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(UroToday.com) In a standalone session at this year’s Society of Urologic Oncology (SUO) virtual annual meeting, titled Understanding the Evolving Therapeutic Landscape in Prostate Cancer: How to Leverage the Latest Advances and Strategies to Optimize Patient Outcomes, Dr Alicia Morgans covered data on the rapidly changing landscape of systemic therapy for patients with advanced prostate cancer, including, in particular, data from recent studies examining modern treatment options in non-metastatic castration-resistant prostate cancer. (nmCRPC), metastatic hormone sensitive prostate cancer (mHSPC) and metastatic castration-resistant prostate cancer (mCRPC).
Dr. Morgans began with a presentation examining the changing treatment options for patients with nmCRPC and mHSPC. Focusing first on the nmCRPC space, Dr. Morgans highlighted data from Dr. Matthew Smith’s work using the control arm of a randomized controlled trial of denosumab in this disease space that clearly demonstrated both prognostic value and absolute prostate specific antigen. (PSA) that PSA doubling time in risk stratification with respect to the development of metastases. As highlighted in this figure, as both absolute PSA increases and PSA doubling time decreases, the risk of metastasis increases. Furthermore, the relationship between PSA doubling time and metastatic risk appeared to be markedly non-linear with a dramatic increase in risk for patients with PSA doubling time of less than 8 months.
These data have stimulated the study of new therapeutic approaches in this disease space. In particular, three new generation androgen receptor inhibitors, enzalutamide, apalutamide and darolutamide, have been studied in this disease space. While enzalutamide and apalutamide are structurally very similar, darolutamide is somewhat unique and, clinically, this is manifested by low blood brain barrier penetration.
Dr Morgans then highlighted data from three phase III randomized controlled clinical trials of these agents (enzalutamide PROSPER, apalutamide SPARTAN, and darolutamide ARAMIS). Overall, these studies were very similar, employing key eligibility criteria of nmCRPC with a baseline PSA of at least 2 ng / mL and a PSA doubling time of no more than 10 months. In particular, the determination of non-metastatic disease was carried out on the basis of conventional imaging using bone scintigraphy and computed tomography. Additionally, SPARTAN allowed the inclusion of patients with pelvic nodal up to 2 cm. In addition, ARAMIS allowed patients with a history of seizures or the use of drugs predisposing to seizures.
Evaluating the primary endpoint of metastasis-free survival, each of the three studies demonstrated statistically significant improvements with the use of next generation androgen receptor inhibitors compared to placebo, with absolute benefits of metastasis-free survival of 22-24 months .
Again, as with the inclusion criteria, the evaluation of the outcome for the development of metastases was based on bone scan and CT. Notably, metastasis-free survival (MFS) is a new endpoint developed by the study sponsors and the United States Federal Drug Administration (FDA) that was subsequently used for the approval of these agents.
Then assessing the key secondary endpoint of overall survival, Dr Morgans again stressed that all three of these agents demonstrated improvement over placebo, regardless of the treatment given afterwards and despite the considerable switch from placebo to active agents. Therefore, he concluded that these data demonstrate that there is a significant survival benefit in early intensification of treatment in this patient population.
Dr. Morgans then moved on to a discussion of the toxicity of these treatments. He stressed that due to the differences between the studies, no comparisons should be made between the active treatment arms but, instead, conclusions should be drawn by looking at the magnitude of the difference between each active treatment and the comparison arm in the associated study . Taking this approach, he concluded that the data suggest that darolutamide may be associated with slightly lower overall rates of adverse events. Furthermore, apalutamide and enzalutamide were particularly associated with greater effects on fatigue, hypertension and falls, compared to their comparison with placebo, compared to darolutamide. Again, he stressed that we lack, to date, direct comparative data for these agents.
Summarizing the available data for next-generation androgen receptor inhibitors in nmCPRC, Dr. Morgans pointed out that the available studies provide strong support for FDA approval of these agents in this disease space, given the improvements in MFS. and overall survival (OS), as well as a favorable risk-benefit ratio and maintenance of health-related quality of life during therapy. Importantly, while the studies had specific criteria for the absolute doubling time of PSA and PSA, FDA approval and associated labeling did not impose these limitations.
Moving on to the role of novel therapeutic approaches in mHSPC, Dr. Morgans first went to the recently presented long-term update of abiraterone’s role in this pathological space from the STAMPEDE study. This analysis was based on the metastatic subgroup of the STAMPEDE cohort and demonstrated a highly significant and prolonged benefit in terms of overall survival, failure-free survival and skeletal-related event-free survival. Notably, about one quarter of all patients randomized to abiraterone were still on study therapy 6 years after randomization.
Dr. Morgans then moved on to discuss the role of enzalutamide in this disease space, starting first with the ARCHES study. The methodology of the ARCHES study was previously reported in their presentation and initial publication. To summarize, patients with mHSPC were randomized 1: 1 to enzalutamide (160 mg / day) + ADT or placebo + ADT. Randomisation was stratified by disease extent (volume) and previous docetaxel treatment and patients were followed for radiographic progression-free survival (primary endpoint) and overall survival (secondary endpoint). To date, radiographic progression-free survival (rPFS) data are available that demonstrate a statistically significant benefit from the use of enzalutamide.
Dr Morgans then highlighted two interesting post-hoc analyzes of the ARCHES study. The first of these demonstrated that the greatest benefit with the use of enzalutamide was seen for patients with lymph node disease and much less benefit was realized among those with visceral disease.
The second post-hoc analysis evaluates the efficacy of enzalutamide based on the baseline PSA level and demonstrated comparable efficacy in patients with baseline PSA <0,2 mcg / L, 0,2-4 mcg / L e> 4 mcg / L. In terms of safety, the ARCHES study demonstrated no new safety signals compared to previous enzalutamide studies and found that patients could maintain health-related quality of life while on therapy.
The second study to evaluate enzalutamide in this disease space that highlighted is ENZAMET. There are a number of noteworthy features of this study: randomization was stratified by disease volume; early use of docetaxel (concomitantly with enzalutamide) was permitted and included as a stratification factor of randomization; and instead of placebo in the control, the patients received a first generation anti-androgen, namely, flutamide, nilutamide, or bicalutamide.
Overall, ENZAMET demonstrated a significant improvement in overall survival with the use of enzalutamide compared to first generation anti-androgens, with a hazard ratio of 0.67 (95% confidence interval 0.52 to 0, 86). Dr. Morgans then highlighted important pre-specified subgroup analyzes examining the role of enzalutamide based on docetaxel use. This analysis showed that although there was an improvement in progression-free survival among patients who received both docetaxel and enzalutamide compared to those who received docetaxel and first generation anti-androgens, there was no survival benefit. global with an almost overlapping of the curves. However, in patients without docetaxel use (who also had lower disease volumes), there were significant improvements in both progression-free and overall survival.
Therefore, he concluded that a “triplet” approach with androgen deprivation therapy (ADT), docetaxel and enzalutamide is clearly not beneficial, although the data remain somewhat immature. In particular, in this group, the addition of enzalutamide was associated with an increase in docetaxel-related toxicity, including neuropathy in particular.
Dr. Morgans then moved on to discuss the role of apalutamide in mHSPC based on data from the TITAN study. This study was similar in design to the others and included previous use of docetaxel as a stratification factor.
The use of apalutamide in mHSPC was associated with improvements in both PFS (hazard ratio 0.48, 95% confidence interval 0.39 to 0.60) and overall survival (hazard ratio 0.67, 95% confidence interval from 0.51 to 0.89). Additionally, toxicity was manageable and health-related quality of life was maintained throughout treatment.
As this presentation drew to a close, Dr. Morgans highlighted ongoing ARASENS studies that have finished enrollment and are now waiting to be read, specifically addressing the role of “triplet escalation” by comparing ADT + docetaxel with or without the addition of darolutamide.
In conclusion, Dr. Morgans pointed out that initial treatment with an intensified regimen that includes abiraterone and prednisone, apalutamide, enzalutamide, or docetaxel is now the standard of care for patients with mHSPC. Treatment decisions should consider the patient’s comorbidities and preferences. Furthermore, the lack of prospective data and informative biomarkers makes treatment sequencing difficult.
Presented by: Alicia Morgans, MD, MPH is Associate Professor of Medicine in the Division of Hematology / Oncology at the Feinberg School of Medicine at Northwestern University in Chicago, Illinois.
Written by: Christopher JD Wallis, MD, Ph.D., Instructor in Urology, Vanderbilt University Medical Center, Nashville, Tennessee @WallisCJD on Twitter at the 2020 Society of Urologic Oncology Annual Meeting – December 2-5, 2020 – Washington, DC
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HIS 2020: Understanding the Evolving Landscape of Metastatic Castration-Resistant Prostate Cancer Treatment: How to Leverage the Latest Advances and Strategies to Optimize Patient Outcomes – Evan Yu
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