Apalutamide Induced Neutropenia: An Unusual Side Effect and a Literature Review

Feras A Moria^1,2, Changsu L Park¹, Ramy R Saleh^1*

¹Department of Medical Oncology, McGill University Health Center, McGill University, Montreal, Quebec H4A 3J1, Canada

²Department of Medicine, Division of Oncology, King Abdulaziz University Hospital, King Abdulaziz University, Jeddah, Saudi Arabia

^*Corresponding Author: Ramy R Saleh, Department of Medicine, Division of Oncology, McGill University Health Center, McGill University, Montreal, Quebec H4A 3J1, Canada

Received: 17 June 2023; Accepted: 27 June 2023; Published: 13 July 2023

1. Introduction

Prostate cancer is among the most frequently diagnosed cancers and a leading cause of cancer-related mortality in men worldwide [1]. Carcinogenesis of prostate cancer relies on androgens for growth and progression. As such, testosterone deprivation and direct targeting of the androgen receptor are common and effective strategies in treatment [2]. Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor (AR) which showed a large impact on radiological PFS and overall survival (OS) in patients with prostate cancer. Apalutamide has been proven to increase OS in non-metastatic castration resistant prostate cancer (nm-CRPC) [3] and in mHSPC [4]. Safety analysis of these studies showed that the side effect profile was comparable to placebo and major side effect profile that leads to drug discontinuation was ranging from 8-15 % [3, 4], with only one case of neutropenia that lead to drug interruption. Neutropenia can be a life-threatening condition and is associated with many drugs including anti-cancer therapy [5, 6]. It is especially important to be cognizant of this complication in cancer patients as sepsis is common and carries a high mortality rate in this patient population [7]. We are reporting a rare case of apalutamide-induced neutropenia in a patient with mHSPC.

2. Case Presentation

An 80-year-old man with no past medical history and with no intake of medications was seen with newly diagnosed mHSPC. He was started on androgen deprivation therapy (ADT). Prostate Specific Antigen (PSA) at the time was 384.56 ug/L reference range [0.00 – 4.00], hemoglobin (HB) 110 g/L [135-175] white blood cell count (WBC) 6.4 × 10⁹ cells/mm3 [4.5-11× 10⁹], absolute neutrophil count (ANC) of 5.14 × 10⁹ cells/mm3 [1.80-7.70× 10⁹] representing 80% of the total white blood cell count, platelet count (PC) 247 ×10⁹ cells/mm³ [140 - 450× 10⁹]. The patient underwent staging with computed tomography (CT) scans and bone scans which revealed no visceral metastasis and was consistent with low-risk low volume disease. He was started on apalutamide 240 mg orally once daily three weeks following ADT initiation, CBC at the time revealed (HB) 106 g/L, WBC 4.9× 10⁹ cells/mm³, ANC  3.35 × 10⁹ cells/mm³, PC 306 × 10⁹ cells/mm³. The treatment was well tolerated with no side effects. The patient had a follow up 4 weeks after initiating apalutamide, the patient reports no side effect and was tolerating the medication well, CBC at the time showed (HB) 96 g/L, (WBC) 1.6× 10⁹ cells/mm³ (ANC) of 0.97 × 10⁹ cells/mm³ representing 59% of the total white blood cell count, (PC) 197 × 10⁹ cells/mm³.

37 days following starting apalutamide the patient started to have fever reaching 39.1 degree Celsius, he reported cough and productive sputum, when arriving to the emergency department he was mildly somnolent but maintaining Glasgow coma scale (GCS) score of 14/15 [E3, V5, M6]. Laboratory work up revealed (HB) 89 g/L, (WBC) 0.3 × 10⁹ cells/mm³, (ANC) of 0.0 × 10⁹ cells/mm³ representing 0.94 % of the total white blood cell count, (PC) 223 × 10⁹ cells/mm³, (PSA) at the time was 2.12 ug/L.

CT scan showed bilateral lower lobe parenchymal opacities suspicious for pneumonia, the patient was treated as high-risk febrile neutropenia with intravenous tazobactam piperacillin and doxycycline. Blood cultures were negative. Blood smear revealed absence of WBC, no blasts or dysplastic cells, the patient was admitted to the oncology floor, apalutamide was held and was started on grastofil 300 mcg, ANC recovered in 5 days following these measures to 0.77. 3 weeks following his hospital admission his neutrophils recovered to baseline without recurrence of neutropenia, it was decided upon discussion with the patient to continue with ADT alone.

3. Discussion

Fever in febrile neutropenia is defined as 38.3 º or higher or sustained elevation of temperature 38.0 and higher for one hour [8]; Severe neutropenia is defined as ANC less than < 0.5 x 10⁹/L or expected to be severely neutropenic in the next 48 hours [8], it represents one of oncology true emergency due to previously high mortality rate [9, 10]. In HSPC setting the reported incidence of febrile neutropenia ranges from 6-30% [11-15], which is markedly higher than the rate of 3% demonstrated in the castrate-resistant phase [16], all these cases were in patients receiving chemotherapy.

Apalutamide is a new generation (ARAT) inhibitor that has regulatory approval to be used in mHSPC and nmCRPC [3, 4]. ARATs work by inhibiting the binding of androgen-to-androgen receptor (AR), nuclear translocation of the androgen–AR complex, and binding of AR transcription complex to DNA-binding sites and transcription elements. The AR plays an essential part in the pathogenesis of the disease and remains a key therapeutic target even in castration resistant disease [17-20].

Apalutamide demonstrated its superiority in both settings as shows in two phase III trials. At a median follow up of 52 months in the SPARTAN trial apalutamide significantly improved overall survival reaching 73.9 months vs 59.9 compared to placebo in nmCRPC [3]. In patients with mHSPC median OS was not reached vs 52.2 months despite 39.5% patient cross over to apalutamide arm at median follow-up of 44.0 months in the TITAN study [4].

About 1611 patient was treated with apalutamide in both studies (including cross over patients), with a median duration of treatment at least 30 months in patient started on apalutamide upfront and 15 months in patient who had crossed over from placebo, there was only one patient in the TITAN study who required dose interruption due to febrile neutropenia [3, 4] [Table 1].

Other Bone marrow adverse events such as anemia were slightly higher in the placebo group 13.7% compared to the treatment group (13.2%) [4], there was no mention of any bone marrow toxicity documented in SPARTAN trial [3], there was no record of any grade of thrombocytopenia in either of the studies.

Table 1: Showing different newer generation ARAT in phase III trials, rate of neutropenia and other bone marrow toxicity.

The risk was similar also in other newer generations ARAT such as darolutamide, as the risk of neutropenia was similar in both groups receiving docetaxel in combination with ARAT or placebo (39.3% and 38.8%, respectively) [21]. Cases of neutropenia and other bone marrow toxicities have been documented with other ARAT’s and were ranging from 1-2% in patients receiving enzalutamide [24-30]. The estimated risk of neutropenia in Abiraterone + prednisone / prednisolone (AAP) ranges from 2-7%, grade ¾ and febrile neutropenia was only 1% [12, 31-36] [Table 1].

4. Conclusion

To our knowledge this is the first case of apalutamide induced neutropenia, although the incidence of such adverse event is rare, it’s a serious adverse event and with the presence of other causes of neutropenia in patients with prostate cancer this may be a future dilemma especially with the emerging evidence to support the use of dual therapy of ARAT and PARP inhibitors in patients with mCRPC [37-41].

Acknowledgements

Conceptualization, F.A.M and R.S.; writing-original draft preparation, F.A.M.; writing-review and editing, C.L.P. AND R.S.; supervision, R.S. All authors have read and agreed to the published version of the manuscript.

Funding

None.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians 71 (2021): 209-249.
2. Teo MY, Rathkopf DE, Kantoff P. Treatment of Advanced Prostate Cancer. Annu Rev Med 70 (2019): 479-499.
3. Smith MR, et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol 79 (2021): 150-158.
4. Chi KN, et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. Journal of Clinical Oncology 39 (2021): 2294-2303.
5. Curtis BR. Non-chemotherapy drug-induced neutropenia: key points to manage the challenges. Hematology Am Soc Hematol Educ Program 2017 (2017): 187-193.
6. Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review. Crit Rev Oncol Hematol 90 (2014): 190-199.
7. Shvetsov YB, et al. Association of Sepsis Mortality with Specific Cancer Sites and Treatment Type: The Multiethnic Cohort Study. Journal of Personalized Medicine 11 (2021): 146.
8. Freifeld AG, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 52 (2011): e56-e93.
9. Schimpff S, et al. Empiric Therapy with Carbenicillin and Gentamicin for Febrile Patients with Cancer and Granulocytopenia. New England Journal of Medicine 284 (1971): 1061-1065.
10. Rosa RG, Goldani LZ. Cohort Study of the Impact of Time to Antibiotic Administration on Mortality in Patients with Febrile Neutropenia. Antimicrobial Agents and Chemotherapy 58 (2014): 3799-3803.
11. Sweeney CJ, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. New England Journal of Medicine 373 (2015): 737-746.
12. James ND, 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. The Lancet 387 (2016): 1163-1177.
13. Rulach RJ, et al. Real-world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer. BJU International 121 (2018): 268-274.
14. Tsao CK, Galsky MD, Oh WK. Docetaxel for Metastatic Hormone-sensitive Prostate Cancer: Urgent Need to Minimize the Risk of Neutropenic Fever. Eur Urol 70 (2016): 707-708.
15. Mahil J, et al. Febrile Neutropenia Rates in Men Treated with Docetaxel Chemotherapy for Metastatic Hormone-sensitive Prostate Cancer. Clin Oncol (R Coll Radiol) 28 (2016): 612.
16. Tannock, I.F., et al., Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. New England Journal of Medicine, 2004. 351(15): p. 1502-1512.
17. Edwards J, Bartlett JMS. The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 1: modifications to the androgen receptor. BJU International 95 (2005): 1320-1326.
18. Vis AN, Schröder FH. Key targets of hormonal treatment of prostate cancer. Part 2: the androgen receptor and 5α-reductase. BJU International 104 (2009): 1191-1197.
19. Tran C, et al. Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer. Science 324 (2009): 787-790.
20. Chong J, W Oh, Liaw B. Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date. OncoTargets and Therapy 11 (2018): 2141-2147.
21. Smith MR, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. New England Journal of Medicine 386 (2022): 1132-1142.
22. Hussain M, et al. Darolutamide Plus Androgen-Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III ARASENS Trial. Journal of Clinical Oncology (2023).
23. Fizazi K, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine 380 (2019): 1235-1246.
24. Davis ID, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. New England Journal of Medicine 381 (2019): 121-131.
25. Armstrong AJ, et al. Improved Survival with Enzalutamide in Patients with Metastatic Hormone-Sensitive Prostate Cancer. Journal of Clinical Oncology 40 (2022): 1616-1622.
26. Armstrong AJ, et al. Five-year Survival Prediction and Safety Outcomes with Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer from the PREVAIL Trial. Eur Urol 78 (2020): 347-357.
27. Sternberg CN, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine 382 (2020): 2197-2206.
28. Fizazi K, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol 15 (2014): 1147-1156.
29. Scher HI, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine 367 (2012): 1187-1197.
30. Merseburger AS, et al. Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b study. Lancet Oncol 23 (2022): 1398-1408.
31. Fizazi K, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 399 (2022): 1695-1707.
32. Fizazi K, 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 20 (2019): 686-700.
33. Sydes MR, et al. Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Annals of Oncology 29 (2018): 1235-1248.
34. Fizazi K, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 13 (2012): 983-992.
35. Ryan CJ, 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 16 (2015): 152-160.
36. Miller K, et al. The Phase 3 COU-AA-302 Study of Abiraterone Acetate plus Prednisone in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer: Stratified Analysis Based on Pain, Prostate-specific Antigen, and Gleason Score. European Urology 74 (2018): 17-23.
37. Agarwal N, et al. Talazoparib plus enzalutamide in metastatic castration-resistant prostate cancer: TALAPRO-2 phase III study design. Future Oncol 18 (2022): 425-436.
38. Saad F. et al. PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC). Journal of Clinical Oncology 40 (2022): 11-11.
39. Chi KN, et al. Phase 3 MAGNITUDE study: First results of niraparib (NIRA) with abiraterone acetate and prednisone (AAP) as first-line therapy in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) with and without homologous recombination repair (HRR) gene alterations. Journal of Clinical Oncology 40 (2022): 12-12.
40. Rathkopf DE, et al. AMPLITUDE: A study of niraparib in combination with abiraterone acetate plus prednisone (AAP) versus AAP for the treatment of patients with deleterious germline or somatic homologous recombination repair (HRR) gene-altered metastatic castration-sensitive prostate cancer (mCSPC). Journal of Clinical Oncology 39 (2021): TPS176-TPS176.
41. Rao A, et al. Alliance A031902 (CASPAR): A randomized, phase (ph) 3 trial of enzalutamide with rucaparib/placebo as novel therapy in first-line metastatic castration-resistant prostate cancer (mCRPC). Journal of Clinical Oncology 40 (2022): TPS194-TPS194.

1. Introduction

Prostate cancer is among the most frequently diagnosed cancers and a leading cause of cancer-related mortality in men worldwide [1]. Carcinogenesis of prostate cancer relies on androgens for growth and progression. As such, testosterone deprivation and direct targeting of the androgen receptor are common and effective strategies in treatment [2]. Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor (AR) which showed a large impact on radiological PFS and overall survival (OS) in patients with prostate cancer. Apalutamide has been proven to increase OS in non-metastatic castration resistant prostate cancer (nm-CRPC) [3] and in mHSPC [4]. Safety analysis of these studies showed that the side effect profile was comparable to placebo and major side effect profile that leads to drug discontinuation was ranging from 8-15 % [3, 4], with only one case of neutropenia that lead to drug interruption. Neutropenia can be a life-threatening condition and is associated with many drugs including anti-cancer therapy [5, 6]. It is especially important to be cognizant of this complication in cancer patients as sepsis is common and carries a high mortality rate in this patient population [7]. We are reporting a rare case of apalutamide-induced neutropenia in a patient with mHSPC.

2. Case Presentation

An 80-year-old man with no past medical history and with no intake of medications was seen with newly diagnosed mHSPC. He was started on androgen deprivation therapy (ADT). Prostate Specific Antigen (PSA) at the time was 384.56 ug/L reference range [0.00 – 4.00], hemoglobin (HB) 110 g/L [135-175] white blood cell count (WBC) 6.4 × 10⁹ cells/mm3 [4.5-11× 10⁹], absolute neutrophil count (ANC) of 5.14 × 10⁹ cells/mm3 [1.80-7.70× 10⁹] representing 80% of the total white blood cell count, platelet count (PC) 247 ×10⁹ cells/mm³ [140 - 450× 10⁹]. The patient underwent staging with computed tomography (CT) scans and bone scans which revealed no visceral metastasis and was consistent with low-risk low volume disease. He was started on apalutamide 240 mg orally once daily three weeks following ADT initiation, CBC at the time revealed (HB) 106 g/L, WBC 4.9× 10⁹ cells/mm³, ANC  3.35 × 10⁹ cells/mm³, PC 306 × 10⁹ cells/mm³. The treatment was well tolerated with no side effects. The patient had a follow up 4 weeks after initiating apalutamide, the patient reports no side effect and was tolerating the medication well, CBC at the time showed (HB) 96 g/L, (WBC) 1.6× 10⁹ cells/mm³ (ANC) of 0.97 × 10⁹ cells/mm³ representing 59% of the total white blood cell count, (PC) 197 × 10⁹ cells/mm³.

37 days following starting apalutamide the patient started to have fever reaching 39.1 degree Celsius, he reported cough and productive sputum, when arriving to the emergency department he was mildly somnolent but maintaining Glasgow coma scale (GCS) score of 14/15 [E3, V5, M6]. Laboratory work up revealed (HB) 89 g/L, (WBC) 0.3 × 10⁹ cells/mm³, (ANC) of 0.0 × 10⁹ cells/mm³ representing 0.94 % of the total white blood cell count, (PC) 223 × 10⁹ cells/mm³, (PSA) at the time was 2.12 ug/L.

CT scan showed bilateral lower lobe parenchymal opacities suspicious for pneumonia, the patient was treated as high-risk febrile neutropenia with intravenous tazobactam piperacillin and doxycycline. Blood cultures were negative. Blood smear revealed absence of WBC, no blasts or dysplastic cells, the patient was admitted to the oncology floor, apalutamide was held and was started on grastofil 300 mcg, ANC recovered in 5 days following these measures to 0.77. 3 weeks following his hospital admission his neutrophils recovered to baseline without recurrence of neutropenia, it was decided upon discussion with the patient to continue with ADT alone.

3. Discussion

Fever in febrile neutropenia is defined as 38.3 º or higher or sustained elevation of temperature 38.0 and higher for one hour [8]; Severe neutropenia is defined as ANC less than < 0.5 x 10⁹/L or expected to be severely neutropenic in the next 48 hours [8], it represents one of oncology true emergency due to previously high mortality rate [9, 10]. In HSPC setting the reported incidence of febrile neutropenia ranges from 6-30% [11-15], which is markedly higher than the rate of 3% demonstrated in the castrate-resistant phase [16], all these cases were in patients receiving chemotherapy.

Apalutamide is a new generation (ARAT) inhibitor that has regulatory approval to be used in mHSPC and nmCRPC [3, 4]. ARATs work by inhibiting the binding of androgen-to-androgen receptor (AR), nuclear translocation of the androgen–AR complex, and binding of AR transcription complex to DNA-binding sites and transcription elements. The AR plays an essential part in the pathogenesis of the disease and remains a key therapeutic target even in castration resistant disease [17-20].

Apalutamide demonstrated its superiority in both settings as shows in two phase III trials. At a median follow up of 52 months in the SPARTAN trial apalutamide significantly improved overall survival reaching 73.9 months vs 59.9 compared to placebo in nmCRPC [3]. In patients with mHSPC median OS was not reached vs 52.2 months despite 39.5% patient cross over to apalutamide arm at median follow-up of 44.0 months in the TITAN study [4].

About 1611 patient was treated with apalutamide in both studies (including cross over patients), with a median duration of treatment at least 30 months in patient started on apalutamide upfront and 15 months in patient who had crossed over from placebo, there was only one patient in the TITAN study who required dose interruption due to febrile neutropenia [3, 4] [Table 1].

Other Bone marrow adverse events such as anemia were slightly higher in the placebo group 13.7% compared to the treatment group (13.2%) [4], there was no mention of any bone marrow toxicity documented in SPARTAN trial [3], there was no record of any grade of thrombocytopenia in either of the studies.

Table 1: Showing different newer generation ARAT in phase III trials, rate of neutropenia and other bone marrow toxicity.

The risk was similar also in other newer generations ARAT such as darolutamide, as the risk of neutropenia was similar in both groups receiving docetaxel in combination with ARAT or placebo (39.3% and 38.8%, respectively) [21]. Cases of neutropenia and other bone marrow toxicities have been documented with other ARAT’s and were ranging from 1-2% in patients receiving enzalutamide [24-30]. The estimated risk of neutropenia in Abiraterone + prednisone / prednisolone (AAP) ranges from 2-7%, grade ¾ and febrile neutropenia was only 1% [12, 31-36] [Table 1].

4. Conclusion

To our knowledge this is the first case of apalutamide induced neutropenia, although the incidence of such adverse event is rare, it’s a serious adverse event and with the presence of other causes of neutropenia in patients with prostate cancer this may be a future dilemma especially with the emerging evidence to support the use of dual therapy of ARAT and PARP inhibitors in patients with mCRPC [37-41].

Acknowledgements

Conceptualization, F.A.M and R.S.; writing-original draft preparation, F.A.M.; writing-review and editing, C.L.P. AND R.S.; supervision, R.S. All authors have read and agreed to the published version of the manuscript.

Funding

None.

Conflicts of Interest

The authors declare no conflict of interest.

References

1. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: A Cancer Journal for Clinicians 71 (2021): 209-249.
2. Teo MY, Rathkopf DE, Kantoff P. Treatment of Advanced Prostate Cancer. Annu Rev Med 70 (2019): 479-499.
3. Smith MR, et al. Apalutamide and Overall Survival in Prostate Cancer. Eur Urol 79 (2021): 150-158.
4. Chi KN, et al. Apalutamide in Patients With Metastatic Castration-Sensitive Prostate Cancer: Final Survival Analysis of the Randomized, Double-Blind, Phase III TITAN Study. Journal of Clinical Oncology 39 (2021): 2294-2303.
5. Curtis BR. Non-chemotherapy drug-induced neutropenia: key points to manage the challenges. Hematology Am Soc Hematol Educ Program 2017 (2017): 187-193.
6. Lyman GH, Abella E, Pettengell R. Risk factors for febrile neutropenia among patients with cancer receiving chemotherapy: A systematic review. Crit Rev Oncol Hematol 90 (2014): 190-199.
7. Shvetsov YB, et al. Association of Sepsis Mortality with Specific Cancer Sites and Treatment Type: The Multiethnic Cohort Study. Journal of Personalized Medicine 11 (2021): 146.
8. Freifeld AG, et al. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 update by the infectious diseases society of america. Clin Infect Dis 52 (2011): e56-e93.
9. Schimpff S, et al. Empiric Therapy with Carbenicillin and Gentamicin for Febrile Patients with Cancer and Granulocytopenia. New England Journal of Medicine 284 (1971): 1061-1065.
10. Rosa RG, Goldani LZ. Cohort Study of the Impact of Time to Antibiotic Administration on Mortality in Patients with Febrile Neutropenia. Antimicrobial Agents and Chemotherapy 58 (2014): 3799-3803.
11. Sweeney CJ, et al. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer. New England Journal of Medicine 373 (2015): 737-746.
12. James ND, 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. The Lancet 387 (2016): 1163-1177.
13. Rulach RJ, et al. Real-world uptake, safety profile and outcomes of docetaxel in newly diagnosed metastatic prostate cancer. BJU International 121 (2018): 268-274.
14. Tsao CK, Galsky MD, Oh WK. Docetaxel for Metastatic Hormone-sensitive Prostate Cancer: Urgent Need to Minimize the Risk of Neutropenic Fever. Eur Urol 70 (2016): 707-708.
15. Mahil J, et al. Febrile Neutropenia Rates in Men Treated with Docetaxel Chemotherapy for Metastatic Hormone-sensitive Prostate Cancer. Clin Oncol (R Coll Radiol) 28 (2016): 612.
16. Tannock, I.F., et al., Docetaxel plus Prednisone or Mitoxantrone plus Prednisone for Advanced Prostate Cancer. New England Journal of Medicine, 2004. 351(15): p. 1502-1512.
17. Edwards J, Bartlett JMS. The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 1: modifications to the androgen receptor. BJU International 95 (2005): 1320-1326.
18. Vis AN, Schröder FH. Key targets of hormonal treatment of prostate cancer. Part 2: the androgen receptor and 5α-reductase. BJU International 104 (2009): 1191-1197.
19. Tran C, et al. Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer. Science 324 (2009): 787-790.
20. Chong J, W Oh, Liaw B. Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date. OncoTargets and Therapy 11 (2018): 2141-2147.
21. Smith MR, et al. Darolutamide and Survival in Metastatic, Hormone-Sensitive Prostate Cancer. New England Journal of Medicine 386 (2022): 1132-1142.
22. Hussain M, et al. Darolutamide Plus Androgen-Deprivation Therapy and Docetaxel in Metastatic Hormone-Sensitive Prostate Cancer by Disease Volume and Risk Subgroups in the Phase III ARASENS Trial. Journal of Clinical Oncology (2023).
23. Fizazi K, et al. Darolutamide in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine 380 (2019): 1235-1246.
24. Davis ID, et al. Enzalutamide with Standard First-Line Therapy in Metastatic Prostate Cancer. New England Journal of Medicine 381 (2019): 121-131.
25. Armstrong AJ, et al. Improved Survival with Enzalutamide in Patients with Metastatic Hormone-Sensitive Prostate Cancer. Journal of Clinical Oncology 40 (2022): 1616-1622.
26. Armstrong AJ, et al. Five-year Survival Prediction and Safety Outcomes with Enzalutamide in Men with Chemotherapy-naïve Metastatic Castration-resistant Prostate Cancer from the PREVAIL Trial. Eur Urol 78 (2020): 347-357.
27. Sternberg CN, et al. Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer. New England Journal of Medicine 382 (2020): 2197-2206.
28. Fizazi K, et al. Effect of enzalutamide on time to first skeletal-related event, pain, and quality of life in men with castration-resistant prostate cancer: results from the randomised, phase 3 AFFIRM trial. Lancet Oncol 15 (2014): 1147-1156.
29. Scher HI, et al. Increased Survival with Enzalutamide in Prostate Cancer after Chemotherapy. New England Journal of Medicine 367 (2012): 1187-1197.
30. Merseburger AS, et al. Continuous enzalutamide after progression of metastatic castration-resistant prostate cancer treated with docetaxel (PRESIDE): an international, randomised, phase 3b study. Lancet Oncol 23 (2022): 1398-1408.
31. Fizazi K, et al. Abiraterone plus prednisone added to androgen deprivation therapy and docetaxel in de novo metastatic castration-sensitive prostate cancer (PEACE-1): a multicentre, open-label, randomised, phase 3 study with a 2 × 2 factorial design. Lancet 399 (2022): 1695-1707.
32. Fizazi K, 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 20 (2019): 686-700.
33. Sydes MR, et al. Adding abiraterone or docetaxel to long-term hormone therapy for prostate cancer: directly randomised data from the STAMPEDE multi-arm, multi-stage platform protocol. Annals of Oncology 29 (2018): 1235-1248.
34. Fizazi K, et al. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol 13 (2012): 983-992.
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