The treatment of advanced prostate cancer has changed significantly in the last decade, as a result of the introduction of multiple new systemic therapies that have had a positive impact on treatment outcomes. The increasing number of therapies, along with new insights into the biological underpinnings of prostate cancer, have led to a growing appreciation for the heterogeneity of the disease and an awareness of emerging subcategories that have direct therapeutic implications for the practicing clinician. In the metastatic hormone-naive setting, the extent of metastatic disease visible on scans can serve as a useful measure to guide treatment decisions; the addition of docetaxel chemotherapy to hormonal therapy has significant benefit in patients whose scans show more extensive disease. In the castration-resistant setting, abiraterone and enzalutamide have both had a transformative impact; however, the emergence of resistance to these therapies often heralds a more aggressive phenotype. Emerging clinically relevant subcategories include disease that demonstrates treatment-emergent neuroendocrine differentiation, as well as tumors with somatic and/or germline alterations in the DNA repair pathway. Identification of these subtypes has direct clinical relevance with regard to the potential benefit of platinum-based chemotherapy, poly (ADP-ribose) polymerase inhibitors, and likely further therapies as new therapeutic targets are identified in these groups.
Prostate cancer represents a clinically and biologically heterogeneous disease entity, ranging from indolent localized tumors that do not result in morbidity or mortality, to aggressive cancers that metastasize and ultimately lead to patient demise. In the localized disease setting, treatment guidelines (eg, National Comprehensive Cancer Network [NCCN], American Society of Clinical Oncology) provide guidance regarding risk factors for metastatic spread—including Gleason grade, serum prostate-specific antigen (PSA) level, and TNM stage—which can be used (along with disease characteristics and life expectancy) to determine whether definitive treatment or active surveillance is the more appropriate strategy.[1,2] In the recurrent/metastatic setting, the “disease states model” of prostate cancer developed by the Prostate Cancer Working Group 3 (PCWG3) provides a useful framework for patient management. This model appropriately regards the development of metastases and castration resistance as distinct events in a patient’s disease course, with the various treatment options organized by disease state (Figure 1).
Now that multiple therapies have been approved by the US Food and Drug Administration for use in metastatic castration-resistant prostate cancer, including abiraterone, enzalutamide, radium-223, sipuleucel-T, mitoxantrone, docetaxel, and cabazitaxel—with more treatments likely to follow—there is a clinical need to move beyond the treatment framework provided by the NCCN and PCWG guidelines and to take into better account the vast clinical and biological heterogeneity underpinning the varying treatment responses observed with these agents.[4-9] As this is done, distinct subsets of advanced prostate cancer are emerging that have direct implications for patient management. In this article, we look at both metastatic hormone-sensitive and metastatic castration-resistant disease, and we highlight several of the emerging categories of advanced prostate cancer that have direct implications for patient management.
Metastatic Hormone-Sensitive Prostate Cancer
The classic disease states model regards metastatic hormone-sensitive prostate cancer as a somewhat uniform disease entity, for which the standard of care has traditionally included primary androgen deprivation therapy (ADT) with a luteinizing hormone-releasing hormone (LHRH) analog, with or without the addition of an anti-androgen therapy. Primary ADT achieves objective and PSA responses in the vast majority of patients; however, the duration of response is variable, ranging from as short as 3 to 6 months to more than 5 years.
Several clinical factors have prognostic utility in predicting long-term outcomes in patients receiving ADT, including nadir PSA level after induction treatment, and extent of metastatic disease.[11,12] In one retrospective analysis of 1,395 patients enrolled in a prospective phase III study of intermittent vs continuous ADT in metastatic hormone-sensitive prostate cancer, a nadir PSA level < 0.2 ng/mL after 6 to 8 months of ADT was associated with a median overall survival (OS) of 75 months, compared with 13 months for those who had a PSA nadir > 4 ng/mL after induction treatment (P < .001). Metastatic tumor burden, with extensive disease defined as four or more bone metastases (including one or more outside the axial column) and/or the presence of visceral metastases, has also been shown to have an impact on outcomes of primary ADT in the setting of metastatic hormone-sensitive disease. For example, in a previous randomized phase III study of bilateral orchiectomy with or without flutamide in patients with metastatic hormone-sensitive prostate cancer, those with extensive disease on scans had a significantly shorter survival than those with limited disease (median OS, 52.1 months vs 28.5 months; P < .05).
Three phase III prospective clinical trials have investigated whether the addition of docetaxel chemotherapy to ADT improves outcomes compared with ADT alone, with varying results (Table).[13-15] The Eastern Cooperative Oncology Group E3805 (CHAARTED) study prospectively stratified patients by limited vs extensive metastatic disease, as defined previously. In patients with extensive metastatic disease, there was a significant improvement in OS with the addition of docetaxel to ADT as compared with ADT alone (median OS, 51.2 months vs 34.4 months; P < .0001). In contrast, in those with a limited volume of disease, at the latest follow-up reported to date, there was no significant improvement in outcomes (median OS, 63.5 months vs not reached; hazard ratio [HR], 1.04; P = .86).
In patients with hormone-sensitive prostate cancer and an extensive volume of metastatic disease, the magnitude of the survival benefit observed with the addition of docetaxel to primary ADT compares favorably with the survival advantage afforded by docetaxel (vs other chemotherapy regimens) in the metastatic castration-resistant setting, and suggests that earlier administration of chemotherapy translates to a greater survival advantage. This may in part reflect the fact that many patients with metastatic castration-resistant prostate cancer never receive chemotherapy during the course of their disease; indeed, among the patients randomized to ADT alone in E3805, of the 287 patients who had developed metastatic castration-resistant prostate cancer by the time of initial study publication, only 137 (48%) had received docetaxel chemotherapy.
Two other phase III studies have investigated the addition of docetaxel chemotherapy to ADT: the STAMPEDE and the GETUG-AFU 15 studies.[14,15] The STAMPEDE study population included an admixture of patients with locally advanced disease, patients with biochemically recurrent disease, and patients with metastatic disease; it demonstrated a significant improvement in OS with the addition of docetaxel in the overall study population, as well as in the subgroup of patients with metastatic disease (61% of patients) (Table). In contrast, GETUG-AFU 15 enrolled only patients with metastatic disease, and failed to demonstrate a survival benefit for the addition of docetaxel chemotherapy (median OS, 60.9 months vs 46.5 months for ADT alone; HR, 0.9; 95% CI, 0.7–1.2; P = .4). However, the GETUG-AFU 15 study was likely underpowered to detect OS differences. Neither GETUG-AFU 15 nor STAMPEDE prospectively stratified patients by extent of metastatic disease at the time of study entry, an important distinction between these two trials and the CHAARTED study.
Taken together, the results of these three studies have transformed the management of metastatic hormone-sensitive prostate cancer, particularly in patients with extensive metastases on systemic imaging. In this setting, in patients fit to receive chemotherapy, the current standard of care is the administration of docetaxel chemotherapy for up to 6 cycles in conjunction with ADT. The management of limited-stage or oligometastatic disease is more individualized, and in the absence of prospective data confirming a survival benefit for the addition of docetaxel chemotherapy in this latter setting, it cannot be routinely recommended for all patients and instead requires discussion with each individual patient.
Ongoing studies are investigating whether other combinatorial therapy may also improve treatment outcomes for patients with metastatic hormone-sensitive prostate cancer. Many studies are utilizing the paradigm followed by the phase III studies of docetaxel outlined previously, in which agents proven to have a survival advantage in the metastatic castration-resistant setting are being evaluated in combination with ADT earlier in the disease course to investigate whether they have a positive impact on long-term disease outcomes when used upfront. These studies include investigations of abiraterone, enzalutamide, and another second-generation androgen receptor antagonist (apalutamide), as well as bone-targeting agents, including radium-223—in combination with primary ADT. Over the next several years, the results of these studies may further change the treatment paradigm in the metastatic hormone-sensitive setting.
With regard to the management of oligometastatic disease (variably defined as fewer than 3 to 5 metastatic lesions), one of the unanswered questions is the role of multimodality treatment (eg, radiation and/or surgical resection in combination with systemic ADT). The current standard of care is to selectively use focally directed therapies palliatively at metastatic sites that are causing an undue symptom burden or that are found in a critical location that may lead to significant morbidity (eg, a prostatic mass that is causing or that may cause urinary obstruction, or an epidural extension of tumor). In the absence of these types of metastatic lesions, definitive treatment of the primary tumor in the metastatic setting, as well as the application of focal therapy to metastatic lesions, has not been routinely performed.
Large retrospective analyses have provided preliminary evidence to suggest that there may be a therapeutic benefit to definitive treatment of the primary tumor in the setting of metastatic prostate cancer, even in the absence of a need for symptom palliation. In one recent review of over 8,000 patients with M1 disease from the Surveillance, Epidemiology, and End Results database, stratified on the basis of whether they did or did not receive local treatment, those at lower risk (≤ 40% risk) for cancer-specific mortality in the ensuing 3 years appeared to derive the most benefit from local treatment, after adjustment for other prognostic variables in the M1 setting. The biological rationale for treatment of the primary tumor and/or focal treatment of metastatic sites includes: 1) decreased seeding of metastatic sites, 2) potentiation of immunologic response against the tumor, 3) synergistic activity with concurrent ADT, and 4) prevention of future comorbidity related to locoregional disease progression. The emerging clinical availability of more sensitive radiotracers for the detection of prostate cancer lesions, including those used in choline- and prostate-specific membrane antigen–based positron emission tomography imaging,[18,19] has provided further impetus for investigating treatment of the primary tumor and metastatic sites with multimodality therapy in patients with oligometastatic disease. At the current time, in the absence of prospective data, local treatment of an asymptomatic or minimally symptomatic primary tumor and/or focal treatment of asymptomatic oligometastatic sites of disease cannot be routinely recommended but is being actively investigated in multiple randomized studies. Whether the optimal management of oligometastatic disease with or without an untreated primary tumor differs in the hormone-sensitive vs the castration-resistant setting is likewise unknown but also is currently being investigated in clinical studies.
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