Emerging Categories of Disease in Advanced Prostate Cancer and Their Therapeutic Implications

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.

Introduction

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).[3]

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.[10]

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).[11] 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).[12]

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).[16]

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.[13]

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.[17] 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.[17] 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.

Emerging Subsets of Metastatic Castration-Resistant Prostate Cancer

The updated PCWG3 guidelines provide a new reference framework for treatment in the metastatic castration-resistant setting. In this new framework, the arbitrary distinction between pre- and post-docetaxel treatment has been removed, and the focus has shifted towards deriving maximal clinical benefit from each successive line of therapy administered.[2] Certain clinical factors, including the presence of visceral metastases, prior therapeutic exposure and treatment response, and the presence of bone pain or other cancer-related symptoms, can help guide clinicians in choosing the most appropriate systemic therapy for their patients with metastatic castration-resistant disease. One such algorithm that can help guide the choice of initial and subsequent therapy in metastatic castration-resistant prostate cancer is shown in Figure 2. It is important to recognize, however, that there is no validated optimal sequence of therapy in this setting.

Recent insights into the biology of metastatic castration-resistant prostate cancer have provided the opportunity to further delineate subcategories of disease with potentially significant therapeutic implications. These categories are not necessarily mutually exclusive, nor are they inclusive of the entire spectrum of metastatic castration-resistant prostate cancer, but rather reflect emerging categories of disease arising in treatment-resistant settings. These emerging categories include: 1) abiraterone- and/or enzalutamide-resistant metastatic castration-resistant prostate cancer, 2) treatment-emergent neuroendocrine prostate cancer, and 3) metastatic castration-resistant prostate cancer with alterations in the DNA damage repair pathway (Figure 3).

Abiraterone- and/or enzalutamide-resistant prostate cancer

Both abiraterone, a potent CYP17 inhibitor of androgen synthesis, in combination with low-dose prednisone, and enzalutamide, a second-generation androgen receptor antagonist, have been shown in prospective randomized phase III studies to lead to significant improvement in radiographic progression-free survival and OS compared with placebo when used either before or after chemotherapy in metastatic castration-resistant prostate cancer.[4,5] Although abiraterone and enzalutamide have been transformative in their ability to improve outcomes in men with metastatic castration-resistant prostate cancer, the development of refractoriness to these therapies frequently heralds a shift in the biology of the cancer toward a more aggressive phenotype. In particular, metastatic castration-resistant prostate cancer for which treatment with abiraterone or enzalutamide has not produced any decline in PSA level-termed “primary or refractory disease”-portends a particularly aggressive disease course.[20] The development of methods to delay or reverse resistance to androgen signaling inhibitors would potentially translate to a significant improvement in outcomes for patients with metastatic castration-resistant prostate cancer.

Sequential treatment with abiraterone following disease progression with enzalutamide, or vice versa, frequently leads to cross-resistance between therapies.[21-24] Although the data are largely from retrospective series, various studies have consistently demonstrated a low response rate and short duration of response to sequential therapy with abiraterone or enzalutamide after frontline therapy with the other of these two agents (≥ 50% PSA declines in < 30% of patients, and average duration of response < 6 months), outcomes that are significantly worse than those seen with frontline therapy in patients who are both abiraterone- and enzalutamide-naive. The clinical phenomenon of cross-resistance may be mediated in part by the development of constitutively active splice variants of the androgen receptor-in particular androgen receptor splice variant 7 (AR-V7), which has been shown to predict for resistance to therapy with androgen pathway inhibitors.[25]

Nonconventional approaches to ablating the androgen signaling pathway, including use of diethylstilbestrol, as well as high-dose testosterone alternating with medical castration (bipolar androgen therapy), may have activity in metastatic castration-resistant prostate cancer resistant to prior treatment with abiraterone and/or enzalutamide.[26,27] Diethylstilbestrol in particular was extensively studied in metastatic castration-resistant prostate cancer in the pre–abiraterone/enzalutamide treatment era, and demonstrated modest antitumor activity, although it does carry an increased risk of thromboembolic events even at lower doses.[27,28]

Multiple investigations are underway to improve on outcomes seen with sequential administration of abiraterone, enzalutamide, and other androgen pathway inhibitors currently in development, including apalutamide. In particular, multiple ongoing trials are evaluating whether combining androgen synthesis inhibitors with androgen receptor antagonists can improve outcomes over those obtained with sequential therapy, given the significant cross-resistance associated with the latter approach. In addition, multiple targeted therapies are in clinical development to potentially reverse resistance to androgen pathway inhibitor therapy. Among the latter are master transcriptional regulators-termed “bromodomain inhibitors”-which have been shown to significantly downregulate the expression of AR-V7, inhibition of cyclin-dependent kinases, and N-terminal domain inhibitors of the androgen receptor.[29]

Treatment-emergent neuroendocrine prostate cancer

Neuroendocrine prostate cancer, including pure small-cell cancer, is very rarely present at the time of diagnosis (< 1% of cases), but may be an increasingly commonly observed phenomenon as a treatment-emergent adaptive response under the pressure of intense androgen signaling inhibition.[30] The precise prevalence of this entity in the setting of metastatic castration-resistant prostate cancer is not known with certainty, but recent prospective studies in which tumor tissue from patients with metastatic castration-resistant disease has been acquired have detected pure small-cell cancer in 10% to 15% of evaluable biopsies, a striking prevalence when considering the rarity of this disease entity in the de novo setting.[30,31] Whether the prevalence of treatment-emergent neuroendocrine prostate cancer will increase with the earlier application of therapies in the hormone-sensitive setting (eg, docetaxel chemotherapy or androgen signaling inhibitors) is not currently known but is the subject of ongoing clinical investigations.

The development of treatment-emergent neuroendocrine prostate cancer is associated with a significantly shorter survival and limited response to androgen receptor pathway–directed therapies. The NCCN guidelines recommend tumor biopsy in cases where small-cell neuroendocrine carcinoma is suspected clinically, based on such factors as presence of visceral metastases, predominantly lytic bone metastases, disease burden on scans out of proportion to serum PSA level, and elevated serum markers of neuroendocrine differentiation (eg, chromogranin, neuron-specific enolase).[1] In cases where pure small-cell prostate cancer is detected, platinum-based chemotherapy achieves tumor regressions in the majority of patients, but duration of response is limited. For example, in one prospective study of carboplatin plus docetaxel, followed by cisplatin plus etoposide, in prostate cancer patients with aggressive variant disease defined on the basis of the clinical factors identified earlier, the objective response rate was 33%-however, median survival was only 16 months.[32] Other cytotoxic chemotherapies also have antitumor activity and palliative benefit in aggressive phenotype prostate cancer; for example, prior studies indicate that metronomic cyclophosphamide and mitoxantrone have activity in this setting.[33,34]

Current efforts are focused on the development of novel therapeutic targets that can improve disease outcomes for patients with neuroendocrine prostate cancer, a disease entity that is likely growing in prevalence. Concurrent development of noninvasive and objective measures of neuroendocrine differentiation, including analysis of circulating tumor cells, molecular imaging, and genomic analysis of tumors, are underway to aid in the detection of this high-risk subset of prostate cancer.

Somatic and germline mutations in the DNA damage repair pathway

One of the most important observations made regarding metastatic castration-resistant prostate cancer in the past few years is that significant genomic heterogeneity underpins the variable course and varying therapeutic responses observed in this disease. Among the genomic alterations seen in metastatic castration-resistant prostate cancer are mutations in genes in the DNA damage repair pathway, including BRCA1, BRCA2, ATM, RAD51, and CHEK2, among others.[35] Biallelic loss of function of one of the genes encoding a protein in the DNA damage repair pathway may be present in approximately 20% of all metastatic castration-resistant prostate tumors. This observation has direct therapeutic implications, as a recent prospective phase II study of the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib demonstrated a high composite (PSA, circulating tumor cell, and/or radiographic) response as a single agent in patients with metastatic castration-resistant prostate cancer who harbored a mutation in a DNA damage repair pathway gene.[36] Platinum-based chemotherapy may also be a particularly efficacious treatment strategy in this patient population, and further prospective studies of both PARP inhibitors and platinum-based chemotherapy are underway. Beyond those in whom specific mutations in the DNA damage repair pathway can be detected, there may exist a larger pool of patients with metastatic castration-resistant prostate cancer who have a “BRCAness” signature and who would potentially benefit from PARP inhibitors and/or platinum-based chemotherapy.[37] The costs and feasibility of performing metastatic tumor biopsies, as well as the sequencing and interpretation of results, represent a hurdle for widespread implementation. Analysis of circulating tumor DNA for evidence of somatic alterations is an alternative strategy in patients without accessible lesions or with clinical sites where metastatic tumor biopsy, particularly of bone metastases, is less feasible. There are commercial assays available for somatic testing of mutations (eg, FoundationOne®, Guardant360®) that may help identify such mutations.

In addition to serving as a predictive biomarker of response, genomic alterations in DNA damage repair pathway genes may also serve as a negative prognostic factor associated with worse outcomes with ADT, including with both LHRH analogs and secondary androgen pathway inhibitors such as abiraterone. This observation requires prospective validation but may ultimately have implications both for treatment selection and clinical trial study design and risk stratification.

Perhaps equally striking is the recent observation that germline mutations in DNA damage repair pathway genes, including BRCA2, ATM, CHEK2, and PALB2, among others, previously thought to occur in < 5% of all patients, were detected in 11.8% of 692 screened patients with metastatic castration-resistant prostate cancer, regardless of family history of cancer.[38] The prevalence of the germline alterations suggests that perhaps more routine screening of patients with metastatic castration-resistant disease is warranted, and updates to consensus practice guidelines are expected. Given that pathogenic germline mutations have an estimated prevalence in patients with metastatic castration-resistant prostate cancer of approximately 10%, regardless of patients’ family history, it may be appropriate to screen all patients with metastatic castration-resistant prostate cancer for the presence of these mutations.

Conclusion

Advanced prostate cancer is a heterogeneous disease, in both the hormone-sensitive and castration-resistant settings. In the metastatic hormone-sensitive setting, the extent of metastatic disease is currently a key factor for guiding patient management. The addition of docetaxel chemotherapy to standard ADT is currently the standard of care for those with extensive metastatic disease. In the castration-resistant setting, there is an increasing appreciation of the biological heterogeneity underpinning the development of abiraterone- and/or enzalutamide-resistant prostate cancer. Emerging subcategories of castration-resistant disease that have therapeutic implications include treatment-emergent neuroendocrine prostate cancer and metastatic castration-resistant prostate cancer with either tumor or germline alteration in DNA damage repair pathway genes. Further investigation is needed to identify new therapeutic targets and to optimize the sequence of therapies for these high-risk disease subgroups.

Financial Disclosure:The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.

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