Updates in Immune Checkpoint Inhibitors for Prostate Cancer

In spite of the rapid progress and many exciting advances in the treatment of metastatic castration-resistant prostate cancer (mCRPC) over the past few years, the disease remains incurable with a median overall survival of 12-35 months.1-4 Targeting the immune system to expand treatment options in the advanced disease state has resulted in significant improvements for patients with many advanced malignancies, although the survival benefits in advanced prostate cancer have remained more elusive. To date, Sipuleucel-T is the only immunotherapeutic intervention approved by the Food and Drug Administration (FDA) for the treatment of advanced prostate cancer.1
Written by: Christopher J.D. Wallis, MD, PhD, & Zachary Klaassen, MD, MSc,
References:
  1. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363(5):411-422.
  2. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2015;16(2):152-160.
  3. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376(9747):1147-1154.
  4. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
  5. Pasero C, Gravis G, Guerin M, et al. Inherent and Tumor-Driven Immune Tolerance in the Prostate Microenvironment Impairs Natural Killer Cell Antitumor Activity. Cancer Res. 2016;76(8):2153-2165.
  6. Flavell RA, Sanjabi S, Wrzesinski SH, Licona-Limon P. The polarization of immune cells in the tumour environment by TGFbeta. Nat Rev Immunol. 2010;10(8):554-567.
  7. Sfanos KS, Bruno TC, Maris CH, et al. Phenotypic analysis of prostate-infiltrating lymphocytes reveals TH17 and Treg skewing. Clin Cancer Res. 2008;14(11):3254-3261.
  8. Maia MC, Hansen AR. A comprehensive review of immunotherapies in prostate cancer. Crit Rev Oncol Hematol. 2017;113:292-303.
  9. Thoma C. Prostate cancer: Towards effective combination of ADT and immunotherapy. Nat Rev Urol. 2016;13(6):300.
  10. Bishop JL, Sio A, Angeles A, et al. PD-L1 is highly expressed in Enzalutamide resistant prostate cancer. Oncotarget. 2015;6(1):234-242.
  11. Abida W, Cheng ML, Armenia J, et al. Analysis of the Prevalence of Microsatellite Instability in Prostate Cancer and Response to Immune Checkpoint Blockade. JAMA Oncol. 2018.
  12. Hansen AR, Massard C, Ott PA, et al. Pembrolizumab for advanced prostate adenocarcinoma: findings of the KEYNOTE-028 study. Ann Oncol. 2018;29(8):1807-1813.
  13. Antonarakis ES, Piulats JM, Gross-Goupil M, et al. Pembrolizumab for Treatment-Refractory Metastatic Castration-Resistant Prostate Cancer: Multicohort, Open-Label Phase II KEYNOTE-199 Study. J Clin Oncol. 2020;38(5):395-405.
  14. Antonarakis ES, Piulats JM, Gross-Goupil M, Goh JC, Vaishampayan U. Update on KEYNOTE-199, cohorts 1-3: Pembrolizumab (pembro) for docetaxel-pretreated metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(Suppl 6):abstr 104.
  15. Graff JN, Antonarakis ES, Hoimes CJ, Tagawa ST. Pembrolizumab (pembro) plus enzalutamide (enza) for enza-resistant metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-199 cohorts 4-5. J Clin Oncol. 2020;38(Suppl 6):abstr 15.
  16. Omlin A, Graff JN, Hoimes CJ, Tagawa ST, Hwang C. KEYNOTE-199 phase II study of pembrolizumab plus enzalutamide for enzalutamide-resistant metastatic castration-resistant prostate cancer (mCRPC): Cohorts (C) 4 and 5 update. Ann Oncol. 2020;31.
  17. Yu EY, Piulats JM, Gravis G, Laguerre B. KEYNOTE-365 cohort A updated results: Pembrolizumab (pembro) plus olaparib in docetaxel-pretreated patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(Suppl 6):abstr 100.
  18. Kolinsky MP, Gravis G, Mourey L, Piulats JM. KEYNOTE-365 cohort B updated results: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(Suppl 6):abstr 103.
  19. Berry WR, Fong PC, Piulats JM, Appleman LJ. KEYNOTE-365 cohort C updated results: Pembrolizumab (pembro) plus enzalutamide (enza) in abiraterone (abi)-pretreated patients (pts) with metastatic castrate-resistant prostate cancer (mCRPC). J Clin Oncol. 2020;38(Suppl 6):abstr 102.
  20. Mourey L, Conter HJ, Shore N, Berry WR. Pembrolizumab (pembro) plus enzalutamide (enza) in patients with abiraterone acetate (abi)-pretreated metastatic castration-resistant prostate cancer (mCRPC): KEYNOTE-365 Cohort C update. Ann Oncol. 2020;31.
  21. Appleman LJ, Kolinsky MP, Berry WR, Retz M, Mourey L, Piulats JM. KEYNOTE-365 cohort B: Pembrolizumab (pembro) plus docetaxel and prednisone in abiraterone (abi) or enzalutamide (enza)–pretreated patients with metastatic castration-resistant prostate cancer (mCRPC)—New data after an additional 1 year of follow-up. J Clin Oncol. 2021;39:10.
  22. Emamekhoo H, Kyriakopoulos C, Liu G, McNeel DG. Phase II trial of a DNA vaccine encoding prostatic acid phosphatase (pTVG-HP) and nivolumab (Nivo) in patients (pts) with nonmetastatic, PSA-recurrent prostate cancer (PCa). J Clin Oncol. 2020;38(Suppl 6):abstr TPS273.
  23. Maughan BL, Nussenzveig R, Swami U, Gupta S, Agarwal N. Prospective trial of nivolumab (Nivo) plus radium-223 (RA) in metastatic castration-resistant prostate cancer (mCRPC) evaluating circulating tumor DNA (ctDNA) levels as a biomarker of response. J Clin Oncol. 2020;38(Suppl 6):abstr TPS267.
  24. Patnaik A, Duttagupta P, Chaudagar K, Alter R. A phase Ib/IIa study of rucaparib (PARP inhibitor) combined with nivolumab in metastatic castrate-resistant prostate cancer. J Clin Oncol. 2020;38(Suppl 6):abstr TPS270.
  25. Fizazi K, Mella PG, Castellano D, Minatta JN, Rezazadeh A. CheckMate 9KD Arm B final analysis: Efficacy and safety of nivolumab plus docetaxel for chemotherapy-naïve metastatic castration-resistant prostate cancer. J Clin Oncol. 2021;39.
  26. Sweeney C, Gillessen-Sommer S, Rathkopf D, Matsubara N, Drake CG. IMbassador250: A phase III trial comparing atezolizumab with enzalutamide vs enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC). AACR Annual Meeting. 2020;Abstr CT014.
  27. Agarwal N, Loriot Y, McGregor BA, Dreicer R, Dorff TB. Cabozantinib (C) in combination with atezolizumab (A) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC): Results of Cohort 6 of the COSMIC-021 Study. J Clin Oncol. 2020;38(Suppl 6):abstr 139.
  28. Kwon ED, Drake CG, Scher HI, et al. Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): a multicentre, randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15(7):700-712.
  29. Beer TM, Kwon ED, Drake CG, et al. Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer. J Clin Oncol. 2017;35(1):40-47.

A Contemporary Update on Sipuleucel-T for Men with Metastatic Castrate-Resistant Prostate Cancer

Despite warranted concerns regarding the overdiagnosis and overtreatment of many cases of biologically indolent prostate cancer, prostate cancer remains the second leading cause of cancer-related death in the United States behind only lung cancer.1 With current treatment paradigms, nearly all patients who die of prostate cancer first receive androgen-deprivation therapy and then progress to castrate-resistant prostate cancer.

Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
References: 1. Siegel, R. L., & Miller, K. D. (2018). Jemal A (2018) cancer statistics. Ca Cancer J Clin68(1), 7-30.
2. Lowrance, William T., Mohammad Hassan Murad, William K. Oh, David F. Jarrard, Matthew J. Resnick, and Michael S. Cookson. "Castration-resistant prostate cancer: AUA Guideline Amendment 2018." The Journal of urology 200, no. 6 (2018): 1264-1272.
3. Goldman, Bruce, and Laura DeFrancesco. "The cancer vaccine roller coaster." Nature biotechnology 27, no. 2 (2009): 129-139.
4. Kantoff, Philip W., Celestia S. Higano, Neal D. Shore, E. Roy Berger, Eric J. Small, David F. Penson, Charles H. Redfern et al. "Sipuleucel-T immunotherapy for castration-resistant prostate cancer." New England Journal of Medicine 363, no. 5 (2010): 411-422.
5. Higano, Celestia S., Andrew J. Armstrong, A. Oliver Sartor, Nicholas J. Vogelzang, Philip W. Kantoff, David G. McLeod, Christopher M. Pieczonka et al. "Real‐world outcomes of sipuleucel‐T treatment in PROCEED, a prospective registry of men with metastatic castration‐resistant prostate cancer." Cancer 125, no. 23 (2019): 4172-4180.
6. Anassi, Enock, and Uche Anadu Ndefo. "Sipuleucel-T (provenge) injection: the first immunotherapy agent (vaccine) for hormone-refractory prostate cancer." Pharmacy and Therapeutics 36, no. 4 (2011): 197.

Ethnic Variation in Prostate Cancer Detection: A Feasibility Study for Use of the Stockholm3 Test in a Multiethnic U.S. Cohort - Beyond the Abstract

African American men are known to have nearly twice the incidence of prostate cancer and more than double the risk of prostate cancer mortality compared to Caucasian men.  There are several possible mechanisms for this including risk factors such as lifestyle, diet, genetic risk, inequalities in access to high-quality care, or other socioeconomic factors, however, the contribution of biology in prostate cancer risk is not well understood in this population.
Written by: Hari T. Vigneswaran, Andrea Discacciati, Peter H. Gann, Henrik Grönberg, Martin Eklund, Michael R. Abern
References:
  1. Darst, B.F., et al., A Germline Variant at 8q24 Contributes to Familial Clustering of Prostate Cancer in Men of African Ancestry. Eur Urol, 2020.
  2. Haiman, C.A., et al., Characterizing genetic risk at known prostate cancer susceptibility loci in African Americans. PLoS Genet, 2011. 7(5): p. e1001387.
  3. Gronberg, H., et al., Prostate cancer screening in men aged 50-69 years (STHLM3): a prospective population-based diagnostic study. Lancet Oncol, 2015. 16(16): p. 1667-76.
  4. Vigneswaran, H.T., et al., Ethnic variation in prostate cancer detection: a feasibility study for use of the Stockholm3 test in a multiethnic U.S. cohort. Prostate Cancer Prostatic Dis, 2020.

Expanding Treatment Options in Non-metastatic Castrate-resistant Prostate Cancer

Prostate cancer (PCa) is the second most common form of cancer diagnosed in US men. It represents 19% of newly diagnosed cancers, and the third leading cause of cancer death, accounting for an estimated 39,430 deaths in 2018.1 
Written by: Hanan Goldberg MD, Department of Urology, SUNY Upstate Medical University, Syracuse, NY, USA
References:
  1. Siegel RL, Miller KD, Jemal A. Cancer statistics, 2018. Jan 2018;68(1):7-30.
  2. Trapasso JG, deKernion JB, Smith RB, Dorey F. The incidence and significance of detectable levels of serum prostate specific antigen after radical prostatectomy. J Urol. Nov 1994;152(5 Pt 2):1821-1825.
  3. Tombal B, Miller K, Boccon-Gibod L, et al. Additional analysis of the secondary end point of biochemical recurrence rate in a phase 3 trial (CS21) comparing degarelix 80 mg versus leuprolide in prostate cancer patients segmented by baseline characteristics. Eur Urol. May 2010;57(5):836-842.
  4. Karantanos T, Evans CP, Tombal B, Thompson TC, Montironi R, Isaacs WB. Understanding the mechanisms of androgen deprivation resistance in prostate cancer at the molecular level. Eur Urol. Mar 2015;67(3):470-479.
  5. Saad F, Hotte SJ. Guidelines for the management of castrate-resistant prostate cancer. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 2010;4(6):380-384.
  6. Alpajaro SIR, Harris JAK, Evans CP. Non-metastatic castration resistant prostate cancer: a review of current and emerging medical therapies. Prostate Cancer Prostatic Dis. Mar 2019;22(1):16-23.
  7. Chandrasekar T, Yang JC, Gao AC, Evans CP. Mechanisms of resistance in castration-resistant prostate cancer (CRPC). Transl Androl Urol. Jun 2015;4(3):365-380.
  8. Sharifi N, Dahut WL, Steinberg SM, et al. A retrospective study of the time to clinical endpoints for advanced prostate cancer. BJU Int. Nov 2005;96(7):985-989.
  9. Macomson B, Lin JH, Tunceli O, et al. Time to metastasis or death in non-metastatic castrate resistant prostate cancer (nmCRPC) patients by National Comprehensive Cancer Network (NCCN) risk groups. Journal of Clinical Oncology. 2017;35(15_suppl):5027-5027.
  10. Scher HI, Solo K, Valant J, Todd MB, Mehra M. Prevalence of Prostate Cancer Clinical States and Mortality in the United States: Estimates Using a Dynamic Progression Model. PLoS One. 2015;10(10):e0139440.
  11. Lowrance WT, Murad MH, Oh WK, Jarrard DF, Resnick MJ, Cookson MS. Castration-Resistant Prostate Cancer: AUA Guideline Amendment 2018. J Urol. Dec 2018;200(6):1264-1272.
  12. Scher HI, Morris MJ, Stadler WM, et al. Trial Design and Objectives for Castration-Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. Apr 20 2016;34(12):1402-1418.
  13. Liede A, Arellano J, Hechmati G, Bennett B, Wong S. International prevalence of nonmetastatic (M0) castration-resistant prostate cancer (CRPC). Journal of Clinical Oncology. 2013;31(15_suppl):e16052-e16052.
  14. Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. New England Journal of Medicine. 2018;378(15):1408-1418.
  15. Virgo KS, Rumble RB, Singer EA. Second-Line Hormonal Therapy for Men With Chemotherapy-Naive Castration-Resistant Prostate Cancer: American Society of Clinical Oncology Provisional Clinical Opinion Summary. J Oncol Pract. Jul 2017;13(7):459-461.
  16. Crawford ED, Stone NN, Yu EY, et al. Challenges and recommendations for early identification of metastatic disease in prostate cancer. Urology. Mar 2014;83(3):664-669.
  17. Sartor AO, Tangen CM, Hussain MH, et al. Antiandrogen withdrawal in castrate-refractory prostate cancer: a Southwest Oncology Group trial (SWOG 9426). Cancer. Jun 2008;112(11):2393-2400.
  18. Murray NP, Reyes E, Tapia P, Badínez L, Orellana N. Differential expression of matrix metalloproteinase-2 expression in disseminated tumor cells and micrometastasis in bone marrow of patients with nonmetastatic and metastatic prostate cancer: theoretical considerations and clinical implications-an immunocytochemical study. Bone marrow research. 2012;2012:259351-259351.
  19. Eiber M, Maurer T, Souvatzoglou M, et al. Evaluation of Hybrid (6)(8)Ga-PSMA Ligand PET/CT in 248 Patients with Biochemical Recurrence After Radical Prostatectomy. J Nucl Med. May 2015;56(5):668-674.
  20. Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective Comparison of 18F-Fluoromethylcholine Versus 68Ga-PSMA PET/CT in Prostate Cancer Patients Who Have Rising PSA After Curative Treatment and Are Being Considered for Targeted Therapy. J Nucl Med. Aug 2015;56(8):1185-1190.
  21. Umbehr MH, Muntener M, Hany T, Sulser T, Bachmann LM. The role of 11C-choline and 18F-fluorocholine positron emission tomography (PET) and PET/CT in prostate cancer: a systematic review and meta-analysis. Eur Urol. Jul 2013;64(1):106-117.
  22. Geynisman DM, Plimack ER, Zibelman M. Second-generation Androgen Receptor-targeted Therapies in Nonmetastatic Castration-resistant Prostate Cancer: Effective Early Intervention or Intervening Too Early? Eur Urol. Dec 2016;70(6):971-973.
  23. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol. Nov 1993;11(11):2167-2172.
  24. Scher HI, Sawyers CL. Biology of progressive, castration-resistant prostate cancer: directed therapies targeting the androgen-receptor signaling axis. J Clin Oncol. Nov 10 2005;23(32):8253-8261.
  25. Shah RB, Mehra R, Chinnaiyan AM, et al. Androgen-independent prostate cancer is a heterogeneous group of diseases: lessons from a rapid autopsy program. Cancer Res. Dec 15 2004;64(24):9209-9216.
  26. Maximum androgen blockade in advanced prostate cancer: an overview of the randomised trials. Prostate Cancer Trialists' Collaborative Group. Lancet. Apr 29 2000;355(9214):1491-1498.
  27. Schweizer MT, Zhou XC, Wang H, et al. Metastasis-free survival is associated with overall survival in men with PSA-recurrent prostate cancer treated with deferred androgen deprivation therapy. Ann Oncol. Nov 2013;24(11):2881-2886.
  28. Schroder FH, Tombal B, Miller K, et al. Changes in alkaline phosphatase levels in patients with prostate cancer receiving degarelix or leuprolide: results from a 12-month, comparative, phase III study. BJU Int. Jul 2010;106(2):182-187.
  29. Tran C, Ouk S, Clegg NJ, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science. May 8 2009;324(5928):787-790.
  30. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2018;378(26):2465-2474.
  31. Fizazi K, Shore N, Tammela TL, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2019;380(13):1235-1246.
  32. El-Amm J, Aragon-Ching JB. The Current Landscape of Treatment in Non-Metastatic Castration-Resistant Prostate Cancer. 2019;13:1179554919833927.
  33. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. Mar 15 2012;72(6):1494-1503.
  34. Scher HI, Fizazi K, Saad F, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine. 2012;367(13):1187-1197.
  35. Beer TM, Armstrong AJ, Rathkopf DE, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med. Jul 31 2014;371(5):424-433.
  36. Xie W, Regan MM, Buyse M, et al. Metastasis-Free Survival Is a Strong Surrogate of Overall Survival in Localized Prostate Cancer. J Clin Oncol. Sep 20 2017;35(27):3097-3104.
  37. Shore ND. Darolutamide (ODM-201) for the treatment of prostate cancer. Expert Opin Pharmacother. Jun 2017;18(9):945-952.
  38. Smith MR, Saad F, Oudard S, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. Oct 20 2013;31(30):3800-3806.
  39. Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. Nov 1 2008;113(9):2478-2487.
  40. Miller K, Moul JW, Gleave M, et al. Phase III, randomized, placebo-controlled study of once-daily oral zibotentan (ZD4054) in patients with non-metastatic castration-resistant prostate cancer. Prostate Cancer Prostatic Dis. Jun 2013;16(2):187-192.
  41. Beinart G, Rini BI, Weinberg V, Small EJ. Antigen-presenting cells 8015 (Provenge) in patients with androgen-dependent, biochemically relapsed prostate cancer. Clin Prostate Cancer. Jun 2005;4(1):55-60.
  42. Madan RA, Gulley JL, Schlom J, et al. Analysis of overall survival in patients with nonmetastatic castration-resistant prostate cancer treated with vaccine, nilutamide, and combination therapy. Clin Cancer Res. Jul 15 2008;14(14):4526-4531.
  43. Ogita S, Tejwani S, Heilbrun L, et al. Pilot Phase II Trial of Bevacizumab Monotherapy in Nonmetastatic Castrate-Resistant Prostate Cancer. ISRN oncology. 2012;2012:242850-242850.
  44. Ryan CJ, Crawford ED, Shore ND, et al. The IMAAGEN Study: Effect of Abiraterone Acetate and Prednisone on Prostate Specific Antigen and Radiographic Disease Progression in Patients with Nonmetastatic Castration Resistant Prostate Cancer. J Urol. Aug 2018;200(2):344-352.
  45. Hussain M, Corn PG, Michaelson MD, et al. Phase II study of single-agent orteronel (TAK-700) in patients with nonmetastatic castration-resistant prostate cancer and rising prostate-specific antigen. Clin Cancer Res. Aug 15 2014;20(16):4218-4227.
  46. Fizazi K, Jones R, Oudard S, et al. Phase III, randomized, double-blind, multicenter trial comparing orteronel (TAK-700) plus prednisone with placebo plus prednisone in patients with metastatic castration-resistant prostate cancer that has progressed during or after docetaxel-based therapy: ELM-PC 5. J Clin Oncol. Mar 1 2015;33(7):723-731.

PARP Inhibitors, Prostate Cancer and a Promise Fulfilled

June 26, 2020, marked the 20th anniversary of the publication of the first working draft from the Human Genome Project. At a special White House event to commemorate the results of this 10-year public effort (it was really more like 50 years since the discovery of DNA, but I digress), then-President Bill Clinton called the project “the most wondrous map ever created by humankind”, and touted its promise to detect, prevent, and treat disease.  Obtaining that first sequence from one human cost about $2B and resulted from a massive global public/private partnership.

Written by: Charles Ryan, MD
References: 1. McKie, Robin. ‘The wondrous map’: how unlocking human DNA changed the course of science. The Guardian. June 21, 2020. Retrieved from: https://www.theguardian.com/science/2020/jun/21/human-genome-project-unlocking-dna-covid-19-cystic-fibrosis-molecular-scientists

Contemporary Radiotherapy Clinical Trials for Prostate Cancer

Localized Treatment – Optimizing Fractionation

Several trials have recently focused on delineating the optimal radiotherapy fractionation schedule for the primary treatment of prostate cancer. In 2016, efficacy results of the Dutch HYPRO trial were published, assessing hypofractionated radiotherapy compared with conventionally fractionated radiotherapy among patients with intermediate-risk to high-risk T1b-T4NX-N0MX-M0 localized prostate cancer.1 Patients were assigned 1:1 to either hypofractionated radiotherapy of 64.6 Gy (19 fractions of 3.4 Gy, three fractions per week) or conventionally fractionated radiotherapy of 78.0 Gy (39 fractions of 2.0 Gy, five fractions per week) with a primary endpoint of relapse-free survival. There were 804 patients assessed in the intention-to-treat analysis, of which 407 were assigned hypofractionated radiotherapy and 397 were allocated to conventionally fractionated radiotherapy. Additionally, 67% of patients received concomitant androgen deprivation therapy (ADT) for a median duration of 32 months (IQR 10-44). Over a median follow-up of 60 months (IQR 51-69), treatment failure was reported in 21% of patients, including 20% in the hypofractionation group and 22% in the conventional fractionation group. The 5-year relapse-free survival was 80.5% (95% CI 75.7-84.4) for patients assigned hypofractionation and 77.1% (71.9-81.5) for those allocated conventional fractionation (hazard ratio [HR] 0.86, 95% confidence interval [CI] 0.63-1.16; log-rank p=0.36). Based on these results, the authors noted that this current regimen of hypofractionated radiotherapy was not superior to conventional radiotherapy.

The CHHiP trial was a multi-center, randomized, Phase III trial, designed as a non-inferiority clinical trial, randomizing men with pT1b-T3aN0M0 prostate cancer 1:1:1 to conventional (74 Gy delivered in 37 fractions over 7.4 weeks) or one of two hypofractionated schedules (60 Gy in 20 fractions over 4 weeks or 57 Gy in 19 fractions over 3.8 weeks) all delivered with intensity-modulated techniques.2 Most patients were given radiotherapy with 3-6 months of neoadjuvant and concurrent androgen suppression. The primary endpoint was time to biochemical or clinical failure, and the critical hazard ratio for non-inferiority was 1.208. In this large trial, 3,216 men were enrolled from 71 centers and randomly assigned: 1,065 patients to the 74 Gy group, 1,074 patients to the 60 Gy group, and 1,077 patients to the 57 Gy group. The median follow-up was 62.4 months (IQR 53.9-77.0) over which the proportion of patients who were biochemical or clinical failure-free at five years was 88.3% (95% CI 86.0-90.2) in the 74 Gy group, 90.6% (95% CI 88.5-92.3) in the 60 Gy group, and 85.9% (95% CI 83.4-88.0) in the 57 Gy group. The 60 Gy hypofractionated schedule was non-inferior to the conventional 74 Gy schedule (HR 0.84, 90% CI 0.68-1.03, p noninferiority = 0.0018), but non-inferiority was not possible for 57 Gy hypofractionation compared with 74 Gy (HR 1.20, 90% CI 0.99-1.46, p noninferiority = 0.48). 

Based on these initial studies, recent interest has related to even more intense radiotherapy fractionation. The Scandinavian HYPO-RT-PC randomized controlled Phase III trial was initially presented at ESTRO 2018, and subsequently published in Lancet Oncology.3 This trial randomized men with intermediate and high-risk prostate cancer to either conventional fractionating (n = 602; 78.0 Gy in 39 fractions, 5 days per week for 8 weeks) or ultrahypofractionated (n=598; 42.7 Gy in seven fractions, three days per week for 2.5 weeks). The primary endpoint was time to biochemical or clinical failure. The estimated failure-free survival at five years was 84% (95% CI 80-87) in both treatment groups, with an adjusted HR of 1.002 (95% CI 0.758-1.325; log-rank p=0.99). There was weak evidence of an increased frequency of acute physician-reported RTOG grade 2 or worse urinary toxicity in the ultra-hypofractionation group at end of radiotherapy (158 [28%] of 569 patients vs 132 [23%] of 578 patients; p=0.057). Based on these results, there has been support for the use of ultra-hypofractionated radiotherapy for prostate cancer.

However, despite encouraging results regarding biochemical/relapse-free survival as described above, studies have not demonstrated an overall survival (OS) benefit. Patients in the NRG Oncology RTOG 0126 trial that had intermediate-risk prostate cancer were randomized to 3-dimensional conformal radiation therapy or intensity-modulated radiation therapy to 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions.4 Over a median follow-up of 8.4 years in 1,499 patients, there was no difference in OS between the 751 men in the 79.2-Gy arm and the 748 men in the 70.2-Gy arm. The 8-year rates of OS were 76% with 79.2 Gy and 75% with 70.2 Gy (HR 1.00, 95% CI, 0.83-1.20), and the 8-year cumulative rates of distant metastases were 4% for the 79.2-Gy arm and 6% for the 70.2-Gy arm (HR 0.65, 95% CI, 0.42-1.01). As the above trials continue to mature, it will be imperative to evaluate survival outcomes. However, adoption of hypofractionation needn’t require improved survival or toxicity outcomes – on the basis of equivalence, improvements in the patient experience/convenience and cost would support the adoption of this approach.

Localized Disease – Optimizing Androgen Deprivation Therapy (ADT)

A second initiative of recent radiotherapy trials has been delineating the appropriate dose of ADT given concurrently with radiotherapy. The DART01/05 GICOR trial was a randomized, controlled Phase III trial assessing high-dose radiotherapy with short-term or long-term ADT for patients with T1c-T3b N0M0 prostate cancer with intermediate-risk and high-risk features.5 Patients were randomly assigned 1:1 to receive either four months of ADT combined with three-dimensional conformal radiotherapy at a minimum dose of 76 Gy (range 76-82 Gy; short-term ADT group) or the same treatment followed by 24 months of adjuvant ADT (long-term ADT group), stratified by prostate cancer risk group (intermediate risk vs high risk). In this Spanish multi-center trial, 178 patients were randomly assigned to receive short-term ADT and 177 to receive long-term ADT. After a median follow-up of 63 months (IQR 50-82), 5-year biochemical disease-free survival was significantly better among patients receiving long-term ADT than among those receiving short-term ADT: 90% (95% CI 87-92) vs 81% (95% CI 78-85), HR 1.88, 95% CI 1.12-3.15. Furthermore, the 5-year OS (95% vs 86%; HR 2.48, 95% CI 1.31-4.68) and 5-year MFS (94% vs 83%; HR 2.31, 95% CI 1.23-3.85) rates were also significantly better in the long-term ADT group than in the short-term ADT group. Not surprisingly, the authors noted that the effect of long-term ADT on biochemical disease-free survival, metastasis-free survival, and overall survival was more evident in patients with high-risk disease than in those with low-risk disease. 

In 2016, the results of the EORTC 22991 randomized trial were published.6 This trial assessed if biochemical disease-free survival (DFS) is improved by adding six months of androgen suppression to primary radiotherapy for intermediate- or high-risk localized prostate cancer. Among 819 patients, the median patient age was 70 years, 74.8% were intermediate risk and 24.8% were high risk. At 7.2 years median follow-up, radiotherapy plus androgen suppression significantly improved biochemical DFS (HR 0.52, 95% CI 0.41-0.66), as well as clinical progression-free survival (HR 0.63, 95% CI 0.48-0.84).

Long-term follow-up of the D’Amico trial assessing ADT plus radiotherapy versus ADT alone for patients with localized, unfavorable risk prostate cancer was published in 20157. This analysis importantly showed that underlying comorbidity significantly modified the benefit of ADT: in patients with moderate or severe comorbidity, use of radiotherapy alone was associated with decreased cardiac mortality (HR 0.17, 95% CI 0.06-0.46), non-prostate cancer mortality (HR 2.79, 95% CI 1.02-7.60), and overall mortality (HR 0.36, 95% CI 0.19-0.67). Conversely, in men with no or minimal comorbidity, radiotherapy alone was associated with an increased risk of overall mortality and prostate cancer mortality, without coinciding decreases in cardiac mortality or non-prostate cancer mortality.

The prior standard ADT duration was 28-36 months when combined with radiotherapy for high-risk disease. As such, the TROG RADAR trial assessed whether the addition of 12 months of adjuvant ADT, 18 months of zoledronic acid, or both, can improve outcomes in men with locally advanced prostate cancer who receive six months of ADT and prostate radiotherapy.8 In 2019, this trial reported 10-year outcomes. There were 1,071 patients randomized to radiotherapy plus six months of ADT or radiotherapy plus 18 months of ADT. This trial found that 18 months of ADT plus radiotherapy is a more effective treatment option for locally advanced prostate cancer than six months of ADT plus radiotherapy (HR 0.70, 95% CI 0.50-0.98), but the addition of zoledronic acid to this treatment regimen is not beneficial. Finally, the PCS IV Trial randomized 630 patients with a median follow-up of 9.4 years to radiotherapy plus 18 months of ADT or radiotherapy plus 36 months of ADT.9 The 5-year OS rates were 91% for long term ADT arm (95% CI 88-95%) and 86% for short term ADT arm (95% CI 83-90%, p=0.07). The quality of life analysis showed a significant difference (p<0.001) in six scales and 13 items favoring 18 months of ADT.           

Localized Disease – Addition of Chemotherapy

The benefit of adding chemotherapy in the treatment of very high-risk disease has also been recently evaluated. Rosenthal et al.10 published the multicenter randomized NRG Oncology RTOG 0521 clinical trial, which enrolled patients with high-risk nonmetastatic disease between 2005 and 2009. Patients were randomly assigned (n=563) to receive standard long-term ADT plus radiotherapy with or without adjuvant chemotherapy. Over a median follow-up of 5.7 years, the 4-year OS rate was 89% (95% CI, 84% to 92%) for ADT and radiotherapy, compared to 93% (95% CI, 90% to 96%) for ADT and radiotherapy plus chemotherapy (HR 0.69, 90% CI 0.49-0.97). Six-year rate of distant metastasis was 14% for ADT and radiotherapy and 9.1% for ADT and radiotherapy plus chemotherapy, (HR 0.60, 95% CI 0.37-0.99).

Treatment after Radical Prostatectomy

For decades, urologists and radiation oncologists have debated the optimal timing, location, and dose of radiotherapy, in addition to the utilization of ADT among those experiencing biochemical recurrence after radical prostatectomy. The much-anticipated NRG Oncology/RTOG 0534 SPPORT trial reported initial results at the 2019 ASTRO meeting.11 This trial randomized 1,736 patients to either (i) salvage radiotherapy to the prostate bed, (ii) salvage radiotherapy to the prostate bed plus ADT, or (iii) salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes. The 5-year freedom from progression rate was 71% for salvage radiotherapy to the prostate bed, 81% for salvage radiotherapy to the prostate bed plus ADT, and 87% for salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes. Based on only 108 patients with metastasis, there were minimal differences between the three arms with regards to metastasis-free survival. It is likely that with continued follow-up, these results will likely continue to favor salvage radiotherapy to the prostate bed plus ADT plus radiotherapy to the pelvic lymph nodes.

Previously, Shipley et al. assessed whether antiandrogen therapy with radiation therapy improves cancer control and prolong OS among patients with biochemical recurrence.12 In this trial, there were 760 patients who had undergone radical prostatectomy with lymphadenectomy and had biochemically recurrent disease who were randomized to radiation therapy and to receive either antiandrogen therapy (24 months of bicalutamide at a dose of 150 mg daily) or daily placebo tablets during and after radiation therapy. The primary endpoint was the OS rate; the actuarial rate of OS at 12 years was 76.3% in the bicalutamide group, as compared with 71.3% in the placebo group (HR 0.77, 95% CI 0.59 to 0.99). The 12-year incidence of death from prostate cancer was 5.8% in the bicalutamide group, as compared with 13.4% in the placebo group (p < 0.001). Finally, the cumulative incidence of metastatic prostate cancer at 12 years was 14.5% in the bicalutamide group, as compared with 23.0% in the placebo group (p = 0.005). As such, the addition of antiandrogen improved clinical outcomes and OS in patients with biochemical recurrence after radical prostatectomy.

Several randomized trials assessing adjuvant vs salvage radiotherapy have been presented earlier this year at academic conferences, but have yet to be published. 

Radiotherapy in the Setting of Metastatic Disease

Several trials have recently assessed the impact of radiotherapy to the prostate in the setting of metastatic disease, given retrospective evidence that patients may derive a survival benefit for treatment to the primary prostate tumor. The HORRAD trial was a multi-center randomized controlled trial recruiting 432 patients with a prostate-specific antigen (PSA) >20ng/ml and primary bone metastatic prostate cancer on bone scan (between 2004 and 2014).13 Patients were randomized to either ADT with external beam radiotherapy or ADT alone. The median PSA level was 142ng/ml and 67% of patients had more than five osseous metastases. Over a median follow up of 47 months, the median OS was 45 months (95% CI, 40.4-49.6) in the radiotherapy group and 43 months (95% CI, 32.6-53.4) in the control group (p = 0.4; HR 0.90, 95% CI 0.70-1.14). The median time to PSA progression in the radiotherapy group was 15 months (95% CI, 11.8-18.2), compared with 12 months (95% CI, 10.6-13.4) in the control group.

Despite the negative results from HORRAD, there was much anticipation for the results of the STAMPEDE arm H clinical trial assessing the efficacy of radiotherapy to the primary in M1 disease.14 This study randomized 2,061 to either standard systemic treatments (ADT +/- chemotherapy) versus standard systemic treatments (ADT +/- chemotherapy) plus radiotherapy to the primary. There were 819 (40%) men that had a low metastatic burden, 1,120 (54%) had a high metastatic burden, and the metastatic burden was unknown for 122 (6%). Radiotherapy improved failure-free survival (HR 0.76, 95% CI 0.68-0.84) but not OS (HR 0.92, 95% CI 0.80-1.06). In a prespecified subgroup analysis, patients receiving radiotherapy to the prostate among patients with low metastatic burden, there was a significant improvement in OS (HR 0.68, 95% CI 0.52-0.90).

The SABR-COMET trial was an important trial published in 2019 assessing stereotactic body radiotherapy to oligometastatic disease.15 The objective of this study was to assess the standard of care of palliative treatments with or without stereotactic body radiotherapy in up to five metastatic lesions. The trialist’s hypothesis was that patients with oligometastatic disease will have improved outcomes with treatment of their metastatic sites. This study included any cancer (primarily breast, prostate, colorectal, and lung) who were then randomized 1:2 to standard of care versus standard of care plus stereotactic body radiotherapy. The standard of care was at the discretion of the physician and the primary endpoint was OS. There were 99 patients at 10 centers and median follow-up was 25.5 months. Median OS was 28 months (95% CI 19-33) in the control group versus 41 months (26-not reached) in the stereotactic body radiotherapy group (HR 0.57, 95% CI 0.30-1.10; p =0.090). Adverse events of grade 2 or worse occurred in three (9%) of 33 controls and 19 (29%) of 66 patients in the stereotactic body radiotherapy group (p=0.026), an absolute increase of 20% (95%CI 5-34). Treatment-related deaths occurred in three (4.5%) of 66 patients after stereotactic body radiotherapy, compared with none in the control group. The authors concluded that stereotactic body radiotherapy was associated with a 13-month increase in OS and doubling of progression-free survival (PFS).

Conclusions

The last five years have seen several important and practice-changing clinical trials for the treatment of prostate cancer with radiotherapy. Early results suggest that ultra-hypofractionation may make primary treatment with radiotherapy an attractive, less arduous option, however long-term OS results for hypofractionation will be important. There is little doubt that the addition of ADT to radiotherapy in high-risk patients for primary treatment and those experiencing biochemical failure after radical prostatectomy improves outcomes. Furthermore, based on results from the STAMPEDE Arm H clinical trial, many clinicians are now treating the prostate primary among men with low-volume metastatic disease. Finally, ongoing studies utilizing stereotactic body radiotherapy to metastatic sites will be important as we focus on improving quality as well as quantity of life for patients with advanced, heavily treated prostate cancer.

Published Date: January 2020

Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
References: 1. Incrocci L, Wortel RC, Alemayehu WG, et al. Hypofractionated versus conventionally fractionated radiotherapy for patients with localised prostate cancer (HYPRO): final efficacy results from a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 2016;17(8):1061-1069.
2. Dearnaley D, Syndikus I, Mossop H, et al. Conventional versus hypofractionated high-dose intensity-modulated radiotherapy for prostate cancer: 5-year outcomes of the randomised, non-inferiority, phase 3 CHHiP trial. Lancet Oncol. 2016;17(8):1047-1060.
3. Widmark A, Gunnlaugsson A, Beckman L, et al. Ultra-hypofractionated versus conventionally fractionated radiotherapy for prostate cancer: 5-year outcomes of the HYPO-RT-PC randomised, non-inferiority, phase 3 trial. Lancet. 2019;394(10196):385-395.
4. Michalski JM, Moughan J, Purdy J, et al. Effect of Standard vs Dose-Escalated Radiation Therapy for Patients With Intermediate-Risk Prostate Cancer: The NRG Oncology RTOG 0126 Randomized Clinical Trial. JAMA Oncol. 2018;4(6):e180039.
5. Zapatero A, Guerrero A, Maldonado X, et al. High-dose radiotherapy with short-term or long-term androgen deprivation in localised prostate cancer (DART01/05 GICOR): a randomised, controlled, phase 3 trial. Lancet Oncol. 2015;16(3):320-327.
6. Bolla M, Maingon P, Carrie C, et al. Short Androgen Suppression and Radiation Dose Escalation for Intermediate- and High-Risk Localized Prostate Cancer: Results of EORTC Trial 22991. J Clin Oncol. 2016;34(15):1748-1756.
7. D'Amico AV, Chen MH, Renshaw A, Loffredo M, Kantoff PW. Long-term Follow-up of a Randomized Trial of Radiation With or Without Androgen Deprivation Therapy for Localized Prostate Cancer. JAMA : the journal of the American Medical Association. 2015;314(12):1291-1293.
8. Denham JW, Joseph D, Lamb DS, et al. Short-term androgen suppression and radiotherapy versus intermediate-term androgen suppression and radiotherapy, with or without zoledronic acid, in men with locally advanced prostate cancer (TROG 03.04 RADAR): 10-year results from a randomised, phase 3, factorial trial. Lancet Oncol. 2019;20(2):267-281.
9. Nabid A, Carrier N, Martin AG, et al. Duration of Androgen Deprivation Therapy in High-risk Prostate Cancer: A Randomized Phase III Trial. Eur Urol. 2018;74(4):432-441.
10. Rosenthal SA, Hu C, Sartor O, et al. Effect of Chemotherapy With Docetaxel With Androgen Suppression and Radiotherapy for Localized High-Risk Prostate Cancer: The Randomized Phase III NRG Oncology RTOG 0521 Trial. J Clin Oncol. 2019;37(14):1159-1168.
11. Pollack A, Karrison TG, Balogh AG. Short term Androgen Deprivation Therapy Without or With Pelvic Lymph Node Treatment Added to Prostate Bed Only Salvage Radiotherapy: The NRG Oncology/RTOG 0534 SPPORT Trial. ASTRO. 2019.
12. Shipley WU, Seiferheld W, Lukka HR, et al. Radiation with or without Antiandrogen Therapy in Recurrent Prostate Cancer. N Engl J Med. 2017;376(5):417-428.
13. Boeve LMS, Hulshof M, Vis AN, et al. Effect on Survival of Androgen Deprivation Therapy Alone Compared to Androgen Deprivation Therapy Combined with Concurrent Radiation Therapy to the Prostate in Patients with Primary Bone Metastatic Prostate Cancer in a Prospective Randomised Clinical Trial: Data from the HORRAD Trial. Eur Urol. 2019;75(3):410-418.
14. Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary tumour for newly diagnosed, metastatic prostate cancer (STAMPEDE): a randomised controlled phase 3 trial. Lancet. 2018;392(10162):2353-2366.
15. Palma DA, Olson R, Harrow S, et al. Stereotactic ablative radiotherapy versus standard of care palliative treatment in patients with oligometastatic cancers (SABR-COMET): a randomised, phase 2, open-label trial. Lancet. 2019;393(10185):2051-2058.

Germline Testing for DNA Repair Mutations in Prostate Cancer: Who, When and How?

Germline testing indications for prostate cancer (PCa) have rapidly expanded and have been catapulted by precision medicine and precision management.1,2 In particular, testing for mutations in DNA repair genes such as in BRCA2, BRCA1, ATM, and other DNA repair genes, has taken front-stage due to the clinical activity of poly (ADP-ribose) polymerase (PARP) inhibitors in metastatic, castration-resistant prostate cancer (mCRPC).3-7 Phase II trial data supported the U.S. Federal Drug Administration (FDA) designations for olaparib, rucaparib, and niraparib due to demonstrated response rates particularly among men with BRCA2 mutations along with other DNA repair genes.5-7 Excitingly, the FDA has recently approved two PARP inhibitors for mCRPC. Rucaparib was granted accelerated approval for BRCA1/2-mutated mCRPC with prior treatment with androgen receptor-directed therapy and taxane-based chemotherapy based on TRITON2.5 Olaparib was FDA-approved for the treatment of mCRPC in men with deleterious or suspected deleterious germline or somatic homologous recombination repair gene mutations who have progressed following prior treatment with enzalutamide or abiraterone based on PROfound.4 These approvals provide exciting therapeutic options for men with mCRPC and will increase the role of germline testing for DNA repair mutations. Furthermore, the National Comprehensive Cancer Network (NCCN) guidelines recommend germline testing for DNA repair mutations in all men with mCRPC, with additional testing criteria proposed.8,9 The international Philadelphia Prostate Cancer Consensus Conference 2019 has provided significant multidisciplinary guidance regarding germline testing for DNA repair mutations across the stage spectrum, along with strategies for implementation of genetic counseling and germline testing.1 Therefore, understanding the role of germline testing in PCa is now critical to urologic and oncology practice for this disease. Here, we will address who should be considered for germline testing, when germline testing may influence treatment and management, and how to implement germline testing involving provider practices and genetic counseling.

Written by: Veda N. Giri, MD
References: 1. Giri, Veda N., Karen E. Knudsen, William K. Kelly, Heather H. Cheng, Kathleen A. Cooney, Michael S. Cookson, William Dahut et al. "Implementation of Germline Testing for Prostate Cancer: Philadelphia Prostate Cancer Consensus Conference 2019." Journal of Clinical Oncology (2020): JCO-20.
2. Cheng, Heather H., Alexandra O. Sokolova, Edward M. Schaeffer, Eric J. Small, and Celestia S. Higano. "Germline and somatic mutations in prostate cancer for the clinician." Journal of the National Comprehensive Cancer Network 17, no. 5 (2019): 515-521.
3. Mateo, Joaquin, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues et al. "DNA-repair defects and olaparib in metastatic prostate cancer." New England Journal of Medicine 373, no. 18 (2015): 1697-1708.
4. de Bono, Johann, Joaquin Mateo, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi et al. "Olaparib for metastatic castration-resistant prostate cancer." New England Journal of Medicine 382, no. 22 (2020): 2091-2102.
5. Abida, Wassim, David Campbell, Akash Patnaik, Jeremy D. Shapiro, Brieuc Sautois, Nicholas J. Vogelzang, Eric G. Voog et al. "Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: Analysis From the Phase II TRITON2 Study." Clinical Cancer Research 26, no. 11 (2020): 2487-2496.
6. Mateo, Joaquin, Nuria Porta, Diletta Bianchini, Ursula McGovern, Tony Elliott, Robert Jones, Isabel Syndikus et al. "Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial." The Lancet Oncology 21, no. 1 (2020): 162-174.
7. Smith, M. R., S. K. Sandhu, W. K. Kelly, H. I. Scher, E. Efstathiou, P. N. Lara, E. Y. Yu et al. "LBA50 Pre-specified interim analysis of GALAHAD: A phase II study of niraparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD)." Annals of Oncology 30, no. Supplement_5 (2019): mdz394-043.
8. National Comprehensive Cancer Network Clinical Guidelines in Oncology (NCCN Guidelines®): Prostate Cancer (Version 4.2019). Accessed June 6, 2020. Available at NCCN.org.
9. National Comprehensive Cancer Network Clinical Guidelines in Oncology (NCCN Guidelines®): Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic (Version 1.2020). Accessed June 6, 2020. Available at NCCN.org.
10. Carter, H. Ballentine, Brian Helfand, Mufaddal Mamawala, Yishuo Wu, Patricia Landis, Hongjie Yu, Kathleen Wiley et al. "Germline mutations in ATM and BRCA1/2 are associated with grade reclassification in men on active surveillance for prostate cancer." European urology 75, no. 5 (2019): 743-749.
11. National Comprehensive Cancer Network Clinical Guidelines in Oncology (NCCN Guidelines®): Prostate Cancer Early Detection (Version 2.2019). Accessed June 6, 2020. Available at NCCN.org.
12. National Cancer Institute Genetics of Prostate Cancer (PDQ®)–Health Professional Version. Accessed June 9, 2020. Available at: https://www.cancer.gov

Bone-Targeted Therapy in Prostate Cancer

Zoledronic acid

To maintain bone integrity during bone remodeling, homeostasis of osteoblasts increasing bone mass and osteoclasts resorbing bone is required. Bisphosphonates are rapidly absorbed on the bone surface and inhibit osteoclast activity by affecting cytoskeletal dynamics. The Phase III Zoledronic acid 039 trial showed that among men with metastatic castration-resistant prostate cancer (mCRPC), a greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%, p =0.021) or those who received zoledronic acid at 8 mg (38.5%, p = 0.222
Written by: Zachary Klaassen, MD, MSc and Christopher J.D. Wallis, MD, PhD
References: 1. Norgaard M, Jensen AO, Jacobsen JB, Cetin K, Fryzek JP, Sorensen HT. Skeletal related events, bone metastasis and survival of prostate cancer: a population based cohort study in Denmark (1999 to 2007). J Urol. 2010;184(1):162-167.
2. Gartrell BA, Coleman R, Efstathiou E, et al. Metastatic Prostate Cancer and the Bone: Significance and Therapeutic Options. Eur Urol. 2015;68(5):850-858.
3. Klaassen Z, Howard LE, de Hoedt A, et al. Factors predicting skeletal-related events in patients with bone metastatic castration-resistant prostate cancer. Cancer. 2017;123(9):1528-1535.
4. Saad F, Gleason DM, Murray R, et al. A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma. J Natl Cancer Inst. 2002;94(19):1458-1468.
5. Smith MR, Halabi S, Ryan CJ, et al. Randomized controlled trial of early zoledronic acid in men with castration-sensitive prostate cancer and bone metastases: results of CALGB 90202 (alliance). J Clin Oncol. 2014;32(11):1143-1150.
6. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. 2011;377(9768):813-822.
7. Smith MR, Saad F, Oudard S, et al. Denosumab and bone metastasis-free survival in men with nonmetastatic castration-resistant prostate cancer: exploratory analyses by baseline prostate-specific antigen doubling time. J Clin Oncol. 2013;31(30):3800-3806.
8. Heidenreich A, Bastian PJ, Bellmunt J, et al. EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. Eur Urol. 2014;65(2):467-479.
9. Parker C, Nilsson S, Heinrich D, et al. Alpha emitter radium-223 and survival in metastatic prostate cancer. N Engl J Med. 2013;369(3):213-223.
10. Smith M, Parker C, Saad F, et al. Addition of radium-223 to abiraterone acetate and prednisone or prednisolone in patients with castration-resistant prostate cancer and bone metastases (ERA 223): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2019;20(3):408-419.
11. Vignani F, Bertaglia V, Buttigliero C, Tucci M, Scagliotti GV, Di Maio M. Skeletal metastases and impact of anticancer and bone-targeted agents in patients with castration-resistant prostate cancer. Cancer Treat Rev. 2016;44:61-73.
12. Basch E, Autio KA, Smith MR, et al. Effects of cabozantinib on pain and narcotic use in patients with castration-resistant prostate cancer: results from a phase 2 nonrandomized expansion cohort. Eur Urol. 2015;67(2):310-318.
13. Araujo JC, Mathew P, Armstrong AJ, et al. Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study. Cancer. 2012;118(1):63-71.
14. Araujo JC, Trudel GC, Saad F, et al. Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial. Lancet Oncol. 2013;14(13):1307-1316.
15. Nelson JB. Endothelin receptor antagonists. World J Urol. 2005;23(1):19-27.
16. Nelson JB, Love W, Chin JL, et al. Phase 3, randomized, controlled trial of atrasentan in patients with nonmetastatic, hormone-refractory prostate cancer. Cancer. 2008;113(9):2478-2487.

PARP Inhibitors - A Breakthrough in Targeted Therapies for Prostate Cancer

PARP inhibition has become a key therapeutic option for a genomically-defined subset of patients with metastatic prostate cancer. Further clinical trial work may expand both the number and setting of PARP inhibitor therapies. In this review, we will summarize the current indications for PARP inhibitor monotherapies and combination(s), review data from clinical trials in prostate cancer, discuss management of commonly encountered side effects, and highlight exciting clinical research on expanding the role of PARP inhibitors in prostate cancer.
Written by: Arpit Rao, MBBS and Charles Ryan, MD
References: 1. Clark, J. B., G. M. Ferris, and S. Pinder. "Inhibition of nuclear NAD nucleosidase and poly ADP-ribose polymerase activity from rat liver by nicotinamide and 5′-methyl nicotinamide." Biochimica et Biophysica Acta (BBA)-Nucleic Acids and Protein Synthesis 238, no. 1 (1971): 82-85.
2. Tentori, Lucio, Ilaria Portarena, and Grazia Graziani. "Potential clinical applications of poly (ADP-ribose) polymerase (PARP) inhibitors." Pharmacological research 45, no. 2 (2002): 73-85.
3. Farmer, H., N. McCabe, C. J. Lord, and A. N. Tutt. "Johnso n DA, Richardson TB, Santarosa M, Dillon KJ, Hickson I, Knights C, Martin NM, Jackson SP, Smith GC and Ashworth A. Targeting the DN A repair defect in BRCA mutant cells as a therapeutic strategy." Nature 434 (2005): 917-921.
4. Bryant, Helen E., Niklas Schultz, Huw D. Thomas, Kayan M. Parker, Dan Flower, Elena Lopez, Suzanne Kyle, Mark Meuth, Nicola J. Curtin, and Thomas Helleday. "Specific killing of BRCA2-deficient tumours with inhibitors of poly (ADP-ribose) polymerase." Nature 434, no. 7035 (2005): 913-917.
5. “Drugs@FDA: FDA-Approved Drugs.” Accessed June 14, 2020. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=reportsSearch.process.
6. U.S. Food and Drug Administration - Full prescribing information for Lynparza (olaparib). U.S. Food and Drug Administration - Full prescribing information for Lynparza (olaparib). Accessed June 14, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208558s013lbl.pdf
7. U.S. Food and Drug Administration - Full prescribing information for Rubraca (rucaparib). U.S. Food and Drug Administration - Full prescribing information for Rubraca (rucaparib). Accessed June 14, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/209115s004lbl.pdf
8. U.S. Food and Drug Administration - Full prescribing information for Zejula (niraparib). U.S. Food and Drug Administration - Full prescribing information for Zejula (niraparib). Accessed June 14, 2020.https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/208447s015s017lbledt.pdf
9. U.S. Food and Drug Administration - Full prescribing information for Talzenna (talazoparib). U.S. Food and Drug Administration - Full prescribing information for Talzenna (talazoparib). Accessed June 14, 2020. https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/211651s005lbl.pdf
10. Mateo, Joaquin, Suzanne Carreira, Shahneen Sandhu, Susana Miranda, Helen Mossop, Raquel Perez-Lopez, Daniel Nava Rodrigues et al. "DNA-repair defects and olaparib in metastatic prostate cancer." New England Journal of Medicine 373, no. 18 (2015): 1697-1708.
11. Mateo, Joaquin, Nuria Porta, Diletta Bianchini, Ursula McGovern, Tony Elliott, Robert Jones, Isabel Syndikus et al. "Olaparib in patients with metastatic castration-resistant prostate cancer with DNA repair gene aberrations (TOPARP-B): a multicentre, open-label, randomised, phase 2 trial." The Lancet Oncology 21, no. 1 (2020): 162-174.
12. de Bono, Johann, Joaquin Mateo, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi et al. "Olaparib for metastatic castration-resistant prostate cancer." New England Journal of Medicine 382, no. 22 (2020): 2091-2102.
13. Abida, W., D. Campbell, A. Patnaik, B. Sautois, J. Shapiro, N. J. Vogelzang, A. H. Bryce et al. "Preliminary results from the TRITON2 study of rucaparib in patients (pts) with DNA damage repair (DDR)-deficient metastatic castration-resistant prostate cancer (mCRPC): Updated analyses." Annals of Oncology 30 (2019): v327-v328.
14. Smith, Matthew Raymond, Shahneen Kaur Sandhu, William Kevin Kelly, Howard I. Scher, Eleni Efstathiou, Primo Lara, Evan Y. Yu et al. "Phase II study of niraparib in patients with metastatic castration-resistant prostate cancer (mCRPC) and biallelic DNA-repair gene defects (DRD): preliminary results of GALAHAD." (2019): 202-202.
15. De Bono, Johann S., Niven Mehra, Celestia S. Higano, Fred Saad, Consuelo Buttigliero, Marielena Mata, Hsiang-Chun Chen et al. "TALAPRO-1: A phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—First interim analysis (IA)." (2020): 119-119.
16. LaFargue, Christopher J., Graziela Z. Dal Molin, Anil K. Sood, and Robert L. Coleman. "Exploring and comparing adverse events between PARP inhibitors." The Lancet Oncology 20, no. 1 (2019): e15-e28.
17. Sandhu, Shahneen K., William R. Schelman, George Wilding, Victor Moreno, Richard D. Baird, Susana Miranda, Lucy Hylands et al. "The poly (ADP-ribose) polymerase inhibitor niraparib (MK4827) in BRCA mutation carriers and patients with sporadic cancer: a phase 1 dose-escalation trial." The lancet oncology 14, no. 9 (2013): 882-892.
18. Francica, Paola, and Sven Rottenberg. "Mechanisms of PARP inhibitor resistance in cancer and insights into the DNA damage response." Genome medicine 10, no. 1 (2018): 1-3.
19. Brenner, J. Chad, Bushra Ateeq, Yong Li, Anastasia K. Yocum, Qi Cao, Irfan A. Asangani, Sonam Patel et al. "Mechanistic rationale for inhibition of poly (ADP-ribose) polymerase in ETS gene fusion-positive prostate cancer." Cancer cell 19, no. 5 (2011): 664-678.
20. Asim, Mohammad, Firas Tarish, Heather I. Zecchini, Kumar Sanjiv, Eleni Gelali, Charles E. Massie, Ajoeb Baridi et al. "Synthetic lethality between androgen receptor signaling and the PARP pathway in prostate cancer." Nature communications 8, no. 1 (2017): 1-10.
21. Clarke, Noel, Pawel Wiechno, Boris Alekseev, Nuria Sala, Robert Jones, Ivo Kocak, Vincenzo Emanuele Chiuri et al. "Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial." The Lancet Oncology 19, no. 7 (2018): 975-986.

Beyond First-line Treatment of Metastatic Castrate-resistant Prostate Cancer

In the previous review article (“First-line treatment of metastatic castrate-resistant prostate cancer”), metastatic castrate-resistant prostate cancer (mCRPC) and its approved first-line treatment options were elaborated. Unfortunately, all mCRPC patients will eventually progress despite evidence-based first-line treatments that patients receive. Therefore, an appropriate treatment strategy must be formalized. The working group of the Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II (RADAR II) study attempted to offer recommendations on identifying disease progression, treatment management strategies, and suggestions on timing of initiating and discontinuing specific (CRPC) treatments.1 They recommended a layering approach comprised of approved therapies with unique or complementary mechanisms of action.1 According to this working group 12 Phase III studies evaluating combinations, layering, or sequencing of these agents are required to help improve clinical outcomes in the castrate clinical state. Following first-line treatment options for mCRPC patients, only second-line treatments given after treatment with docetaxel have been extensively assessed and these are detailed below.

Second-line treatment options for metastatic castrate-resistant prostate cancer

Cabazitaxel

Cabazitaxel is a new taxane drug with activity in docetaxel-resistant cancers. In the TROPIC study, a Phase III prospective randomized trial, cabazitaxel plus prednisone was compared to mitoxantrone plus prednisone in 755 mCRPC patients, who progressed after or during treatment with docetaxel2 (Figure 1). Patients received a maximum of ten cycles of cabazitaxel or mitoxantrone plus prednisone. Overall survival (OS) was the primary end-point, being significantly longer in cabazitaxel-treated patients (median: 15.1 vs. 12.7 months p < 0.0001). Progression-free survival (PFS) was significantly improved as well (median: 2.8 vs. 1.4 months, p < 0.0001), and prostate-specific antigen (PSA) response rate was also better (39.2% vs. 17.8%, p < 0.0002). Grade 3-4 adverse events developed more significantly in patients taking cabazitaxel, particularly hematological adverse effects (68.2% vs. 47.3%, p < 0.0002).3 Therefore, cabazitaxel should be given with prophylactic granulocyte colony-stimulating factor and needs to be administered by physicians with expertise in handling neutropenia and sepsis.4 When compared to docetaxel in the first-line setting, cabazitaxel was not shown to be superior.5


figure 1 TROPIC design

Figure 1
. TROPIC study design

Abiraterone following docetaxel

The COU-AA-301 was a large Phase III randomized trial with a total of 1,195 mCRPC patients being randomised in a 2:1 ratio to abiraterone acetate plus prednisone or placebo plus prednisone (Figure 2). Abiraterone is an antiandrogen agent which inhibits the 17α-hydroxylase/C17,20-lyase (CYP17) enzyme. Initial positive results of this trial were reported after a median follow-up of 12.8 months6 and confirmed by the final analysis.7 All patients in this trial failed at least one chemotherapy regimen, which included docetaxel. The primary end-point was OS, and in the final analysis, after a median follow-up of 20.2 months there was a clear advantage to the abiraterone arm (median survival of 15.8 vs.11.2 months, HR: 0.74, p < 0.0001). The benefit for abiraterone remained in all secondary endpoints as well (PSA, radiologic tissue response, time to PSA or objective progression). No significant difference between the treatment arms was seen in the rate of grade 3-4 adverse events, aside from a higher rate of mineralocorticoid-related side-effects (mainly grade 1-2 fluid retention, edema, and hypokalaemia).7

figure 2 COU AA 301

Figure 2. COU-AA-301 study design

Enzalutamide after docetaxel

The AFFIRM trial randomized 1,199 mCRPC patients in a 2:1 fashion to enzalutamide, a nonsteroidal antiandrogen, or placebo (Figure 3). All accrued patients had progressed after docetaxel treatment.8 The planned interim analysis of the AFFIRM study was published in 2012 and after a median follow-up of 14.4 months, a clear benefit was shown for the enzalutamide-treated patients (median survival of 18.4 vs. 13.6 months, HR: 0.63, p < 0.001).8 This led to the recommendation to halt and unblind the study. Importantly, the observed benefit occurred irrespective of age, baseline pain intensity, and type of progression. Enzalutamide was also beneficial in patients with visceral metastases. The final analysis with longer follow-up had confirmed the OS results despite the crossover and extensive post-progression therapies. Enzalutamide also conferred a clear advantage in all the secondary endpoints (PSA, soft tissue response, quality of life, time to PSA or objective progression).8 No significant difference in the rate of side-effects was observed in the two groups, with a lower incidence of grade 3-4 adverse events in the enzalutamide arm. Importantly, enzalutamide-treated patients had a 0.6% incidence of seizures compared to none in the placebo arm.8


figure 3 AFFIRM trial

Figure 3. AFFIRM trial design

Apalutamide
Radium-223

Radium-223 is a targeted alpha therapy and is the only bone-specific drug that has been associated with a survival benefit in the mCRPC space. The ALSYMPCA trial was a large Phase III trial accruing 921 symptomatic mCRPC patients, who failed or were unfit for docetaxel chemotherapy.13 In this trial, patients were randomized to six injections of radium-223 or placebo, plus standard of care in both arms (Figure 4). The primary end-point was OS, and radium-223 significantly improved median OS by 3.6 months (HR: 0.70, p < 0.001).13 Radium-223 also conferred prolonged time to first skeletal event, improvement in pain scores and quality of life.13 No significant difference was noted in the rate of adverse effects between the treatment arms, aside from slightly more haematologic toxicity and diarrhea with radium-223.13 Whether patients were pretreated with docetaxel did not affect the benefit and safety of radium-223.14 Due to safety concerns, the label of radium-223 was restricted to use after docetaxel and at least one AR targeted agent.15 Importantly, the ERA-223 study assessed the effectiveness of early use of radium-223 together with abiraterone acetate and prednisolone (Figure 5). Unfortunately, this trial showed significant safety risks, especially with fractures and more deaths. Therefore, this combination is currently not recommended. These safety risks were more significant in patients without the concurrent use of antiresorptive agents.16


figure 4 ALSYMPCA trial

Figure 4
. ALSYMPCA trial design



figure 5 EERA 223 trial

Figure 5. ERA 223 study design

Third line treatment following treatment with docetaxel and one hormonal treatment for metastatic castrate-resistant prostate cancer


Currently, there are no clear guidelines or recommendations regarding which treatment option is appropriate in this setting and this is open for debate. The choice for further treatment after docetaxel and one line of hormonal treatment for mCRPC is unclear.17 The available options include radium-223 or second-line chemotherapy (cabazitaxel). In unselected patients, subsequent treatments are expected to have a lower benefit than with earlier use18. There is also evidence that cross-resistance between enzalutamide and abiraterone exists.19, 20 There is a unique subset of patients worth mentioning with tumors demonstrating homozygous deletions or deleterious mutations in DNA-repair genes. In these patients Poly(ADP-ribose) polymerase (PARP) inhibitors have been reported to confer high rates of response. Therefore, patients who were previously treated with docetaxel and at least one novel hormonal agent; and whose tumors demonstrated homozygous deletions or deleterious mutations in DNA-repair genes showed an 88% response rate to Olaparib, a PAPR inhibitor.21 This represents an example of how treatment can be tailored according to the tumor mutation profile.22 In a randomized Phase II study of mCRPC patients, olaparib combined with abiraterone was compared to placebo and abiraterone. This study demonstrated a clinical benefit in olaparib-treated patients, regardless if mutations in DNA-repair genes existed.23 However, this combination treatment was shown to be toxic with significant side effects reported in 34% of patients vs. only 18% in the placebo arm.23 

For patients with mismatch repair deficiency, the PD-1 inhibitor pembrolizumab was approved by the FDA for all tumors, including PCa. More specifically, pembrolizumab demonstrated antitumor activity and disease control with acceptable safety in RECIST-measurable and bone-predominant mCRPC, which was previously treated with docetaxel and novel AR antagonists.24 

In the COMET-1 trial 1028 patients with progressive mCRPC after treatment with docetaxel and abiraterone and/or enzalutamide were randomly assigned at a 2:1 ratio to either cabozantinib 60 mg, a tyrosine kinase inhibitor, or prednisone 5 mg twice per day.25 The primary endpoint was OS, and the secondary endpoint included bone scan response after 12 weeks of treatment. Additional exploratory analyses included radiographic PFS (rPFS) and effects on circulating tumor cells, bone biomarkers, serum PSA, and symptomatic skeletal events.25 This trial demonstrated that cabozantinib did not significantly improve OS compared with prednisone in heavily pre-treated mCRPC patients (median OS was 11.0 months with cabozantinib and 9.8 months with prednisone, HR 0.90; 95% CI, 0.76 to 1.06; stratified log-rank P = 0.213).25 Cabozantinib had some activity in improving bone scan response, rPFS, symptomatic skeletal events, and bone biomarkers but not PSA outcomes.25

Changing and sequencing treatment in metastatic castrate-resistant prostate cancer


There are several open questions and dilemmas regarding when to change treatment in mCRPC patients and what is the most appropriate treatment sequence.

The appropriate time to change treatment in mCRPC patients is not entirely clear. No controversy exists regarding the need to change treatment when patients have symptomatic progression of their metastatic disease. Despite the many available treatment options to date, no head to head comparison has been made publicly available, while data assessing the correct sequence of treatment is being assessed. As data are lacking, physicians have been using the ECOG performance score to stratify patients before deciding on the “appropriate” treatment plan. Men with a good performance status are likely to tolerate more treatments as opposed to men with lower performance scores.

The National Comprehensive Cancer Network (NCCN) considers the onset of visceral disease to be a detrimental factor. Patients with liver metastases have especially poor outcomes for as of yet an unknown reason. In a meta-analysis including over 8,000 mCRPC patients who were enrolled in Phase III trials, patients with lymph-node- only disease appeared to have the best OS (median, 31.6 months; 95% CI, 27.9 to 36.6 months), with patients with lung and bone metastases having shorter and similar median OS (19.4 months [95% CI, 17.8 to 20.7 months] vs. 21.3 months [20.8 to 21.9], respectively), and patients with liver metastases demonstrating the worst OS (median, 13.5 months; 95% CI, 12.7 to 14.4 months).26 Therefore, the type of metastases the patient has can be used as a guide to when and how aggressive the treatment strategy should be.

Abiraterone and enzalutamide are highly active agents harboring a substantial effect on PFS, with trials comparing monotherapy with prednisone or placebo.27, 28 However, a subset of patients will not respond to these drugs. A patient who does not respond well will require a change of treatment. It is therefore important to see these patients frequently once starting therapy and assess their response. If no PSA decline is witnessed, the treatment needs to be changed.

When considering the appropriate treatment sequence in mCRPC, there are no clear guidelines or recommendations to date, and our limited knowledge is based mainly on retrospective data. In one non-randomized retrospective study, PFS, OS, and PSA responses from consecutive patients with chemotherapy-naïve mCRPC were compared between those who received abiraterone followed by enzalutamide and those who received enzalutamide followed by abiraterone.29 Initially, a slight improvement in patients who started with abiraterone and transitioned to enzalutamide was seen with improved PFS. An expanded retrospective study confirmed the general trend, showing that patients who started with abiraterone and then transitioned to enzalutamide had better PFS (median, 455 days [95% CI, 385 to 495 days]) than patients who started with enzalutamide and transitioned to abiraterone (median, 296 days; 95% CI, 235 to 358 days).30 However, OS was not significantly different between the groups.30 Furthermore, the authors of an ongoing randomized Phase II study comparing abiraterone vs. enzalutamide in patients with treatment-naïve mCRCP reported their interim results.31 After a median follow-up of 22.3 months, a PSA decline of more than 50% occurred in 34% of abiraterone treated patients compared to 4% in the enzalutamide treated patients (p<0.001).31 Additionally, the median time to PSA progression on 2nd-line therapy was 2.7 vs 1.3 months (HR 0.38, 95% CI 0.26-0.56) in favor of abiraterone.31 Lastly, the median OS was not reached vs 24.3 months (HR 0.82, 95% CI 0.53-1.27) in favor of abiraterone.31 As data regarding appropriate treatment sequencing is still being collected and analyzed, many physicians currently base their decision on which medication to start according to the adverse effects that we want to avoid. Abiraterone is commonly associated with edema, and therefore should be avoided in men with congestive heart failure,27 while enzalutamide is more likely to cause central nervous system toxicity and should probably be avoided in older patients.32 

Radioligand therapy for metastatic castrate-resistant prostate cancer patients


PSMA-PET/CT imaging has significantly become more common in recent years. This has led to the emergence of a new field of radioligand directed therapy among heavily pretreated mCRPC patients. PCa metastases express PSMA, making it a promising approach to developing new tracers for targeted radionuclide therapies. PSMA is a non-secreted type II transmembrane protein produced almost exclusively by prostatic tissue and on tumor-associated neovasculature.33 Unlike other biomarkers, such as PSA, which may decrease with increasing neoplastic de-differentiation, PSMA has been shown to be upregulated in high-grade, de-differentiated PCa.34 

Since 2015, several institutional studies have reported promising response rates and a favorable safety profile for radioligand therapy with 177Lu-PSMA-617 in mCRPC patients.35-37 However, these studies had small sample sizes and questionable generalizability. To addresses these limitations, a large multicenter German analysis assessed a cohort of patients treated with 177Lu-PSMA-617.38 This study included 145 mCRPC patients treated with 177Lu-PSMA-617 at 12 centers undergoing 1-4 therapy cycles. The study reported an overall biochemical response rate of 45% after all therapy cycles, with 40% of patients responding after a single cycle. Notably, negative predictors of the biochemical response included elevated alkaline phosphatase and the presence of visceral metastases.38

In a large meta-analysis published in 2017, 10 studies were assessed including 369 patients. This meta-analysis assessed the safety and efficacy of 177-Lutetium in mCRPC patients.39 The pooled proportion of patients with any PSA decline was 68% (95% CI: 61–74%); and the pooled proportion of patients with 450% PSA decline was 37% (95% CI: 22–52).39 This meta-analysis suggested promising early results for the treatment of mCRPC patients, especially in patients treated with the more recently developed radioligands, with approximately two-thirds of them showing a biochemical response.39 

Although 177Lu-PSMA-617 is the most well-studied radioligand to date, there are additional compounds in development and undergoing initial testing. These include 177Lu-J591, 90Y-J591, 131I-MIP 1095, 177Lu-PSMA-I&T, and 225Ac-PSMA-617.40

Treatment and prevention of skeletal-related events


Patients with mCRPC commonly endure painful bone metastases with external beam radiotherapy (EBRT) being a highly effective treatment.41 Possible complications due to bone metastases include vertebral collapse or deformity, pathological fractures, and spinal cord compression. Cementation can be an effective treatment for a painful spinal fracture, clearly improving both pain and quality of life.42 However, standard palliative surgery can still be offered for managing osteoblastic metastases.43 Impending spinal cord compression is an emergency event that must be recognized as soon as possible. Patients should be educated to recognize the warning signs. If this is suspected, high-dose corticosteroids must be given and an MRI is required. A neurosurgeon or orthopedic surgeon consultation needs to be planned to discuss a possible decompression, followed by EBRT.44

Zoledronic acid, a bisphosphonate, has been evaluated in mCRPC patients in an attempt to reduce skeletal-related events (SRE). 643 mCRPC patients with bone metastases were randomized to receive zoledronic acid, 4 or 8 mg every three weeks for fifteen consecutive months, or placebo.45 The 8 mg dose was poorly tolerated without showing a significant benefit. However, at 15 and 24 months of follow-up, the 4 mg dose conferred fewer SREs compared to the placebo group (44 vs. 33%, p = 0.021), and less pathological fractures (13.1 vs. 22.1%, p = 0.015). Additionally, the time to first SRE was longer in the zoledronic acid group. However, no survival benefit was seen in any prospective trial assessing bisphosphonates.

Denosumab is a fully human monoclonal antibody directed against RANKL (receptor activator of nuclear factor kappa-B ligand). It is a key mediator of osteoclast formation, function, and survival. In non-metastatic CRPC, denosumab has been associated with increased bone-metastasis-free survival compared to placebo (median benefit: 4.2 months, HR: 0.85, p = 0.028).44 Like zoledronic acid, this benefit did not translate into a survival difference and neither the FDA or the EMA had approved denosumab for this indication.46 A Phase III trial compared the efficacy and safety of denosumab (n = 950) with zoledronic acid (n = 951) in mCRPC patients. Denosumab was shown to be superior to zoledronic acid in delaying or preventing SREs, as shown by time to first SRE (pathological fracture, radiation or surgery to bone, or spinal cord compression) of 20.7 vs. 17.1 months, respectively (HR: 0.82, p = 0.008). However, these findings were not associated with any survival benefit, and in a recent post-hoc re-evaluation of end-points, denosumab had actually shown an identical rate of SREs to zoledronic acid.47 It is critical to remember that these medications are associated with substantial toxicity, of 5% and 8.2% in non-metastatic CRPC and mCRPC, respectively.47, 48 All patients are required to be examined by a dentist prior to initiating this therapy, as the risk of jaw necrosis is increased by several risk factors including a history of trauma, dental surgery or dental infection.49 and the number of years the medication is used.

Recently, the randomized, double-blind Phase III trial (COMET-2; NCT01522443) was published, comparing cabozantinib, to mitoxantrone + prednisone in mCRPC patients with narcotic-dependent pain from bone metastases.50 All patients had progressed after treatment with docetaxel and either abiraterone or enzalutamide.50 The primary endpoint was pain response at week 6 and confirmed again at week 12. Enrollment was terminated early because cabozantinib did not demonstrate any survival benefit in mCRPC patients in the companion COMET-1 trial,25 described earlier. At study closure of the COMET-2 trial, only 119 patients were randomized. The trial demonstrated no significant difference in the pain response with cabozantinib versus mitoxantrone-prednisone.50

Future and ongoing trials


There are currently 24 registered ongoing Phase III trials involving mCRPC patients.

Some studies worth mentioning with much-anticipated results include the following:

  1. The combination of abiraterone and Olaparib as first-line therapy in mCRPC patients (NCT03732820)
  2. A study assessing the role of Rucaparib (a PARP inhibitor) vs. physician’s choice therapy in mCRPC patients (TRITON3 trial - NCT02975934)
  3. The combination of pembrolizumab with various other medications including enzalutamide (NCT03834493 - as part of the MK-3475-641/KEYNOTE-641 trial), docetaxel (NCT03834506 - as part of the MK-3475-921/KEYNOTE-921 trial), and olaparib (NCT03834519 – as part of the MK-7339-010/KEYLYNK-010)
  4. The ACIS trial, which will assess the combination of apalutamide, and abiraterone + prednisone in mCRPC patients (NCT02257736)
  5. A study assessing Masitinib (a tyrosine kinase inhibitor) plus docetaxel (NCT03761225)
  6. The combination of Talazoparib (a PARP inhibitor) + plus enzalutamide (NCT03395197),
  7. The combination of Atezolizumab (an anti-PD-L1 monoclonal antibody) + enzalutamide (NCT03016312)
  8. The combination of docetaxel and Radium-223 (NCT03574571)
  9. A study assessing 177Lu-PSMA-617 in mCRPC patients (NCT03511664)
  10. The IPATential150 trial – assessing the combination of Ipatasertib (an orally administered, ATP-competitive, selective AKT inhibitor) plus abiraterone (NCT03072238)

Conclusions


Substantial progress has been made in the mCRPC space in the last several years. Optimal management of mCRPC patients is a growing challenge as more potential treatments are added to the armamentarium. Choosing the right treatment for the right patient, and the correct sequence and combination of the increasing number of available medications will be the main challenge in the years to come. We currently lack level one evidence regarding the proper sequence and/or combination of current available medications, and physicians are faced with making these decisions without supporting data. Patients will most likely benefit from unique medications with complementary mechanisms of action in order to avoid cross-resistance. An important unmet clinical need thus far consists of acquiring evidence about the efficacy, safety, and tolerability of combination regimens, and optimized approaches for identifying patients most suited for specific treatments.

Published Date: November 19th, 2019

Written by: Hanan Goldberg, MD
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  31. Khalaf D, Annala M, Finch DL, et al. Phase 2 randomized cross-over trial of abiraterone + prednisone (ABI+P) vs enzalutamide (ENZ) for patients (pts) with metastatic castration resistant prostate cancer (mCPRC): Results for 2nd-line therapy. Journal of Clinical Oncology. 2018;36(15_suppl):5015-5015.
  32. Pilon D, Behl AS, Gozalo L, et al. Assessment of central nervous system (CNS) and dose reduction events in patients treated with abiraterone acetate plus prednisone (AA+P) or enzalutamide (ENZ). Journal of Clinical Oncology. 2016;34(15_suppl):5078-5078.
  33. Kulkarni HR, Singh A, Schuchardt C, et al. PSMA-Based Radioligand Therapy for Metastatic Castration-Resistant Prostate Cancer: The Bad Berka Experience Since 2013. J Nucl Med. Oct 2016;57(Suppl 3):97s-104s.
  34. Baum RP, Kulkarni HR, Schuchardt C, et al. 177Lu-Labeled Prostate-Specific Membrane Antigen Radioligand Therapy of Metastatic Castration-Resistant Prostate Cancer: Safety and Efficacy. J Nucl Med. Jul 2016;57(7):1006-1013.
  35. Ahmadzadehfar H, Eppard E, Kurpig S, et al. Therapeutic response and side effects of repeated radioligand therapy with 177Lu-PSMA-DKFZ-617 of castrate-resistant metastatic prostate cancer. Oncotarget. Mar 15 2016;7(11):12477-12488.
  36. Kratochwil C, Giesel FL, Stefanova M, et al. PSMA-Targeted Radionuclide Therapy of Metastatic Castration-Resistant Prostate Cancer with 177Lu-Labeled PSMA-617. J Nucl Med. Aug 2016;57(8):1170-1176.
  37. Rahbar K, Schmidt M, Heinzel A, et al. Response and Tolerability of a Single Dose of 177Lu-PSMA-617 in Patients with Metastatic Castration-Resistant Prostate Cancer: A Multicenter Retrospective Analysis. J Nucl Med. Sep 2016;57(9):1334-1338.
  38. Rahbar K, Ahmadzadehfar H, Kratochwil C, et al. German Multicenter Study Investigating 177Lu-PSMA-617 Radioligand Therapy in Advanced Prostate Cancer Patients. J Nucl Med. Jan 2017;58(1):85-90.
  39. Calopedos RJS, Chalasani V, Asher R, Emmett L, Woo HH. Lutetium-177-labelled anti-prostate-specific membrane antigen antibody and ligands for the treatment of metastatic castrate-resistant prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis. Sep 2017;20(3):352-360.
  40. Awang ZH, Essler M, Ahmadzadehfar H. Radioligand therapy of metastatic castration-resistant prostate cancer: current approaches. Radiat Oncol. May 23 2018;13(1):98.
  41. Dy SM, Asch SM, Naeim A, Sanati H, Walling A, Lorenz KA. Evidence-based standards for cancer pain management. J Clin Oncol. Aug 10 2008;26(23):3879-3885.
  42. Frankel BM, Monroe T, Wang C. Percutaneous vertebral augmentation: an elevation in adjacent-level fracture risk in kyphoplasty as compared with vertebroplasty. Spine J. Sep-Oct 2007;7(5):575-582.
  43. Frankel BM, Jones T, Wang C. Segmental polymethylmethacrylate-augmented pedicle screw fixation in patients with bone softening caused by osteoporosis and metastatic tumor involvement: a clinical evaluation. Neurosurgery. Sep 2007;61(3):531-537; discussion 537-538.
  44. Marco RA, Sheth DS, Boland PJ, Wunder JS, Siegel JA, Healey JH. Functional and oncological outcome of acetabular reconstruction for the treatment of metastatic disease. J Bone Joint Surg Am. May 2000;82(5):642-651.
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  46. Fizazi K, Carducci M, Smith M, et al. Denosumab versus zoledronic acid for treatment of bone metastases in men with castration-resistant prostate cancer: a randomised, double-blind study. Lancet. Mar 5 2011;377(9768):813-822.
  47. Smith MR, Saad F, Coleman R, et al. Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial. Lancet. Jan 7 2012;379(9810):39-46.
  48. Stopeck AT, Fizazi K, Body JJ, et al. Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer. Support Care Cancer. Jan 2016;24(1):447-455.
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  50. Basch EM, Scholz M, de Bono JS, et al. Cabozantinib Versus Mitoxantrone-prednisone in Symptomatic Metastatic Castration-resistant Prostate Cancer: A Randomized Phase 3 Trial with a Primary Pain Endpoint. Eur Urol. Jun 2019;75(6):929-937.

What Are the Most Common Genomic Aberrations Seen in DNA Damage Response (DDR) Pathways in Advanced Prostate Cancer?

What are the most common genomic aberrations seen in DNA damage response (DDR) pathways in advanced prostate cancer?


Men with advanced prostate cancer have a 10-15% risk of carrying a hereditary, or germline, variant in a DNA damage response (DDR) gene, as previously discussed. Pathogenic or deleterious variants in these same DDR genes can also be found at the somatic, or tumor-associated level, in up to 25% of metastatic castrate-resistant prostate cancer.1 Precision medicine currently centers mostly on discovering these somatic aberrations through DNA sequencing to then guide targeted treatment selection for patients with advanced cancer. Compared to other solid tumors such as melanoma or urothelial cancers, advanced prostate cancer overall displays relatively low tumor mutational burden (TMB), with rare exceptions including those tumors with mismatch repair (MMR) deficiency and/or subsequent high microsatellite instability (MSI-H). Defective MMR genes and/or MSI-H are seen in ~3-8% of prostate cancer, with the majority being of sporadic origin and with Lynch syndrome not displaying high penetrance in prostate cancer.2-4 The remainder of DDR defects seen in prostate cancer center mostly around the DNA double-strand break repair, replication stress signaling, and cell cycle regulation pathways. DDR gene alterations occur in ~25% of metastatic castration-resistant prostate cancer (mCRPC), with BRCA2 being by far the most frequently altered gene in this pathway, followed by ATM, and then to a lesser degree BRCA1 and CDK12, with more rare deleterious variants found in multiple other homologous recombination repair (HRR) and cell cycle genes.1 Alterations in BRCA2 are found significantly greater in advanced prostate cancer compared to primary disease, and certain histologic subtypes like ductal and cribriform disease are enriched for deleterious variants in DDR genes.5
Written by: Patrick G. Pilié, MD
References: 1. Robinson, Dan, Eliezer M. Van Allen, Yi-Mi Wu, Nikolaus Schultz, Robert J. Lonigro, Juan-Miguel Mosquera, Bruce Montgomery et al. "Integrative clinical genomics of advanced prostate cancer." Cell 161, no. 5 (2015): 1215-1228.
2. Rodrigues, Daniel Nava, Pasquale Rescigno, David Liu, Wei Yuan, Suzanne Carreira, Maryou B. Lambros, George Seed et al. "Immunogenomic analyses associate immunological alterations with mismatch repair defects in prostate cancer." The Journal of clinical investigation 128, no. 10 (2018): 4441-4453.
3. Bauer, Christina M., Anna M. Ray, Bronwen A. Halstead-Nussloch, Robert G. Dekker, Victoria M. Raymond, Stephen B. Gruber, and Kathleen A. Cooney. "Hereditary prostate cancer as a feature of Lynch syndrome." Familial cancer 10, no. 1 (2011): 37-42.
4. Abida, Wassim, Michael L. Cheng, Joshua Armenia, Sumit Middha, Karen A. Autio, Hebert Alberto Vargas, Dana Rathkopf et al. "Analysis of the prevalence of microsatellite instability in prostate cancer and response to immune checkpoint blockade." JAMA oncology 5, no. 4 (2019): 471-478.
5. Schweizer, Michael T., Emmanuel S. Antonarakis, Tarek A. Bismar, Liana B. Guedes, Heather H. Cheng, Maria S. Tretiakova, Funda Vakar-Lopez et al. "Genomic characterization of prostatic ductal adenocarcinoma identifies a high prevalence of DNA repair gene mutations." JCO precision oncology 3 (2019): 1-9.
6. Gundem, Gunes, Peter Van Loo, Barbara Kremeyer, Ludmil B. Alexandrov, Jose MC Tubio, Elli Papaemmanuil, Daniel S. Brewer et al. "The evolutionary history of lethal metastatic prostate cancer." Nature 520, no. 7547 (2015): 353-357.
7. Wyatt, Alexander W., Matti Annala, Rahul Aggarwal, Kevin Beja, Felix Feng, Jack Youngren, Adam Foye et al. "Concordance of circulating tumor DNA and matched metastatic tissue biopsy in prostate cancer." JNCI: Journal of the National Cancer Institute 109, no. 12 (2017).
8. Li, Marilyn M., Michael Datto, Eric J. Duncavage, Shashikant Kulkarni, Neal I. Lindeman, Somak Roy, Apostolia M. Tsimberidou et al. "Standards and guidelines for the interpretation and reporting of sequence variants in cancer: a joint consensus recommendation of the Association for Molecular Pathology, American Society of Clinical Oncology, and College of American Pathologists." The Journal of molecular diagnostics 19, no. 1 (2017): 4-23.
9. Ng, Patrick Kwok-Shing, Jun Li, Kang Jin Jeong, Shan Shao, Hu Chen, Yiu Huen Tsang, Sohini Sengupta et al. "Systematic functional annotation of somatic mutations in cancer." Cancer Cell 33, no. 3 (2018): 450-462.
10. Yi, Song, Shengda Lin, Yongsheng Li, Wei Zhao, Gordon B. Mills, and Nidhi Sahni. "Functional variomics and network perturbation: connecting genotype to phenotype in cancer." Nature Reviews Genetics 18, no. 7 (2017): 395.
11. Johnson, Amber, Jia Zeng, Ann M. Bailey, Vijaykumar Holla, Beate Litzenburger, Humberto Lara-Guerra, Gordon B. Mills, John Mendelsohn, Kenna R. Shaw, and Funda Meric-Bernstam. "The right drugs at the right time for the right patient: the MD Anderson precision oncology decision support platform." Drug discovery today 20, no. 12 (2015): 1433-1438.
12. Li, Quan, and Kai Wang. "InterVar: clinical interpretation of genetic variants by the 2015 ACMG-AMP guidelines." The American Journal of Human Genetics 100, no. 2 (2017): 267-280.
13. Kurnit, Katherine C., Ecaterina E. Ileana Dumbrava, Beate Litzenburger, Yekaterina B. Khotskaya, Amber M. Johnson, Timothy A. Yap, Jordi Rodon et al. "Precision oncology decision support: current approaches and strategies for the future." Clinical Cancer Research 24, no. 12 (2018): 2719-2731.
14. Cheng, Heather H., Alexandra O. Sokolova, Edward M. Schaeffer, Eric J. Small, and Celestia S. Higano. "Germline and somatic mutations in prostate cancer for the clinician." Journal of the National Comprehensive Cancer Network 17, no. 5 (2019): 515-521.
15. Le, Dung T., Jennifer N. Uram, Hao Wang, Bjarne R. Bartlett, Holly Kemberling, Aleksandra D. Eyring, Andrew D. Skora et al. "PD-1 blockade in tumors with mismatch-repair deficiency." New England Journal of Medicine 372, no. 26 (2015): 2509-2520.
16. Marcus, Leigh, Steven J. Lemery, Patricia Keegan, and Richard Pazdur. "FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors." Clinical Cancer Research 25, no. 13 (2019): 3753-3758.
17. Center for Drug Evaluation and Research. “FDA Grants Accelerated Approval to Rucaparib for BRCA-Mutated Metastatic Castration-Resistant Prostate Cancer.” U.S. Food and Drug Administration, FDA, www.fda.gov/drugs/fda-grants-accelerated-approval-rucaparib-brca-mutated-metastatic-castration-resistant-prostate.
18. Center for Drug Evaluation and Research. “FDA Approves Olaparib for HRR Gene-Mutated Metastatic Castration-Resistant Prostate Cancer.” U.S. Food and Drug Administration, FDA, https://www.fda.gov/drugs/drug-approvals-and-databases/fda-approves-olaparib-hrr-gene-mutated-metastatic-castration-resistant-prostate-cancer.
19. de Bono, Johann, Joaquin Mateo, Karim Fizazi, Fred Saad, Neal Shore, Shahneen Sandhu, Kim N. Chi et al. "Olaparib for metastatic castration-resistant prostate cancer." New England Journal of Medicine 382, no. 22 (2020): 2091-2102.
20. Dubbury, Sara J., Paul L. Boutz, and Phillip A. Sharp. "CDK12 regulates DNA repair genes by suppressing intronic polyadenylation." Nature 564, no. 7734 (2018): 141-145.
21. Wu, Yi-Mi, Marcin Cieślik, Robert J. Lonigro, Pankaj Vats, Melissa A. Reimers, Xuhong Cao, Yu Ning et al. "Inactivation of CDK12 delineates a distinct immunogenic class of advanced prostate cancer." Cell 173, no. 7 (2018): 1770-1782.
22. Antonarakis, Emmanuel S., Pedro Isaacsson Velho, Wei Fu, Hao Wang, Neeraj Agarwal, Victor Sacristan Santos, Benjamin L. Maughan et al. "CDK12-altered prostate cancer: clinical features and therapeutic outcomes to standard systemic therapies, poly (ADP-ribose) polymerase inhibitors, and PD-1 inhibitors." JCO Precision Oncology 4 (2020): 370-381.
23. Nguyen, Bastien, Jose Mauricio Mota, Subhiksha Nandakumar, Konrad H. Stopsack, Emily Weg, Dana Rathkopf, Michael J. Morris et al. "Pan-cancer Analysis of CDK12 Alterations Identifies a Subset of Prostate Cancers with Distinct Genomic and Clinical Characteristics." European Urology (2020).
24. Abida, Wassim, David Campbell, Akash Patnaik, Jeremy D. Shapiro, Brieuc Sautois, Nicholas J. Vogelzang, Eric G. Voog et al. "Non-BRCA DNA damage repair gene alterations and response to the PARP inhibitor rucaparib in metastatic castration-resistant prostate cancer: Analysis From the Phase II TRITON2 Study." Clinical Cancer Research 26, no. 11 (2020): 2487-2496.
25. Jonsson, Philip, Chaitanya Bandlamudi, Michael L. Cheng, Preethi Srinivasan, Shweta S. Chavan, Noah D. Friedman, Ezra Y. Rosen et al. "Tumour lineage shapes BRCA-mediated phenotypes." Nature 571, no. 7766 (2019): 576-579.
26. Pilié, Patrick G., Carl M. Gay, Lauren A. Byers, Mark J. O'Connor, and Timothy A. Yap. "PARP inhibitors: extending benefit beyond BRCA-mutant cancers." Clinical Cancer Research 25, no. 13 (2019): 3759-3771.
27. Leo, Elisabetta, Jeffrey Johannes, Giuditta Illuzzi, Andrew Zhang, Paul Hemsley, Michal J. Bista, Jonathan P. Orme et al. "Abstract LB-273: A head-to-head comparison of the properties of five clinical PARP inhibitors identifies new insights that can explain both the observed clinical efficacy and safety profiles." (2018): LB-273.
28. De Bono, Johann S., Niven Mehra, Celestia S. Higano, Fred Saad, Consuelo Buttigliero, Marielena Mata, Hsiang-Chun Chen et al. "TALAPRO-1: A phase II study of talazoparib (TALA) in men with DNA damage repair mutations (DDRmut) and metastatic castration-resistant prostate cancer (mCRPC)—First interim analysis (IA)." (2020): 119-119.
29. Gershenson, David Marc, A. Miller, W. Brady, J. Paul, K. Carty, W. Rodgers, D. Millan et al. "LBA61 A randomized phase II/III study to assess the efficacy of trametinib in patients with recurrent or progressive low-grade serous ovarian or peritoneal cancer." Annals of Oncology 30, no. Supplement_5 (2019): mdz394-058.
30. Antonarakis, Emmanuel S. "Olaparib for DNA repair-deficient prostate cancer—one for all, or all for one?." Nature Reviews Clinical Oncology (2020): 1-2.
31. Pilié, Patrick G., Chad Tang, Gordon B. Mills, and Timothy A. Yap. "State-of-the-art strategies for targeting the DNA damage response in cancer." Nature Reviews Clinical Oncology 16, no. 2 (2019): 81-104.
32. Clarke, Noel, Pawel Wiechno, Boris Alekseev, Nuria Sala, Robert Jones, Ivo Kocak, Vincenzo Emanuele Chiuri et al. "Olaparib combined with abiraterone in patients with metastatic castration-resistant prostate cancer: a randomised, double-blind, placebo-controlled, phase 2 trial." The Lancet Oncology 19, no. 7 (2018): 975-986.

First-line Treatment for Metastatic Castrate-resistant Prostate Cancer

In 2019 Prostate cancer (PCa) accounts for nearly 1 in 5 new diagnoses of cancer in men in the USA.1 In the last several years the overall prostate cancer (PCa) incidence rate declined by approximately 7% per year.1 The sharp drop in incidence has been commonly attributed to decreased prostate-specific antigen (PSA) testing from 2008 to 2013. The decreased use of PSA screening was caused by the United States (US) Preventive Services Task Force recommendations against routine PSA screening. This was a grade D recommendation specifically in men aged 75 years and older, which was declared in 2008, and later on expanded to all men in 2011, due to rising concerns of overdiagnosis and overtreatment.2 Although the prevalence of PSA testing stopped decreasing and stabilized from 2013 to 2015,3 the effect of screening reduction on the incidence of advanced disease is still unclear. An analysis of a large cancer registry covering 89% of the US population reported that the overall decline in PCa incidence is, in fact, masking an increase in distant-stage diagnoses from 2010 across age and race.4

Regardless of the treatment given, approximately 20%-30% of patients with localized PCa progress to metastatic disease, commonly treated with hormonal therapy.5 This can be given through surgical castration (bilateral orchiectomy) or through medical castration using androgen deprivation therapy (ADT). Both methods achieve a castrate level of serum testosterone which is regarded as the standard of care for treating metastatic hormone-sensitive PCa (mHSPC). However, mHSPC is destined to progress to metastatic castrate-resistant prostate cancer (mCRPC).6 The castrate-resistant prostate cancer (CRPC) state is defined as disease progression despite reaching castrate testosterone levels (serum testosterone < 50 ng/dL or 1.7 nmol/L), and can present as either a continuous rise in serum PSA levels, progression of pre-existing disease, and/or the appearance of new metastases.7 CRPC has a median survival of approximately three years8 and is associated with a significant deterioration of quality of life.9 The exact mechanism of transition from mHSPC to mCRPC is still unclear. However, it is known that despite castrate levels of androgens, the androgen receptor (AR) remains active and continues to drive PCa progression in CRPC.10 This has led to the development of novel agents aimed at further decreasing androgen production or blocking AR function. However, there are other biologic pathways that function independently of androgen signaling and also result in CRPC.

Several significant shifts have occurred in the treatment options of the mHSPC space resulting in substantial survival benefit (please see “The rapidly evolving management strategy of metastatic Hormone-Sensitive Prostate Cancer” link), including the introduction of chemotherapy in the CHAARTED study11 and STAMPEDE trial,12 the addition of abiraterone acetate and prednisone in the LATITUDE study13 and STAMPEDE trial,14 the addition of enzalutamide in the ARCHES trial15 and the ENZAMET study,16 and lastly, the addition of apalutamide, an oral nonsteroidal anti-androgen, which like enzalutamide, binds directly to the ligand-binding domain of the AR and prevents AR translocation, DNA binding, and AR-mediated transcription.17 The TITAN trial showed overall survival (OS) benefit in apalutamide-treated mHSPC patients.18 Apalutamide has also shown benefit over placebo in the non-metastatic CRPC (nmCRP) setting in the SPARTAN phase 3 placebo-controlled trial,19 similar to the benefit shown by enzalutamide-treated nonmetastatic castrate-resistant prostate cancer (nmCRPC) patients, in the PROSPER trial20 (please see “The novel treatments for the non-metastatic castrate-resistant prostate cancer” link). These treatment advances in the mHSPC and nmCRPC setting have raised the question of which treatment options should be offered to patients in the mCRPC setting.21

The treatment of men with CRPC has dramatically changed over the last 15 years. Prior to 2004, when patients failed primary ADT, treatments were administered solely for palliation. The landmark trials by Tannock et al.22 and Petrylak et al.23 in 2004 were the first to introduce docetaxel chemotherapy in mCRPC patients that were shown to improve their survival. However, since docetaxel was FDA approved, five additional beneficial agents showing a survival advantage have been FDA-approved based on randomized clinical trials (Table 1). These include enzalutamide, and abiraterone, which specifically affect the androgen axis, sipuleucel-T, which stimulates the immune system;24 cabazitaxel, which is another chemotherapeutic agent;25 and radium-223, a radionuclide therapy.26 Other treatments for mCRPC have shown to improve outcomes but have yet been approved by the FDA and will be discussed in another review. Due to the substantial increase in multiple FDA-approved therapeutic agents in patients with CRPC, clinicians are challenged with a plethora of treatment options and multitude potential sequences of these agents, making clinical decision-making in mCRPC significantly more complex.

Table 1. Agents that have been approved for the treatment of metastatic castrate-resistant prostate cancer in the US

table 1 atents approved for treatment of mCRPC

mCRPC is usually a debilitating disease, and patients will most likely benefit from a management strategy formalized by a multidisciplinary team consisting of urologists, medical oncologists, radiation oncologists, nurses, psychologists, and social workers.28 It is imperative to discuss palliation treatment options when considering additional systemic treatment, including management of pain, constipation, anorexia, nausea, depression, and fatigue.

Another crucial point to consider when establishing the appropriate treatment sequence in this disease space is the associated cost. Using models that included additional lines of treatment before or after docetaxel, the mean cost of mCRPC treatment during a mean period of 28.1 months was approximately $48,000 per patient.29 This cost is quite high due to the fact that patients may receive multiple lines of therapy and incur ongoing medical services during the course of their disease.30

Only two trials have demonstrated a marginal survival benefit for patients remaining on LHRH analogs instead of adding second- and third-line therapies.31, 32 Studies have shown that CRPC is not resistant to ADT, but rather hypersensitive to it.10 Treatment-mediated selection pressure during ADT causes the AR to amplify, and ensure the situation does not escalate, ADT is continued to be administered in the mCRPC setting. Treatment-mediated selection pressure also continues throughout the entire lifespan of the tumor, intensifying the need to correctly sequence therapies. However, because prospective data are lacking, the minute potential benefit of continuing castration still outweighs the minimal risk of this treatment. In addition, all subsequently approved treatments have been studied in men with ongoing ADT, adding another reason why it should be continued.

Before delving into the actual available treatment options, it is important to recognize that it is still unclear when to begin therapy in mCRPC patients who are completely asymptomatic. It is still unknown whether earlier treatment is superior, or if we should wait until the patient becomes symptomatic and develops pain. Before starting treatment, we should consider the patient’s existing comorbidities and expected adverse effects of starting therapy. Patients with early-stage mCRPC in the COU-AA-302 trial who received abiraterone typically survived almost one year longer than those who received placebo (median OS, 53.6 months vs. 41.8 months, respectively, HR, 0.61; 95% CI, 0.43 to 0.87; P = .006).33 Thus, early-stage mCRPC patients benefited from earlier start of abiraterone. In the same trial patients with asymptomatic or mildly symptomatic mCRPC, with baseline PSA < 15.6 ng/mL abiraterone also led to a faster rate and a greater degree of PSA decline than placebo.34 Although the currently available data is limited, it most likely suggests that starting treatment earlier rather than later is more advantageous.33, 34

Approved first-line treatment options for metastatic castrate-resistant prostate cancer

Abiraterone

Abiraterone is an antiandrogen which is an inhibitor of 17α-hydroxylase/C17,20-lyase (CYP17) enzyme. The COU-AA-302 phase III study evaluated abiraterone in 1,088 chemo-naïve, asymptomatic or mildly symptomatic mCRPC patients without visceral metastases. In this trial patients were randomized to abiraterone acetate or placebo, both combined with prednisone35 (Figure 1). Patients were stratified by either the Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 and by asymptomatic or mildly symptomatic disease.35 OS and radiographic progression-free survival (rPFS) was the co-primary end-points. The trial demonstrated that after a median follow-up of 22.2 months, there was a significant improvement of rPFS in the abiraterone arm (median 16.5 vs. 8.2 months, HR 0.52, p < 0.001). At the final analysis after a median follow-up of 49.2 months, the OS end-point was significantly positive (34.7 vs. 30.3 months, HR: 0.81, 95% CI: 0.70-0.93, p = 0.0033).36 It is important to remember that mCRPC spans a broad prognostic spectrum even when it is chemotherapy-naïve.37 In an analysis of the abiraterone arm of the COU-AA-302 study, patients who had no pain at baseline, normal alkaline phosphatase and LDH levels, and less than 10 bone metastases had a median OS of 42.6 months.37 However, patients with more risk factors for progression had significantly shorter median OS.37 When assessing the toxicity profile of abiraterone, it seemed to confer more adverse events related to mineralocorticoid excess and liver function abnormalities, but these were mostly graded 1-2 adverse effects. Lastly, abiraterone was also shown to be equally effective in the elderly population (> 75 years).38

figure 1 COU AA 302 study

Figure 1
. COU-AA-302 study design

Enzalutamide

Enzalutamide is a nonsteroidal antiandrogen. The PREVAIL study which is a randomized phase III trial included 1,717 chemo-naïve mCRPC patients and patients with visceral metastases were eligible as well.39 This trial compared enzalutamide to placebo (Figure 2). The PREVAIL trial showed a significant improvement in enzalutamide-treated patients in both co-primary endpoints, which included rPFS (HR: 0.186; CI: 0.15-0.23, p < 0.0001), and OS (HR: 0.706; CI: 0.6-0.84, p < 0.001). Extended follow-up and final analysis confirmed a benefit in OS and rPFS for enzalutamide.40 In 78% of patients treated with enzalutamide a PSA decrease of more than 50% was reported. The most common clinically relevant adverse events were fatigue and hypertension. Enzalutamide was also equally effective and well-tolerated in older men (> 75 years)41 and in those with or without visceral metastases.42 However, for men with liver metastases, there seemed to be no discernible benefit.43 The TERRAIN trial compared enzalutamide with bicalutamide, an older antiandrogen, in a randomized double-blind phase II study, showing a significant improvement in PFS (15.7 months vs. 5.8 months, HR: 0.44, p < 0.0001) in favor of enzalutamide.44

figure 2 PREVAIL study

Figure 2
. PREVAIL study design

Docetaxel

The landmark trial TAX 327 showed a significant improvement in median OS of 2-2.9 months in mCRPC patients treated with docetaxel-based chemotherapy when compared to patients who were treated with mitoxantrone plus prednisone therapy.22 The SWOG 9916 trial compared mitoxantrone to docetaxel and showed similar results23 (Figure 3). The standard first-line chemotherapy is docetaxel 75 mg/m2 in three-weekly doses combined with prednisone 5 mg twice a day, up to ten cycles. There are several important prognostic factors to consider when administering docetaxel: visceral metastases, pain, anemia (Hb < 13 g/dL), bone scan progression, and prior estramustine therapy. These prognostic factors may help to stratify response to docetaxel. Using these prognostic factors the disease can be categorized into low, intermediate and high risk, with significantly different corresponding median OS estimates of 25.7, 18.7 and 12.8 months, respectively.45 Although age by itself is not a contraindication to docetaxel therapy, patients must be fit enough to endure this type of treatment and comorbidities should be assessed prior to treatment initiation. In men who are thought to be unable to tolerate the standard dose and schedule of docetaxel, this can be decreased from 75 to 50 mg/m2 every two weeks, showing less grade 3-4 adverse events and a longer time to treatment failure.46

figure 3 SWOG 9916 and TAX trials

Figure 3
. SWOG 9916 and TAX 327 trial designs

Sipuleucel-T

Sipuleucel-T, an autologous active cellular immunotherapy, was shown in a phase III trial (IMPACT trial) to confer a survival benefit in 512 asymptomatic or minimally symptomatic mCRPC patients when compared to placebo24 (Figure 4). After a median follow-up of 34 months, the median survival was significantly higher in the sipuleucel-T group (25.8 vs. 21.7 months, with an HR of 0.78,p = 0.03).24 Importantly, no PSA decline was observed during or after treatment and PFS was similar in both arms. The overall tolerance to sipuleucel-T was very good, with mostly grade 1-2 adverse events occurring. Currently, this treatment is only available in the US and is no longer available in Europe.

figure 4 IMPACT trial

Figure 4. IMPACT trial design

Conclusions

In the last 15 years, there has been considerable scientific progress and investment in drug development for patients with mCRPC. This has resulted in the FDA approval of several lines of systemic therapies on grounds of pain palliation, minimizing disease adverse effects, and OS prolongation. To date, the reported impact on OS in mCRPC patients from each of these individual agents is still modest, resulting in an addition of only a few months. It is necessary to enhance our understanding of the disease biology of mCRPC, integrate a comprehensive molecular understanding of castration resistance, and analyze mechanisms of resistance to current therapies to improve future treatment development. It is also crucial to invest and develop predictive biomarkers to assist in the personalization of therapy. Lastly, on a more practical note, more data is needed on the appropriate second and third-line therapies, and sequencing and combination of available medications, discussed in more detail in the next review article (“Beyond first line treatment of metastatic castrate-resistant prostate cancer”).

Published Date: November 19th, 2019
Written by: Hanan Goldberg, MD
References:
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  3. Fedewa SA, Ward EM, Brawley O, Jemal A. Recent Patterns of Prostate-Specific Antigen Testing for Prostate Cancer Screening in the United States. JAMA Intern Med. Jul 1 2017;177(7):1040-1042.
  4. Negoita S, Feuer EJ, Mariotto A, Cronin KA, Petkov VI, Hussey SK. Annual Report to the Nation on the Status of Cancer, part II: Recent changes in prostate cancer trends and disease characteristics. Jul 1 2018;124(13):2801-2814.
  5. Amling CL, Blute ML, Bergstralh EJ, Seay TM, Slezak J, Zincke H. Long-term hazard of progression after radical prostatectomy for clinically localized prostate cancer: continued risk of biochemical failure after 5 years. J Urol. Jul 2000;164(1):101-105.
  6. Hotte SJ, Saad F. Current management of castrate-resistant prostate cancer. Curr Oncol. Sep 2010;17 Suppl 2:S72-79.
  7. Saad F, Hotte SJ. Guidelines for the management of castrate-resistant prostate cancer. Canadian Urological Association journal = Journal de l'Association des urologues du Canada. 2010;4(6):380-384.
  8. Tangen CM, Hussain MH, Higano CS, et al. Improved overall survival trends of men with newly diagnosed M1 prostate cancer: a SWOG phase III trial experience (S8494, S8894 and S9346). J Urol. Oct 2012;188(4):1164-1169.
  9. Damodaran S, Lang JM, Jarrard DF. Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches. J Urol. May 2019;201(5):876-885.
  10. Mohler JL, Titus MA, Bai S, et al. Activation of the androgen receptor by intratumoral bioconversion of androstanediol to dihydrotestosterone in prostate cancer. Cancer Res. Feb 15 2011;71(4):1486-1496.
  11. Sweeney CJ, Chen Y-H, Carducci M, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. New England Journal of Medicine. 2015;373(8):737-746.
  12. James ND, Sydes MR, Clarke NW, et al. Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial. Lancet. Mar 19 2016;387(10024):1163-1177.
  13. Fizazi K, Tran N, Fein L, et al. Abiraterone acetate plus prednisone in patients with newly diagnosed high-risk metastatic castration-sensitive prostate cancer (LATITUDE): final overall survival analysis of a randomised, double-blind, phase 3 trial. Lancet Oncol. May 2019;20(5):686-700.
  14. James ND, de Bono JS, Spears MR, et al. Abiraterone for Prostate Cancer Not Previously Treated with Hormone Therapy. N Engl J Med. Jul 27 2017;377(4):338-351.
  15. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: A Randomized, Phase III Study of Androgen Deprivation Therapy With Enzalutamide or Placebo in Men With Metastatic Hormone-Sensitive Prostate Cancer. J Clin Oncol. Jul 22 2019:Jco1900799.
  16. Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. New England Journal of Medicine. 2019;381(2):121-131.
  17. Clegg NJ, Wongvipat J, Joseph JD, et al. ARN-509: a novel antiandrogen for prostate cancer treatment. Cancer Res. Mar 15 2012;72(6):1494-1503.
  18. Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer. N Engl J Med. Jul 4 2019;381(1):13-24.
  19. Smith MR, Saad F, Chowdhury S, et al. Apalutamide Treatment and Metastasis-free Survival in Prostate Cancer. New England Journal of Medicine. 2018;378(15):1408-1418.
  20. Hussain M, Fizazi K, Saad F, et al. Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine. 2018;378(26):2465-2474.
  21. Gartrell BA, Saad F. Managing bone metastases and reducing skeletal related events in prostate cancer. Nat Rev Clin Oncol. Jun 2014;11(6):335-345.
  22. Tannock IF, de Wit R, Berry WR, et al. Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. New England Journal of Medicine. 2004;351(15):1502-1512.
  23. Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med. Oct 7 2004;351(15):1513-1520.
  24. Kantoff PW, Higano CS, Shore ND, et al. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. Jul 29 2010;363(5):411-422.
  25. de Bono JS, Oudard S, Ozguroglu M, et al. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. Oct 2 2010;376(9747):1147-1154.
  26. Parker C, Nilsson S, Heinrich D, et al. Alpha Emitter Radium-223 and Survival in Metastatic Prostate Cancer. New England Journal of Medicine. 2013;369(3):213-223.
  27. Crawford ED, Petrylak DP, Shore N, et al. The Role of Therapeutic Layering in Optimizing Treatment for Patients With Castration-resistant Prostate Cancer (Prostate Cancer Radiographic Assessments for Detection of Advanced Recurrence II). Urology. Jun 2017;104:150-159.
  28. Esper PS, Pienta KJ. Supportive care in the patient with hormone refractory prostate cancer. Semin Urol Oncol. Feb 1997;15(1):56-64.
  29. Dragomir A, Dinea D, Vanhuyse M, Cury FL, Aprikian AG. Drug costs in the management of metastatic castration-resistant prostate cancer in Canada. BMC Health Serv Res. Jun 13 2014;14:252.
  30. Wen L, Valderrama A, Costantino ME, Simmons S. Real-World Treatment Patterns in Patients with Castrate-Resistant Prostate Cancer and Bone Metastases. Am Health Drug Benefits. May 2019;12(3):142-149.
  31. Hussain M, Wolf M, Marshall E, Crawford ED, Eisenberger M. Effects of continued androgen-deprivation therapy and other prognostic factors on response and survival in phase II chemotherapy trials for hormone-refractory prostate cancer: a Southwest Oncology Group report. J Clin Oncol. Sep 1994;12(9):1868-1875.
  32. Taylor CD, Elson P, Trump DL. Importance of continued testicular suppression in hormone-refractory prostate cancer. J Clin Oncol. Nov 1993;11(11):2167-2172.
  33. Miller K, Carles J, Gschwend JE, Van Poppel H, Diels J, Brookman-May SD. The Phase 3 COU-AA-302 Study of Abiraterone Acetate Plus Prednisone in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Stratified Analysis Based on Pain, Prostate-specific Antigen, and Gleason Score. Eur Urol. Jul 2018;74(1):17-23.
  34. Ryan CJ, Londhe A, Molina A, et al. Relationship of baseline PSA and degree of PSA decline to radiographic progression-free survival (rPFS) in patients with chemotherapy-naive metastatic castration-resistant prostate cancer (mCRPC): Results from COU-AA-302. Journal of Clinical Oncology. 2013;31(15_suppl):5010-5010.
  35. Ryan CJ, Smith MR, de Bono JS, et al. Abiraterone in metastatic prostate cancer without previous chemotherapy. N Engl J Med. Jan 10 2013;368(2):138-148.
  36. Ryan CJ, Smith MR, Fizazi K, et al. Abiraterone acetate plus prednisone versus placebo plus prednisone in chemotherapy-naive men with metastatic castration-resistant prostate cancer (COU-AA-302): final overall survival analysis of a randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. Feb 2015;16(2):152-160.
  37. Ryan CJ, Kheoh T, Li J, et al. Prognostic Index Model for Progression-Free Survival in Chemotherapy-Naive Metastatic Castration-Resistant Prostate Cancer Treated With Abiraterone Acetate Plus Prednisone. Clin Genitourin Cancer. Jul 25 2017.
  38. Roviello G, Cappelletti MR, Zanotti L, et al. Targeting the androgenic pathway in elderly patients with castration-resistant prostate cancer: A meta-analysis of randomized trials. Medicine (Baltimore). Oct 2016;95(43):e4636.
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  40. Beer TM, Armstrong AJ, Rathkopf D, et al. Enzalutamide in Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer: Extended Analysis of the Phase 3 PREVAIL Study. Eur Urol. Feb 2017;71(2):151-154.
  41. Graff JN, Baciarello G, Armstrong AJ, et al. Efficacy and safety of enzalutamide in patients 75 years or older with chemotherapy-naive metastatic castration-resistant prostate cancer: results from PREVAIL. Ann Oncol. Feb 2016;27(2):286-294.
  42. Evans CP, Higano CS, Keane T, et al. The PREVAIL Study: Primary Outcomes by Site and Extent of Baseline Disease for Enzalutamide-treated Men with Chemotherapy-naive Metastatic Castration-resistant Prostate Cancer. Eur Urol. Oct 2016;70(4):675-683.
  43. Alumkal JJ, Chowdhury S, Loriot Y, et al. Effect of Visceral Disease Site on Outcomes in Patients With Metastatic Castration-resistant Prostate Cancer Treated With Enzalutamide in the PREVAIL Trial. Clin Genitourin Cancer. Oct 2017;15(5):610-617.e613.
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PARP Inhibitors in Prostate Cancer: PROfound and Beyond

Prostate cancer is a clinically heterogeneous disease with many patients having an indolent course requiring no interventions and others who either present with or progress to metastasis. While underlying dominant driving mutations are not widespread, there have been a number of key genomic mutations that have been consistently identified in prostate cancer patients, across the disease spectrum including gene fusion/chromosomal

Written by: Christopher J.D. Wallis, MD, PhD and Zachary Klaassen, MD, MSc
References:

The Impact of Visceral Metastasis in Prostate Cancer Patients

Introduction and Epidemiology

In 2018 in the United States, there will be an estimated 164,690 new cases of prostate cancer (19% of all male cancer incident cases, 1st) and an estimated 29,430 prostate cancer mortalities (9% of all male cancer deaths, 2nd only to lung/bronchus cancer).1 For the last 30 or more years, prostate cancer has been the most common noncutaneous malignancy among men in the United States, with 1 in 7 men being diagnosed with the disease.2 De-novo metastatic prostate cancer incidence seems to vary by geographical region and ranges from 4.4 to 9.9 per 100,000 men. A recent study found that over the last several decades, the incidence of de novo metastatic prostate cancer was decreasing in the United States (12.0 to 4.4 per 100,000 men) but increasing in Denmark (6.7 to 9.9 per 100,000 men).3 The exact mechanism for these epidemiologic differences is not clear, but likely related to varying uptake and utilization of PSA surveillance.

With improvements in the treatment of advanced prostate cancer over the last decade, men with advanced disease are living longer and developing non-lymph node visceral metastases.  In a single-institution Japanese study (from 2000-2014), among 1,038 prostate cancer patients, there were 144 (19.8 %) men with castration-resistant prostate cancer (CRPC) and 43 (33.1%) patients developing visceral metastases after CRPC progression.4 At diagnosis, the sites of visceral metastases included lung (89.5%), liver (5.3%), and adrenal glands (5.3%). After CRPC progression, new visceral metastases were found in the lung (47.3%), liver (43.6%), and adrenal gland (9.1%). Among 359 CRPC patients in the UK (June 2003 to December 2011), the frequency of radiologically detected visceral metastases before death was 32%; among the 92 patients with a CT scan performed within 3 months of death, 49% had visceral metastases, most commonly involving the liver (20%) and lung (13%).5 These findings confirm a large autopsy study that found among 1,500 prostate cancer patients, 25% of men had liver metastases and 46% had lung metastases.6 Of men participating in first-line studies for metastatic CRPC (mCRPC), ~20% of patients had non-lymph node soft tissue visceral metastases.7,8 As such, leaders in the field have suggested that men with visceral metastases have been an underestimated and understudied subgroup of patients with advanced and heavily treated mCRPC.9,10 The objective of this article is to discuss the biology of visceral metastases, assess the impact of visceral metastases on survival, highlight several large trials that have performed subgroup analyses of visceral metastases patients, and discuss emerging therapeutic regimens for these patients, specifically radioligand targeted therapy.

The Biology of Visceral Metastases

We are likely only beginning to understand the biology of visceral metastases, particularly as it differs from that of bone metastases. There are several interrelated factors leading to differing pathophysiology between visceral and bone metastases, namely intrinsic cellular factors, the tumor microenvironment, and systemic factors.

1. Cellular Factors: Immunohistochemical analysis of tissue microarrays examining the antiapoptotic pathways expressed in visceral vs bone metastases found that soft-tissue metastases are more likely to express nuclear survivin, whereas bone lesions demonstrate relative overexpression of cytoplasmic survivin, B-cell lymphoma 2, and myeloid cell leukemia 1.11
2. Tumor Microenvironment: microarray studies have found physiologically and clinically important differences between bone, liver, and lymph node metastases. Visceral lesions derived from liver and lymph nodes were found to express an angiogenic profile different from that of liver metastases alone, with significant relative overexpression of the proangiogenic factor angiopoietin-2.12
3. Systemic Factors: serum cytokine levels are associated with prognosis as well as with the presence of liver metastases among prostate cancer patients.9,13 A number of studies have examined levels of TGF-β and interleukin-6 (IL-6) as prognostic markers, finding that the addition of TGF-β and soluble IL-6 receptor levels to a preoperative nomogram significantly improved the ability to predict biochemical progression of the disease.14

Impact of Visceral Metastases on Survival

Patients with visceral metastases invariably have a worse prognosis than patients with bone-only metastases, likely secondary to an overall increased disease burden.5,10,15-26 In a study including patients in the SEER database (2010-2013), patients with de-novo bone-metastases plus visceral metastases had significantly worse prostate cancer-specific mortality (vs bone only): bone + brain metastases HR 1.48, 95%CI 1.05-2.10; bone + liver metastases HR 2.18, 95%CI 1.79-2.65; bone + lung metastases HR 1.33, 95%CI 1.13-1.56.27

Several large phase III randomized controlled trials (RCTs) have assessed the impact of visceral metastases on survival outcomes using post-hoc analysis of the trial data. The TAX 327 trial found that docetaxel plus prednisone improved OS, pain scores, PSA level, and quality of life compared to mitoxantrone plus prednisone among patients with mCRPC.8 A decade after this publication, Pond et al.25 performed a post-hoc analysis of this data stratified by metastasis site. They found that men with liver metastases with or without other metastases had a shorter median OS (10.0 months; 95%CI 5.4-11.5) than men with lung metastases with or without bone or nodal metastases (median OS: 14.4 months; 95%CI 11.5-22.4). The AFFIRM trial showed that treatment with the androgen receptor inhibitor enzalutamide led to significant improvements in outcomes for patients with mCRPC.28 A subsequent study assessed patients in the AFFIRM trial who had liver and/or lung metastases.20 In patients with liver metastases (n = 92), enzalutamide treatment was associated with a lower risk of radiographic progression (HR 0.645, 95%CI 0.413-1.008), improved 12-month OS (37.7% vs 20.6%) and radiographic progression-free survival (rPFS) (11.6% vs 3.0%) rates compared to those on placebo. Furthermore, patients treated with enzalutamide had higher PSA response rates (35.1% vs 4.8%) compared with placebo. Similarly, patients with lung metastases (n = 104) treated with enzalutamide also had an improved median OS (HR 0.848, 95%CI 0.510-1.410), reduced risk of radiographic progression (HR, 0.386, 95%CI 0.259-0.577), improved 12-month OS (65.1% vs 55.3%) and rPFS (30.9% vs 8.2%) rates, and a better PSA response rate (52.1% vs 4.9%) compared with those who received placebo. The PREVAIL clinical trial tested enzalutamide in men with mCRPC prior to chemotherapy, finding a decreased risk of radiographic progression and death among those taking enzalutamide compared to placebo.29 Of the 1,717 patients in PREVAIL, 12% had visceral metastases: 74 with liver-only or liver/lung metastases and 130 with lung only metastases.19 In patients with liver metastases, treatment with enzalutamide was associated with an improvement in rPFS (HR 0.44, 95%CI 0.22-0.90) but not OS. Among patients with lung metastases only, enzalutamide significantly improved rPFS (HR 0.14, 95%CI 0.06-0.36) and OS (HR 0.59, 95%CI 0.33-1.06). Patients with liver metastases had worse outcomes than those with lung metastases, regardless of treatment.

Results of post-hoc analyses of phase III RCTs showing poor outcomes among patients with visceral metastases have also been confirmed using population-level studies. Gandaglia et al.24 utilized the SEER-Medicare database (1991-2009) to assess outcomes of 3,857 patients presenting with metastatic prostate cancer. Among these patients, 80.2% had bone metastases, 10.9% had bone plus visceral metastases, 6.1% had visceral only metastases, and 2.8% had lymph node only metastases. Patients with bone plus visceral metastases had the worst cancer-specific survival (median 19 months), following by visceral only metastases (median 26 months), bone-only metastases (median 32 months) and lymph node only metastases (median 61 months). Patients with visceral metastases had a significantly higher risk of overall and cancer-specific mortality compared to those with exclusively lymph node metastases (p<0.001), and the unfavorable impact of visceral metastases persisted in the oligometastatic subgroup. Whitney et al.18 studied 494 men with M0 CRPC (diagnosed after 1999) from five Veterans Affairs hospitals in the Shared Equal Access Regional Cancer Hospital (SEARCH) database who later developed metastases. Among these patients, 236 men had a CT scan performed, of which 38 (16%) had visceral metastases, including 19 patients with liver metastases, 8 patients with lung metastases, and 16 patients with other locations of metastases. The authors found that visceral metastases were a predictor of OS on univariate analysis and after risk adjustment (HR 1.84, 95%CI 1.24-2.72).

To further assess the impact of metastatic site on OS among men with mCRPC, a collaborative group performed an individual patient data meta-analysis of 8,820 men with mCRPC who received docetaxel chemotherapy in nine phase III RCTs.22 Site of metastases was categorized as lymph node only, bone with or without lymph node involvement (with no visceral metastases), and lung metastases (but no liver), and any liver metastases. 72.8% of patients had a bone with or without lymph node metastases, 20.8% had a visceral disease, and 6.4% had lymph node-only disease. Men with lymph node-only disease had the best survival with a median OS of 31.6 months, followed by men with non-visceral bone metastases (median OS 21.3 months), men lung metastases (median OS 19.4 months), and those with liver metastases (median OS 13.5 months).

There are several take-home messages from these studies assessing survival outcomes among patients with visceral metastases:

1. Patients with any degree of liver metastases typically have the worst survival outcomes compared to those with bone metastases or other sites of visceral metastases
2. Patients with visceral metastases do have a response to enzalutamide (either in the pre- or post-chemotherapy setting), although their prognosis remains poor

Radioligand Therapy for mCRPC Patients

The recent uptake in the utilization of PSMA-PET/CT imaging has led to a new field of therapy among heavily pretreated mCRPC patients: radioligand directed therapy. The high PSMA expression in prostate cancer metastases makes it a promising approach to developing new tracers for targeted radionuclide therapies. Since 2015, several institutional studies have reported promising results for response rates and a favorable safety profile after radioligand therapy with 177Lu-PSMA-617 in patients with mCRPC,30-34, however, these studies have suffered from small sample sizes and thus poor generalizability. In an effort to overcome these issues, Rahbar and colleagues35 performed a multicenter German analysis among a cohort of patients treated with 177Lu-PSMA-617.  There were 145 patients with mCRPC treated with 177Lu-PSMA-617 at 12 centers undergoing 1-4 therapy cycles with an activity range of 2-8 GBq per cycle. Among these patients, 87% had bone, 77% lymph node, 20% liver, 14% lung, and 2% other sites of metastases. The study reported an overall biochemical response rate of 45% after all therapy cycles, including 40% of patients who responded after a single cycle. Notably, negative predictors of biochemical response include elevated alkaline phosphatase and the presence of visceral metastases.

A study published last month reported on 100 consecutive patients at a single institution receiving 177Lu-PSMA-I&T, treated with a median of two cycles of therapy (range 1-6).36 Among these 100 patients, 57 had received ≥3 prior treatment regimens for mCRPC. There were 87 patients that had lymph metastases and 35 with visceral metastases, including 18 with liver, 11 with lung and 8 with adrenal metastases. A PSA decline of ≥50% was achieved in 38 patients, the median clinical progression-free survival was 4.1 months, and median OS was 12.9 months.  The presence of visceral metastasis was the only variable associated with a poor PSA response (p = 0.049), as only nine of 35 (26%) patients with visceral metastasis achieved a maximum PSA decline of ≥50%. The authors concluded that the presence of visceral metastases and rising LDH were associated with worse treatment outcome.

Although 177Lu-PSMA-617 is the most well-studied radioligand to date, there are several other compounds in development and undergoing initial testing. These compounds include: 177Lu-J591, 90Y-J591, 131I-MIP 1095, 177Lu-PSMA-I&T, and 225Ac-PSMA-617.37

Conclusions  

Secondary to the improved treatment options available for patients with mCRPC, these men are living longer and thus increasing the prevalence of mCRPC patients with visceral metastases. Although post-hoc studies of enzalutamide trials in the pre- and post-chemotherapy mCRPC setting demonstrate a degree of response, visceral metastases are associated with poor survival outcomes. Initial radioligand therapy studies, primarily with 177Lu-PSMA-617, show promise for heavily treated mCRPC patients, although subgroup analyses of these studies also demonstrate worse survival among patients with visceral metastases. For the future design of phase II and phase III clinical trials among men with mCRPC, patients should be stratified by metastasis site to preclude patients with visceral metastases being inadvertently randomized to an unbalanced trial arm. Further efficacious treatment options for these patients are in dire need. The treatment of visceral metastases is one of the new therapeutic frontiers for prolonging not only quantity but also the quality of life.

Published Date: April 16th, 2019

Written by: Zachary Klaassen, MD
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