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Novel Hormone Therapy and Coordination of Care in High-Risk Biochemically Recurrent Prostate Cancer - Beyond the Abstract

Biochemical recurrence (BCR) has been defined as rising prostate-specific antigen (PSA) levels after definitive therapy (e.g., radical prostatectomy or radiotherapy) without evidence of metastasis by conventional imaging (i.e., bone scan and computed tomography).1

Novel Hormone Therapy and Coordination of Care in High-Risk Biochemically Recurrent Prostate Cancer - Beyond the Abstract



Between 20–50% of patients with prostate cancer will experience BCR within 10 years of definitive therapy.2-4 Patients with high-risk BCR have an increased likelihood of distant metastasis and prostate cancer-specific and overall mortality.5 Managing high-risk BCR is challenging due to disease heterogeneity and the need for risk stratification.6 In addition, there is a lack of consensus among experts regarding the appropriate definition of high-risk BCR and the landscape of treatments and diagnostic/imaging modalities for this disease is highly complex and rapidly evolving. In this review, we discuss challenges associated with BCR management and explore the potential benefits and opportunities of multidisciplinary care (MDC) and treatments based on optimizing risk stratification.7

The risk of metastatic progression among patients with BCR is determined by clinicopathologic factors such as a short interval to biochemical failure, high Gleason score, and short PSA doubling time.5 Commercially available molecular biomarkers (e.g., Decipher Prostate Genomic Classifier, which uses a collection of 22 genes), may also be helpful in stratifying patients for appropriate treatment.8 Prostate-specific membrane antigen (PSMA) positron emission tomography has emerged as the preeminent imaging modality for detecting clinical progression in patients with BCR.9

Patients with prostate cancer and high-risk BCR may benefit from treatment intensification. However, management of this highly heterogeneous patient population is confounded by the lack of clarity among experts on optimal timing, dosing, and sequencing of various therapies. In some cases, androgen deprivation therapy (ADT) may be used to treat patients with high-risk BCR but has potentially serious adverse events including cardiovascular side effects.10,11 Evidence suggests that next-generation hormonal therapies, including the CYP17 inhibitor abiraterone and the androgen pathway signaling inhibitors apalutamide/darolutamide/enzalutamide, could also delay disease progression in patients with high-risk BCR.12 Notably, the international phase 3 EMBARK trial demonstrated that enzalutamide in combination with ADT and enzalutamide monotherapy improved metastasis-free survival in patients with high-risk BCR compared with ADT alone while maintaining quality of life.13 Other emerging therapies that may be useful in patients with BCR include cancer vaccines, checkpoint inhibitors, poly-ADP ribose polymerase (PARP) inhibitors, and PSMA-targeting radioligand therapies. Finally, there is encouraging evidence supporting the potential benefit of combining radiation therapy with systemic therapies.14 These combinations represent excellent examples of the need for MDC since they leverage the combined expertise of oncologists and radiologists.

In MDC, multiple experts work together to assist in stratifying individualized risk based on clinicopathological parameters, next-generation imaging, and molecular biomarker analysis. This team-based approach incorporates urologists, radiation oncologists, and medical oncologists working together with other healthcare professionals (e.g., pharmacists, nurse practitioners, etc.). There are several potential benefits of MDC including increased patient engagement/satisfaction, reduced risk of physician bias, improved cross-referral, increased patient participation in clinical trials, increased adherence to treatment guidelines, and enhanced shared decision-making.15-17 When combined, these factors should improve patient survival outcomes. Indeed, there is evidence that MDC clinics and MDC referrals can be beneficial in prostate cancer.15,18,19 However, evidence of MDC implemented for the treatment of patients with high-risk BCR is rare and remains an unmet need.

Written by:

  • Jason A. Efstathiou, MD, DPhil, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA
  • Alicia K. Morgans, MD, MPH, Dana-Farber Cancer Institute, Boston, MA
References:

  1. Lowrance WT, Breau RH, Chou R, et al. Advanced Prostate Cancer: AUA/ASTRO/SUO Guideline PART I. J Urol. 2021;205(1):14–21.
  2. Kupelian PA, Buchsbaum JC, Elshaikh M, Reddy CA, Zippe C, Klein EA. Factors affecting recurrence rates after prostatectomy or radiotherapy in localized prostate carcinoma patients with biopsy Gleason score 8 or above. Cancer. 2002;95(11):2302–2307.
  3. Freedland SJ, Humphreys EB, Mangold LA, et al. Risk of prostate cancer-specific mortality following biochemical recurrence after radical prostatectomy. JAMA. 2005;294(4):433–439.
  4. Kupelian PA, Mahadevan A, Reddy CA, Reuther AM, Klein EA. Use of different definitions of biochemical failure after external beam radiotherapy changes conclusions about relative treatment efficacy for localized prostate cancer. Urology. 2006;68(3):593–598.
  5. Van den Broeck T, van den Bergh RCN, Arfi N, et al. Prognostic Value of Biochemical Recurrence Following Treatment with Curative Intent for Prostate Cancer: A Systematic Review. Eur Urol. 2019;75(6):967–987.
  6. Shore ND, Antonarakis ES, Cookson MS, et al. Optimizing the role of androgen deprivation therapy in advanced prostate cancer: Challenges beyond the guidelines. Prostate. 2020;80(6):527–544.
  7. Efstathiou JA, Morgans AK, Bland CS, Shore ND. Novel hormone therapy and coordination of care in high-risk biochemically recurrent prostate cancer. Cancer Treat Rev. 2023;122:102630.
  8. Eggener SE, Rumble RB, Armstrong AJ, et al. Molecular Biomarkers in Localized Prostate Cancer: ASCO Guideline. J Clin Oncol. 2020;38(13):1474–1494.
  9. Sonni I, Eiber M, Fendler WP, et al. Impact of (68)Ga-PSMA-11 PET/CT on Staging and Management of Prostate Cancer Patients in Various Clinical Settings: A Prospective Single-Center Study. J Nucl Med. 2020;61(8):1153–1160.
  10. Weiner AB, Siebert AL, Fenton SE, et al. First-line Systemic Treatment of Recurrent Prostate Cancer After Primary or Salvage Local Therapy: A Systematic Review of the Literature. Eur Urol Oncol. 2022;5(4):377–387.
  11. Brawer MK. Hormonal therapy for prostate cancer. Rev Urol. 2006;8 Suppl 2(Suppl 2):S35–47.
  12. Armstrong AJ, Azad AA, Iguchi T, et al. Improved Survival With Enzalutamide in Patients With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. 2022;40(15):1616–1622.
  13. Freedland SJ, de Almeida Luz M, De Giorgi U, et al. Improved Outcomes with Enzalutamide in Biochemically Recurrent Prostate Cancer. New England Journal of Medicine. 2023;389(16):1453–1465.
  14. Sachdev S, Carroll P, Sandler H, et al. Assessment of Postprostatectomy Radiotherapy as Adjuvant or Salvage Therapy in Patients With Prostate Cancer: A Systematic Review. JAMA Oncol. 2020;6(11):1793–1800.
  15. Tang C, Hoffman KE, Allen PK, et al. Contemporary prostate cancer treatment choices in multidisciplinary clinics referenced to national trends. Cancer. 2020;126(3):506–514.
  16. Aizer AA, Paly JJ, Zietman AL, et al. Models of care and NCCN guideline adherence in very-low-risk prostate cancer. J Natl Compr Canc Netw. 2013;11(11):1364-1372.
  17. Aizer AA, Paly JJ, Zietman AL, et al. Multidisciplinary care and pursuit of active surveillance in low-risk prostate cancer. J Clin Oncol. 2012;30(25):3071-3076.
  18. Knipper S, Sadat-Khonsari M, Boehm K, et al. Impact of Adherence to Multidisciplinary Recommendations for Adjuvant Treatment in Radical Prostatectomy Patients With High Risk of Recurrence. Clin Genitourin Cancer. 2020;18(2):e112–e121.
  19. Shore ND, Morgans AK, El-Haddad G, Srinivas S, Abramowitz M. Addressing Challenges and Controversies in the Management of Prostate Cancer with Multidisciplinary Teams. Target Oncol. 2022;17(6):709–725.
Disclosures:

  • Dr. Efstathiou reports consulting roles for Blue Earth Diagnostics, Boston Scientific, AstraZeneca, Genentech, Astellas Pharma Inc., Pfizer Inc., and Lantheus; honoraria from IBA, Elekta, and UpToDate; advisory boards for Merck, Roivant Pharma, Sumitomo Pharma America, Inc. (formerly Myovant Sciences), Janssen, Bayer Healthcare, Progenics Pharmaceuticals, Pfizer Inc., Gilead, Blue Earth Diagnostics, Lantheus Medical Imaging, and Angiodynamics.
  • Dr. Morgans reports grant support from Bayer, Sanofi, Sumitomo Pharma America, Inc. (formerly Myovant Sciences), Pfizer, Inc., Astellas Scientific and Medical Affairs Inc., and Dendreon Pharmaceuticals; honoraria from AstraZeneca, Advanced Accelerator Applications, Novartis, and Pfizer, Inc.; consulting or advisory roles for AstraZeneca, Sanofi, Bayer, Astellas Pharma, Janssen, Advanced Accelerator Applications, Sumitomo Pharma America, Inc. (formerly Myovant Sciences), Blue Earth Diagnostics, Exelixis, Novartis, Myriad Genetics, Lantheus Medical Imaging, Merck, and Gilead.
  • Medical writing and editorial support were provided by Peter Gray, PhD, and Rosie Henderson, MSc, both of Onyx (a division of Prime, London, UK) and funded by Pfizer Inc. and Astellas Pharma Inc., the co-developers of enzalutamide.
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