An Update on Non Metastatic Castration-Resistant Prostate Cancer

Androgen deprivation therapy (ADT) is the backbone of therapy for advanced prostate cancer patients who have failed primary interventional therapy.  Most of these patients will develop, through a potential multitude of resistance mechanisms, neoplastic cellular progression, and proliferation which subsequently leads to PSA relapse.2 Castration-resistant prostate cancer (CRPC), a rising PSA with castrate levels of testosterone alongside no radiographic imaging findings with conventional imaging (CT/Bone scans) are designated as non-metastatic (nmCRPC), or sometimes as M0CRPC.

The US annual incidence of nmCRPC has not been accurately established. The metastatic castration-resistant prostate cancer (mCRPC) patient population evolves from patients initially diagnosed metastatic hormone-sensitive prostate cancer (mHSPC), possibly ranging from 4-6 % of the approximate 160,000 newly diagnosed US patients, yet this same group of patients represents a disproportionally higher contribution the percentage of mCRPC patients. That said, most would agree that the majority of eventual mCRPC patients herald from the PSA relapse disease state. Large data registries and retrospective observational studies of nmCRPC have correlated higher grade International Society of Urological Pathology (ISUP) stage, and a more rapid PSA doubling time to both earlier onset on nmCRPC as well as the development of metastasis.18 Prior to 2018, there was no level one evidence FDA-approved therapy for nmCRPC. Hence, most nmCRPC patients were managed expectantly or with second-line (vintage) hormonal manipulations, e.g. first generation lutamides, estrogens, steroids, or ketoconazole.

At ASCO GU, 2018,  two landmark studies reported their results  from their randomized, double-blind, placebo-controlled, phase III global trials: SPARTAN (A Study of Apalutamide (ARN-509) in Men With Non-Metastatic Castration-Resistant Prostate Cancer) and PROSPER (Safety and Efficacy Study of Enzalutamide in Patients With Nonmetastatic Castration-Resistant Prostate Cancer) trials. 3,7 In both of these placebo-controlled studies, next-generation androgen receptor inhibition, utilizing either apalutamide or enzalutamide, extended metastasis-free survival (MFS) by approximately 2 years (median) when added to ADT in men with documented nmCRPC and whose  PSA doubling times of <10 months were confirmed.3,7 These trial results led to the FDA approvals of apalutamide (ERLEADA™) and enzalutamide (XTANDI®) in 2018, a new regulatory endpoint had been accepted by the FDA, metastasis-free survival (MFS), and an unmet need of therapy, see index case 1 AUA CRPC guidelines, had now been answered. 3,4,7,8

The efficacy of enzalutamide has been well established for CRPC patients and assuredly, there are numerous ongoing trials further investigating both apalutamide and enzalutamide throughout the prostate cancer disease continuum.4 As a result of these trials, as well as next-generation imaging (NGI) techniques, which improve our diagnostic accuracy and acumen, with modalities such as positron-emission tomography (PET) with targeted radiotracers, e.g., 68Ga-labelled prostate specific membrane antigen (PSMA), C-11 choline, and  F-18 fluciclovine, these NGI techniques have demonstrated higher sensitivity and arguably enhanced accuracy for the detection of bone and soft tissue metastases compared with conventional technetium-99m bone scans, computed tomography (CT), and magnetic resonance imaging (MRI).13,14, 4 Consequently, some CRPC patients who would have been categorized as non-metastatic on conventional imaging will be classified as M1 on NGI. This may be the case for many patients within the SPARTAN and PROSPER trials, especially given the inclusion criteria for a rapid PSA doubling time. Nonetheless, like all prior CRPC phase III trials which have led to therapeutic approvals, conventional imaging was and still remains the gold standard; however, the duration of this imaging ‘gold standard’ may be soon approaching obsolescence.

Additional data on the efficacy of apalutamide and enzalutamide have been made available since their respective NEJM publications of their results from both SPARTAN and PROSPER. At ASCO GU this year, researchers reported that apalutamide significantly delayed time to further progression or death on subsequent therapy after patients stopped treatment because of disease progression (HR, 0.50 vs. patients who stopped placebo; 95% CI, 0.39-0.63; P < .0001).23 Enzalutamide, for its part, induced PSA responses (defined as at least a 50% decrease in baseline PSA) in more than 90% of patients in PROSPER, and PSA response was associated with a decreased risk of bowel, hormonal, and urinary symptoms.17 Enzalutamide also significantly delayed symptom worsening, pain progression, and declines in functional status,21 and also significantly lowered the risk of metastasis or death regardless of specific treatment history (surgery, radiation, or bone-targeting therapy).19

The overall survival (OS) benefit from these approved nmCRPC therapies is awaiting more death events before an OS endpoint of comparison to the respective placebo-controlled treatment arms can be analyzed; hopefully, we may have an interpretation of the OS findings before 2020.

Many nmCRPC patients are elderly, however one defines ‘elderly’, with the median age of enrolled patients on the trials being  in their mid-70s, and thus many will have attendant comorbidities  which augurs that the safety and tolerability of nmCRPC therapy must be an important concern in an ostensibly asymptomatic population, albeit for the effects of chronic ADT.. Both apalutamide and enzalutamide in addition to ADT may increase the risk of fatigue, falls, and fractures.4,6,7 Also reported recently, an analysis of all four phase 3, placebo-controlled trials of enzalutamide in men with CRPC (PROSPER, PREVAIL, AFFIRM, and 9785-CL-0232) linked enzalutamide with a two to three-fold higher rates of falls (9.1%) and fractures (10.2%) versus placebo.20

Enzalutamide and apalutamide are associated with an increase in the risk of certain cardiovascular events. In the aggregate study of the four enzalutamide trials, this medication was associated with a low incidence of treatment-emergent ischemic heart disease and cardiac death.20 Although rates were low (2.6% and 0.4%, respectively), they were two to four times higher than in the placebo group.20 Finally, in SPARTAN, apalutamide was associated with an increase in all-grade and grade 3-4 hypertension, and four patients who received apalutamide died of myocardial infarction, cardiorespiratory arrest, or cerebral hemorrhage, versus only one comparable death in the placebo group.7,22

These data are not surprising—ADT can cause or exacerbate cardiovascular disease,11 and augmenting anti-androgen therapy can intensify this risk.7,12 Rates of major adverse cardiovascular events on these treatments will likely remain low but may be higher outside the carefully controlled settings of clinical trials. Discussing the benefits and risks of next-generation antiandrogen therapy with patients, ensuring initial and ongoing cardiometabolic monitoring, and educating and referring patients to resources to help them implement risk-reduction measures (dietary changes, exercise, and optimization of care for comorbid cardiovascular disease, diabetes, or the metabolic syndrome) are essential to the minimization of complications.  On an individual patient basis, attempts can be made to balance and assess performance status, frailty, and comorbidity burdens with regard to their risk of disease progression.

Monitoring treatment response is nmCRPC is predicated upon PSA response, patient tolerability and imaging progression.  PSA is a downstream biomarker effect of androgen receptor signaling and an indirect indicator of tumor AR signaling activity, but a decline or rise in PSA may not always correlate with tumor cell response, especially in poorly differentiated tumors.13

Hence, we need additional measures and predictors of treatment response. Researchers are evaluating histologic, molecular, and genomic data for this purpose and it is certainly hoped that future data might better inform our treatment selection, sequencing, and intensity of monitoring based on the risk of relapse or progression. One approach is to use “molecularly detectable residual disease”—that is, circulating tumor material.13

Finally, only a few trials of next-generation antiandrogen therapies for nmCRPC have utilized an active comparator, which has drawn criticism from some reviewers.10 As we continue to develop and hone treatments for high-risk nmCRPC, we can expect trials with active comparators and those that combine next-generation anti-androgen inhibition with highly targeted treatments guided by NGI. I look forward to reviewing and sharing these findings as part of the nmCRPC Center of Excellence.

Written by: Neal Shore, MD, Medical Director of the Carolina Urologic Research Center, Atlantic Urology Clinics, Myrtle Beach, South Carolina.

References
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23. Small, Eric J. “ASCO GU 2019: Updated Analysis of Progression-Free Survival with First Subsequent Therapy and Safety in the SPARTAN Study of Apalutamide in Patients with High-Risk Nonmetastatic Castration-Resistant Prostate Cancer.” UroToday, 15 Feb. 2019, www.urotoday.com/conference-highlights/asco-gu-2019/asco-gu-2019-prostate-cancer/110262-asco-gu-2019-updated-analysis-of-progression-free-survival-with-first-subsequent-therapy-and-safety-in-the-spartan-study-of-apalutamide-in-patients-with-high-risk-nonmetastatic-castration-resistant-prostate-cancer.html