board for Astellas, Novartis, Sanofi, AstraZeneca, Tolmar, Pfizer and Telix; research funding from Astellas Pharma and Merck Serono.
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