PSA Kinetics Affect Prognosis in Patients With Castration-resistant Prostate Cancer Treated With Enzalutamide

Abstract

Background/Aim: There is little evidence regarding the predictive value of prostate-specific antigen (PSA) kinetics in patients with castration-resistant prostate cancer treated with an androgen receptor signaling inhibitor. This study investigated the correlation between PSA kinetics and prognosis in patients with castration-resistant prostate cancer treated with enzalutamide. Patients and Methods: We analyzed data from 103 patients who received enzalutamide as primary treatment for castration-resistant prostate cancer at our hospital, focusing on the associations between overall survival and PSA kinetics variables, such as maximal PSA response, PSA nadir, and time to PSA nadir. Results: The median PSA level at the initiation of enzalutamide was 18.1 ng/ml (interquartile range=7.9-61.2 ng/ml). The median maximal PSA response rate was 88% (interquartile range 55-98), and the median PSA nadir was 1.84 (interquartile range (IQR)=0.38-14.7) ng/ml. The median time to PSA nadir was 19 (IQR=6-28.5) weeks. Maximal PSA response rate <90% [hazard ratio (HR)=2.28, 95% confidence interval (CI)=1.03-5.03, p=0.0413], PSA nadir >2 ng/ml (HR=2.30, 95%CI=1.05-5.07, p=0.0379), time to nadir <19 weeks (HR=2.48, 95%CI=1.15-5.35, p=0.0204) were all independently predictive of shortened overall survival even after adjusting for pre-treatment factors. Conclusion: Maximal PSA response, PSA nadir, and time to PSA nadir correlated with survival in patients with castration-resistant prostate cancer receiving enzalutamide as a first-line therapy.

Prostate cancer (PCa) treatment is advancing rapidly, and upfront therapy with docetaxel or androgen receptor signaling inhibitors (ARSI) is now widely used for metastatic castration-sensitive PCa (mCSPC). However, in the real world, mCSPC is often treated with androgen deprivation therapy (ADT) (1).

Enzalutamide is effective for castration-resistant prostate cancer (CRPC) (2). We have previously reported that in patients receiving enzalutamide as primary treatment for CRPC, the time to castration resistance and metastases to the lymph nodes at the initiation of enzalutamide treatment are associated with the response to enzalutamide (3). However, we could not identify the independent pre-treatment factors that correlated with overall survival (OS). A biomarker for predicting OS has yet to be established.

There is accumulating evidence that PSA kinetics have prognostic value in patients treated with ADT (4). In recent years, post hoc analyses of the LATITUDE and TITAN trials found that PSA kinetics predict OS in mCSPC patients receiving ARSI as upfront therapy (5,6). However, few reports have shown a correlation between PSA kinetics and prognosis in patients with CRPC, and there is no consensus. The biology of CSPC and CRPC treated with ARSI differs significantly from that of those treated with conventional hormone therapy, and PSA kinetics change accordingly (7,8). Analyzing the association between PSA kinetics and prognosis during ARSI treatment is important both in terms of predicting patient prognosis and understanding the biology of CRPC treated with ARSI.

In this study, we focused on PSA kinetics after the initiation of enzalutamide treatment to explore the factors that may affect OS.

Patients and Methods

Study design and data collection. The previously analyzed cohort was updated with an increased number of cases and observation period (6). Patients who were started on enzalutamide for CRPC at Osaka University Hospital from 2014 to August 2022 and who had not yet received treatment with docetaxel and ARSI for CRPC were included in the present study. The definitions of CRPC and PSA progression are the same as in our previous reports (3,9). The history of docetaxel administration to CSPC was acceptable. Patients with insufficient clinical data were excluded. We obtained the patients’ ages, Gleason scores, laboratory and imaging data at the initiation of enzalutamide treatment, and PSA levels from their medical records. Tumors were classified as high volume if they had four or more bone metastases, with at least one outside the pelvis or spine, or if they had at least one visceral metastasis according to the criteria of the CHAARTED trial (10).

Endpoints. We defined OS as the primary endpoint. We analyzed the effects of PSA kinetics, such as maximal PSA response, PSA nadir, and time to PSA nadir (TTN), on OS. We also analyzed the impact of pretreatment variables on OS. Multivariate analysis was performed using pre- and post-treatment variables that showed significant differences in the univariate analysis. We defined OS as the time from the initiation of enzalutamide administration to death. PSA progression-free survival (PSA–PFS) was the secondary endpoint. The definition of PSA-PFS is the same as in our previous study (3).

Statistical analysis. Clinical variables are presented as frequencies and percentages for categorical variables and as medians and interquartile ranges (IQRs) for continuous variables. Survival curves were constructed using the log-rank test and the Kaplan-Meier method. Cox proportional hazard models were utilized to evaluate relationships between clinical variables and endpoints. Each factor related to PSA kinetics that was a significant predictor in the univariate analysis was subjected to multivariate analysis, along with the pretreatment parameters significantly associated with prognosis in the univariate analysis. The two groups were compared using Fisher’s exact test for categorical variables and the t-test for continuous variables. Statistical significance was set at p

Approval of the research protocol by the Institutional Reviewer Board and the approval number. This study was approved by the Institutional Review Board of Osaka University Hospital. (Ethics review number: 13397-20) This study complies with the provisions of the Declaration of Helsinki.

Results

Patient characteristics. As shown inFigure 1, 103 patients met the inclusion criteria.Table Ishows the clinical characteristics of the 103 patients. The median duration of treatment with enzalutamide and observation were 11 (IQR=6-22.5) and 23 months (IQR=11.5-44), respectively. The median PSA level at the start of enzalutamide treatment was 18.1 (IQR=7.9-61.2) ng/ml. The median maximum PSA response rate, PSA nadir, and TTN were 88% (IQR=55-98), 1.84 (IQR=0.38-14.7) ng/ml, and 19 (IQR=6-28.5) weeks, respectively. During the observation period, 35 patients died and 72 patients developed PSA exacerbations.

Factors affecting OS. In this study, we analyzed the correlation between OS and three parameters: the maximal PSA response rate, PSA nadir, and TTN. The maximal PSA response rate2 ng/ml (HR=3.23, 95%CI=1.61-6.47, p=0.0010), and TTNTable II). We previously reported that in univariate analysis, time to CRPCupper limit of normal (ULN), and PSA >20 ng/ml were correlated with worse OS (There were no significant factors in the multivariate analysis). In this cohort, time to CRPCULN (HR=2.89, 95%CI=1.30-6.44, p=0.0092), and PSA >20 ng/ml (HR=2.24, 95%CI=1.11-4.50, p=0.0243) were also associated with worse OS. Each of the three PSA kinetic parameters was subjected to multivariate analysis along with the pretreatment factors (Table III, Models 1-3). Maximal PSA response rate2 ng/ml (HR=2.30, 95%CI=1.05-5.07, p=0.0379), TTN

Factors affecting PSA-PFS. The effect of PSA kinetics on PSA-PFS was also analyzed. Maximal PSA response rate2 ng/ml (HR=11.3, 95%CI=5.92-21.7, pULN, and PSA >20 ng/ml were factors that were correlated with worse PSA-PFS in a univariate analysis. In this cohort, ageULN (HR=1.89, 95%CI=1.08-3.30, p=0.0249), and PSA >20 ng/ml (HR=2.80, 95%CI=1.72-4.56, pTable IV, Models 1-3). Maximal PSA response rate2 ng/ml (HR=8.99, 95%CI=3.87-20.9, p

Comparison of outcomes and characteristics between TTN ≥19 weeks andFigure 2shows how long it takes for PSA nadir. In many cases, a longer time was required to reach the nadir. As noted above, OS and PSA-PFS are significantly prolonged in cases with TTN ≥19 weeks. Therefore, we divided the patients into two groups according to TTN ≥19 weeks or not and compared outcomes (Figure 3). The median OS for the TTN ≥19 weeks group was 82 (IQR=38-not reached) months, which was significantly longer than the median OS of 43 (IQR=17-76) months for theTable V). The TTN

Discussion

In the present study, the analysis of patients treated with enzalutamide as the primary therapy for CRPC revealed that PSA kinetics after enzalutamide initiation were correlated with OS. Maximal PSA response rate2 ng/ml, and TTN

Post hoc analyses of several large clinical trials have demonstrated that PSA kinetics predict prognosis in mCSPC patients treated with ARSI. The post hoc analysis of the LATITUDE trial revealed that PSA response rate, reduction of PSA to

However, few studies have shown an association between PSA kinetics and prognosis in patients with CRPC treated with ARSI. Tseng et al. reported that PSA nadir ≤2 was a factor in prolonging OS in a group of patients treated with ARSI as the primary therapy for CRPC (11). A post-hoc analysis of the PROSPER study revealed that the PSA nadir and PSA decline rate affected metastatic free survival and OS in patients with non-metastatic CRPC treated with enzalutamide (12). España et al. analyzed a group of patients with metastatic CRPC (mCRPC) who received abiraterone after progression on docetaxel and reported that early PSA response and TTN were independent predictors of OS (13). Miyazawa et al. reported that PSA velocity and PSA doubling time during PSA progression predicted OS in patients with metastatic CRPC treated with enzalutamide (14). Thus, although there are few reports, PSA kinetics is expected to be a prognostic tool for patients with CRPC treated with ARSI. PSA kinetics also predict prognosis in patients with CRPC treated with docetaxel. We have previously demonstrated in a multicenter study that a 50% or greater reduction in PSA levels prolongs OS in patients treated with docetaxel as the primary therapy for CRPC (15).

This study showed that TTN at

There are several reports about longer TTN being correlated with better prognosis in patients with mCSPC treated with ADT (18). Tomioka et al. reported that TTN

We need to be careful when interpreting PSA values in patients with PCa treated with ARSI. Although most patients with mCRPC have strong AR activity (26), those who have progressed with ARSI tend to have AR-null tumors compared to those who have progressed with ADT (7), and PSA levels may not reflect the disease status. Furthermore, among patients with mCSPC, more patients who received ARSI or docetaxel in the upfront setting had imaging progression without an increase in PSA than patients who received conventional hormone therapy (8). ARSI treatment induces transformation of AR-positive cells into highly invasive neuroendocrine cancer and double-negative PC (negative for both AR and neuroendocrine markers), causing disease progression that deviates from the PSA level (27). Despite this, the previous reports and the current study demonstrate that PSA kinetics correlate with prognosis in patients with CRPC treated with ARSI (11-14). PSA kinetics can be an effective tool for predicting prognosis when regular imaging studies are performed to avoid missing progression without PSA elevation.

In this study, a low hemoglobin (Hb) level was associated with a shorter TTN, although no laboratory data were found to independently predict OS. Hakozaki et al. reported low Hb levels as a poor prognostic factor in patients with mCRPC (28). They suggest that low Hb levels reflect the replacement of cancer cells with bone marrow, chronic inflammation, and cytokine-mediated disorders, which may result in a worsening of OS.

One limitation of this study is that it was a single-center retrospective study. It is expected that more data will be accumulated in the future and that solid evidence will be provided for the prognostic effect of PSA kinetics in patients with CRPC.

Conclusion

This study revealed that the maximal PSA response rate, PSA nadir, and TTN were associated with prognosis in patients with CRPC treated with enzalutamide as a first-line therapy.

Funding

None.

Conflicts of Interest

Koji Hatano and Norio Nonomura received Grants/research supports from Astellas Global.

Authors’ Contributions

Toshiki Oka: Methodology; data curation; formal analysis; writing—original draft; investigation; visualization. Koji Hatano: Conceptualization; data curation; project administration; writing—review & editing; investigation. Masaru Tani: Investigation. Akihiro Yoshimura: Investigation. Yuki Horibe: Data curation. Yutong Liu: Investigation. Nesrine Sassi: Investigation. Yohei Okuda: Writing—review & editing. Akinaru Yamamoto: Writing—review & editing. Toshihiro Uemura: Writing—review & editing. Gaku Yamamichi: Writing—review & editing. Yu Ishizuya: Writing—review & editing. Yoshiyuki Yamamoto: Writing—review & editing. Taigo Kato: Writing—review & editing; supervision. Atsunari Kawashima: Writing—review & editing; supervision. Kazutoshi Fujita: writing—review & editing; supervision. Norio Nonomura: Writing—review & editing; supervision.

References

1 Barata PC , Leith A , Ribbands A , Montgomery R , Last M , Arondekar B , Ivanova J & Niyazov A . Real-world treatment trends among patients with metastatic castration-sensitive prostate cancer: results from an international study. Oncologist. 28(9) 780 - 789 2023. DOI: 10.1093/oncolo/oyad045 Crossref | Google Scholar

2 Hatano K & Nonomura N . Systemic therapies for metastatic castration-resistant prostate cancer: an updated review. World J Mens Health. 41(4) 769 - 784 2023. DOI: 10.5534/wjmh.220200 Crossref | Google Scholar

3 Oka T , Hatano K , Okuda Y , Yamamoto A , Uemura T , Yamamichi G , Tomiyama E , Ishizuya Y , Yamamoto Y , Kato T , Kawashima A , Fujita K & Nonomura N . The presence of lymph node metastases and time to castration resistance predict the therapeutic effect of enzalutamide for castration-resistant prostate cancer. Int J Clin Oncol. 28(3) 427 - 435 2023. DOI: 10.1007/s10147-022-02288-5 Crossref | Google Scholar

4 Afriansyah A , Hamid ARAH , Mochtar CA & Umbas R . Prostate specific antigen (PSA) kinetic as a prognostic factor in metastatic prostate cancer receiving androgen deprivation therapy: systematic review and meta-analysis. F1000Res. 7 246 2018. DOI: 10.12688/f1000research.14026.1 Crossref | Google Scholar

5 Matsubara N , Chi KN , Özgüroğlu M , Rodriguez-Antolin A , Feyerabend S , Fein L , Alekseev BY , Sulur G , Protheroe A , Li S , Mundle S , De Porre P , Tran N & Fizazi K . Correlation of prostate-specific antigen kinetics with overall survival and radiological progression-free survival in metastatic castration-sensitive prostate cancer treated with abiraterone acetate plus prednisone or placebos added to androgen deprivation therapy: Post hoc analysis of phase 3 LATITUDE study. Eur Urol. 77(4) 494 - 500 2020. DOI: 10.1016/j.eururo.2019.11.021 Crossref | Google Scholar

6 Chowdhury S , Bjartell A , Agarwal N , Chung BH , Given RW , Pereira de Santana Gomes AJ , Merseburger AS , Özgüroğlu M , Juárez Soto Á , Uemura H , Ye D , Brookman-May SD , Londhe A , Bhaumik A , Mundle SD , Larsen JS , McCarthy SA & Chi KN . Deep, rapid, and durable prostate-specific antigen decline with apalutamide plus androgen deprivation therapy is associated with longer survival and improved clinical outcomes in TITAN patients with metastatic castration-sensitive prostate cancer. Ann Oncol. 34(5) 477 - 485 2023. DOI: 10.1016/j.annonc.2023.02.009 Crossref | Google Scholar

7 Bluemn EG , Coleman IM , Lucas JM , Coleman RT , Hernandez-Lopez S , Tharakan R , Bianchi-Frias D , Dumpit RF , Kaipainen A , Corella AN , Yang YC , Nyquist MD , Mostaghel E , Hsieh AC , Zhang X , Corey E , Brown LG , Nguyen HM , Pienta K , Ittmann M , Schweizer M , True LD , Wise D , Rennie PS , Vessella RL , Morrissey C & Nelson PS . Androgen receptor pathway-independent prostate cancer is sustained through FGF signaling. Cancer Cell. 32(4) 474 - 489.e6 2017. DOI: 10.1016/j.ccell.2017.09.003 Crossref | Google Scholar

8 Hara T , Terakawa T , Okamura Y , Bando Y , Furukawa J , Harada K , Nakano Y & Fujisawa M . Real-world analysis of metastatic prostate cancer demonstrates increased frequency of PSA-imaging discordance with visceral metastases and upfront ARAT/docetaxel therapy. Prostate. 83(13) 1270 - 1278 2023. DOI: 10.1002/pros.24588 Crossref | Google Scholar

9 Scher HI , Morris MJ , Stadler WM , Higano C , Basch E , Fizazi K , Antonarakis ES , Beer TM , Carducci MA , Chi KN , Corn PG , de Bono JS , Dreicer R , George DJ , Heath EI , Hussain M , Kelly WK , Liu G , Logothetis C , Nanus D , Stein MN , Rathkopf DE , Slovin SF , Ryan CJ , Sartor O , Small EJ , Smith MR , Sternberg CN , Taplin ME , Wilding G , Nelson PS , Schwartz LH , Halabi S , Kantoff PW , Armstrong AJ & Prostate Cancer Clinical Trials Working Group 3 . Trial design and objectives for castration-resistant prostate cancer: updated recommendations from the Prostate Cancer Clinical Trials Working Group 3. J Clin Oncol. 34(12) 1402 - 1418 2016. DOI: 10.1200/JCO.2015.64.2702 Crossref | Google Scholar

10 Sweeney CJ , Chen YH , Carducci M , Liu G , Jarrard DF , Eisenberger M , Wong YN , Hahn N , Kohli M , Cooney MM , Dreicer R , Vogelzang NJ , Picus J , Shevrin D , Hussain M , Garcia JA & DiPaola RS . Chemohormonal therapy in metastatic hormone-sensitive prostate cancer. N Engl J Med. 373(8) 737 - 746 2015. DOI: 10.1056/NEJMoa1503747 Crossref | Google Scholar

11 Tseng CS , Yang JH , Huang SW , Wang YJ , Chen CH , Pu YS , Cheng JC & Huang CY . Survival outcomes and prognostic factors for first-line abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer. BMC Cancer. 23(1) 568 2023. DOI: 10.1186/s12885-023-10885-4 Crossref | Google Scholar

12 Hussain M , Sternberg CN , Efstathiou E , Fizazi K , Shen Q , Lin X , Sugg J , Steinberg J , Noerby B , De Giorgi U , Shore ND & Saad F . Nadir prostate-specific antigen as an independent predictor of survival outcomes: a post hoc analysis of the PROSPER randomized clinical trial. J Urol. 209(3) 532 - 539 2023. DOI: 10.1097/JU.0000000000003084 Crossref | Google Scholar

13 España S , Ochoa de Olza M , Sala N , Piulats JM , Ferrandiz U , Etxaniz O , Heras L , Buisan O , Pardo JC , Suarez JF , Barretina P , Comet J , Garcia Del Muro X , Sumoy L & Font A . PSA kinetics as prognostic markers of overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate. Cancer Manag Res. 12 10251 - 10260 2020. DOI: 10.2147/CMAR.S270392 Crossref | Google Scholar

14 Miyazawa Y , Sekine Y , Shimizu N , Takezawa Y , Nakamura T , Miyao T , Nakayama H , Kurihara S , Syuto T , Nomura M , Koike H , Matsui H , Shibata Y & Suzuki K . An exploratory retrospective multicenter study of prognostic factors in mCRPC patients undergoing enzalutamide treatment: Focus on early PSA decline and kinetics at time of progression. Prostate. 79(12) 1457 - 1465 2019. DOI: 10.1002/pros.23865 Crossref | Google Scholar

15 Hatano K , Nishimura K , Nakai Y , Yoshida T , Sato M , Kawashima A , Mukai M , Nagahara A , Uemura M , Oka D , Nakayama M , Takayama H , Shimizu K , Meguro N , Tanigawa T , Yamaguchi S , Tsujimura A & Nonomura N . Weekly low-dose docetaxel combined with estramustine and dexamethasone for Japanese patients with metastatic castration-resistant prostate cancer. Int J Clin Oncol. 18(4) 704 - 710 2013. DOI: 10.1007/s10147-012-0429-1 Crossref | Google Scholar

16 Miyake H , Hara T , Tamura K , Sugiyama T , Furuse H , Ozono S & Fujisawa M . Independent association between time to prostate-specific antigen (PSA) nadir and PSA progression-free survival in patients with docetaxel-naïve, metastatic castration-resistant prostate cancer receiving abiraterone acetate, but not enzalutamide. Urol Oncol. 35(6) 432 - 437 2017. DOI: 10.1016/j.urolonc.2017.01.006 Crossref | Google Scholar

17 Wu KJ , Pei XQ , Tian G , Wu DP , Fan JH , Jiang YM & He DL . PSA time to nadir as a prognostic factor of first-line docetaxel treatment in castration-resistant prostate cancer: evidence from patients in Northwestern China. Asian J Androl. 20(2) 173 - 177 2018. DOI: 10.4103/aja.aja_34_17 Crossref | Google Scholar

18 Sasaki T & Sugimura Y . The importance of time to prostate-specific antigen (PSA) nadir after primary androgen deprivation therapy in hormone-naïve prostate cancer patients. J Clin Med. 7(12) 565 2018. DOI: 10.3390/jcm7120565 Crossref | Google Scholar

19 Tomioka A , Tanaka N , Yoshikawa M , Miyake M , Anai S , Chihara Y , Okajima E , Hirayama A , Hirao Y & Fujimoto K . Nadir PSA level and time to nadir PSA are prognostic factors in patients with metastatic prostate cancer. BMC Urol. 14 33 2014. DOI: 10.1186/1471-2490-14-33 Crossref | Google Scholar

20 Hamano I , Hatakeyama S , Narita S , Takahashi M , Sakurai T , Kawamura S , Hoshi S , Ishida M , Kawaguchi T , Ishidoya S , Shimoda J , Sato H , Mitsuzuka K , Tochigi T , Tsuchiya N , Arai Y , Habuchi T & Ohyama C . Impact of nadir PSA level and time to nadir during initial androgen deprivation therapy on prognosis in patients with metastatic castration-resistant prostate cancer. World J Urol. 37(11) 2365 - 2373 2019. DOI: 10.1007/s00345-019-02664-3 Crossref | Google Scholar

21 Kitagawa Y , Ueno S , Izumi K , Mizokami A , Hinotsu S , Akaza H & Namiki M . Nadir prostate-specific antigen (PSA) level and time to PSA nadir following primary androgen deprivation therapy as independent prognostic factors in a Japanese large-scale prospective cohort study (J-CaP). J Cancer Res Clin Oncol. 140(4) 673 - 679 2014. DOI: 10.1007/s00432-014-1612-8 Crossref | Google Scholar

22 Lin YC , Lin PH , Shao IH , Chu YC , Kan HC , Liu CY , Yu KJ , Chang YH , Pang ST , Huang JL & Chuang CK . Prostate-specific antigen kinetics effects on outcomes of low-volume metastatic prostate cancer patients receiving androgen deprivation therapy. J Oncol. 2021 9648579 2021. DOI: 10.1155/2021/9648579 Crossref | Google Scholar

23 Choueiri TK , Xie W , D’Amico AV , Ross RW , Hu JC , Pomerantz M , Regan MM , Taplin ME , Kantoff PW , Sartor O & Oh WK . Time to prostate-specific antigen nadir independently predicts overall survival in patients who have metastatic hormone-sensitive prostate cancer treated with androgen-deprivation therapy. Cancer. 115(5) 981 - 987 2009. DOI: 10.1002/cncr.24064 Crossref | Google Scholar

24 Huang SP , Bao BY , Wu MT , Choueiri TK , Goggins WB , Huang CY , Pu YS , Yu CC & Huang CH . Impact of prostate-specific antigen (PSA) nadir and time to PSA nadir on disease progression in prostate cancer treated with androgen-deprivation therapy. Prostate. 71(11) 1189 - 1197 2011. DOI: 10.1002/pros.21334 Crossref | Google Scholar

25 Sasaki T , Ishii K , Iwamoto Y , Kato M , Miki M , Kanda H , Arima K , Shiraishi T & Sugimura Y . Fibroblasts prolong serum prostate-specific antigen decline after androgen deprivation therapy in prostate cancer. Lab Invest. 96(3) 338 - 349 2016. DOI: 10.1038/labinvest.2015.136 Crossref | Google Scholar

26 Kumar A , Coleman I , Morrissey C , Zhang X , True LD , Gulati R , Etzioni R , Bolouri H , Montgomery B , White T , Lucas JM , Brown LG , Dumpit RF , DeSarkar N , Higano C , Yu EY , Coleman R , Schultz N , Fang M , Lange PH , Shendure J , Vessella RL & Nelson PS . Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat Med. 22(4) 369 - 378 2016. DOI: 10.1038/nm.4053 Crossref | Google Scholar

27 Labrecque MP , Coleman IM , Brown LG , True LD , Kollath L , Lakely B , Nguyen HM , Yang YC , da Costa RMG , Kaipainen A , Coleman R , Higano CS , Yu EY , Cheng HH , Mostaghel EA , Montgomery B , Schweizer MT , Hsieh AC , Lin DW , Corey E , Nelson PS & Morrissey C . Molecular profiling stratifies diverse phenotypes of treatment-refractory metastatic castration-resistant prostate cancer. J Clin Invest. 129(10) 4492 - 4505 2019. DOI: 10.1172/JCI128212 Crossref | Google Scholar

28 Hakozaki Y , Yamada Y , Takeshima Y , Taguchi S , Kawai T , Nakamura M , Iwaki T , Teshima T , Kinoshita Y , Akiyama Y , Sato Y , Yamada D , Suzuki M & Kume H . Low hemoglobin and PSA kinetics are prognostic factors of overall survival in metastatic castration-resistant prostate cancer patients. Sci Rep. 13(1) 2672 2023. DOI: 10.1038/s41598-023-29634-5 Crossref | Google Scholar