The Effect of Upfront Intensive Therapy on Primary Resistance in Metastatic Castration-sensitive Prostate Cancer: A Multicenter Retrospective Study

We investigated the effect of upfront intensive therapy on primary resistance in patients with metastatic castration-sensitive prostate cancer (mCSPC) in real-world practice. We retrospectively evaluated the medical records of 348 patients with newly diagnosed mCSPC who had a high tumor-burden between January 2008 and May 2021. We compared the oncological outcomes between patients who received conventional androgen deprivation therapy ± bicalutamide (ADT group) and those treated with upfront intensive therapies (upfront group). The primary purpose was comparing the rate of primary resistance between the ADT and upfront groups. The primary resistance was dened as a castration-resistant prostate cancer (CRPC) progression < 6 or < 12 months. The secondary purposes were comparing the CRPC-free survival and overall survival (OS) between the ADT and upfront groups, and assessing safety in the upfront group. We identied 206 and 142 patients for the ADT and upfront groups, respectively. We found the rate of CRPC progression < 6 and < 12 months was signicantly lower in the upfront group (9.2% and 18%, respectively) than that in the ADT group (21% and 51%, respectively). The upfront therapy was signicantly associated with favorable CRPC-free survival and OS than that in the ADT group in propensity-score adjusted models. A higher rate of any grade adverse events was observed in the upfront docetaxel (94%) than that of the upfront abiraterone (34%) or apalutamide/enzalutamide (39%). In conclusion, the upfront intensive therapy signicantly improved the rate of primary resistance and oncological outcomes in patients with mCSPC in real-world practice.


Introduction
In Western countries and Japan, prostate cancer (PC) is the most frequent cancer in men. [1][2][3] Although androgen deprivation therapy (ADT) is the standard treatment for metastatic castration-sensitive prostate cancer (mCSPC), progression to metastatic castration-resistant PC (CRPC) remains a major cause of deaths in men with cancer. [4][5][6][7][8] Recent studies have shown that upfront intensive therapy, including docetaxel (DTX), abiraterone (ABI), apalutamide (APA), and enzalutamide (ENZ), has a signi cant bene t in treating mCSPC [9][10][11][12][13] and became a standard of care for patients with mCSPC. 14 However, there is a concern about the bene t-harm balance in these upfront intensive therapies because Japanese patients have relatively better responses to primary ADT plus bicalutamide (complete androgen blockade) than Westerners. 15 Therefore, real-world data to prove the advantage of upfront intensive therapy over ADT plus bicalutamide in Japanese patients are awaited. We retrospectively investigated the effect of upfront intensive therapy on the rate of primary resistance, oncological outcomes, and safety in patients with mCSPC.

Results
Of the 554, we identi ed 348 eligible patients with high tumor burden. Of 348, 206 and 142 patients were divided in the ADT and upfront groups, respectively (Fig. 1). The median age in this cohort was 72 years.

Exploratory outcomes
Unadjusted CRPC-free survival was signi cantly longer in the upfront ARATs and DTX than that in the ADT group (median, unde ned, 27, vs. 12 months, respectively) (Fig. 5A). Unadjusted CRPC-free survival was not signi cantly different between the upfront ABI and APA/ENZ groups (Fig. 5B). Unadjusted OS was signi cantly longer in the upfront ARATs than that in the ADT group (median, unde ned, unde ned, vs. 48 months) (Fig. 5C). The achievement rate of PSA ≤ 0.2 ng/mL was signi cantly higher in the upfront group (57%) than that in the ADT group (31%) (Fig. 5D). The rate of PSA ≤ 0.2 ng/mL in the upfront DTX, ABI, and APA/ENZ was 45%, 66%, and 54%, respectively.

Discussion
We compared the rate of primary resistance and oncological outcomes between the conventional ADT and upfront intensive therapies in patients with newly diagnosed mCSPC in our clinical practice. We found signi cantly improved CRPC progression rate < 6 or 12 months after upfront therapy than those in the conventional ADT therapy. Moreover, we observed signi cantly prolonged CRPC-free survival and OS in patients treated with upfront intensive therapy than those who received conventional ADT therapy. This study demonstrated the bene t of upfront intensive therapy over the ADT therapy on the oncological outcomes in real-world practice in Japan.
As radiological imaging tests were performed around 6 to 12 months in clinical practice, the main de nition for CRPC progression within 6 months was the PSA progression in this study. The rate of primary resistance within 6 months in the upfront intensive therapy was approximately 3-12% in several phase III clinical trials. The time to PSA progression within the rst 6 months in the upfront arm vs.
The selection of upfront DTX or ARATs therapy for mCSPC is debatable. As no study directory has compared the e cacy of upfront intensive therapies, indirect comparisons using network meta-analysis support the superiority of upfront ARATs therapy over upfront DTX. 18- 20 We found persistent decline of CRPC-free survival in the patients with upfront DTX therapy (Fig. 5A). Although the rate of primary resistance was similar group, treatment e cacy of upfront DTX may be not sustainable. In consideration with higher AEs rate in the upfront DTX, this regimen can be used in patients who might have neuroendocrine differentiation. 21 As mCSPC had heterogeneous characteristics, molecular biomarkers are necessary for selecting treatment in those patients. [22][23][24][25] The safety pro le between the upfront DTX and ARATs therapies is a key factor for treatment selection. We observed a signi cant difference in toxicities between the upfront DTX and ARATs groups. Although no study directory compared the safety between upfront DTX and ARATs therapies, a recent network meta-analysis showed that the prevalence of high-grade AEs was signi cantly lower in patients treated with enzalutamide (OR, 0.56; 95% CI, 0.35-0.92) and apalutamide (OR, 0.44; 95% CI, 0.24-0.79) than those who received DTX. 20 Furthermore, ad-hoc analysis of quality of life (QOL) comparison in the Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug E cacy trial reported that global QOL was signi cantly higher in the ABI arm compared to the DTX arm (+ 3.9; 95% CI, 0.6-7.1; P = 0.021). Although the results of that network meta-analysis need careful consideration, upfront ARATs therapies might have less toxicity than upfront DTX therapy. Similarly, we observed a signi cantly higher rate of AEs in the upfront DTX group than that in the upfront ARATs group. However, the major AE in the DTX group was non-symptomatic hematotoxicities and preventable by granulocyte colony-stimulating factor. 26 Caution is required for the higher rate of AE-related hospitalization and discontinuation in the upfront ABI group (9.9% and 17%, respectively) than in the upfront DTX (3.1% and 3.1%, respectively) or upfront APA/ENZ (2.6% and 10%, respectively) group. We should recognize that upfront intensive therapies can increase the risk of harmful toxicities despite their e cacy.
The retrospective study design, small sample size, selection bias, and immeasurable confounding factors limit this study. Our results may not be applied to other countries because of racial, regional, and insurance system differences. Despite these limitations, our results con rmed the potential utility of upfront intensive therapy in real-world practice. Further long-term observations are necessary to clarify the bene ts of upfront therapies in patients with mCSPC.
In conclusion, upfront intensive therapies signi cantly improved the rate of primary resistance and oncological outcomes in patients with newly diagnosed mCSPC in real-world practice.

Patients And Methods
This retrospective study follows the ethical standards of the Declaration of Helsinki, and the ethics review board of the Hirosaki University School of Medicine approved this study (authorization number: 2019-094) and all hospitals in this study. Pursuant to the provisions of the ethics committee and the ethics guideline in Japan, 27 written consent was not required in exchange for public disclosure of study information (opt-out approach) in the case of retrospective and/or observational study using a material such as the existing documentation.

Study population and patient selection
We retrospectively evaluated the medical records of 554 patients with mCSPC who were treated at Hirosaki University Hospital and associated hospitals between January 2008 and March 2021. Inclusion criteria were mCSPC patients with CHAARTED high-volume or LATITUDE high-risk (high tumor burden) 10,13 , and who were treated with ADT alone, ADT plus bicalutamide, or upfront intensive therapy as a standard of care. Patients without insu cient baseline clinical information were excluded. Finally, 332 patients with mCSPC who had high tumor burden were enrolled (Fig. 1). Patients were divided into two groups: those treated with ADT alone or ADT plus bicalutamide (ADT group) and those who received upfront intensive therapy (upfront group) such as upfront DTX, upfront abiraterone (ABI), upfront apalutamide (APA) or upfront enzalutamide (ENZ).

Variable evaluations
The following variables were investigated at diagnosis: age, Eastern Cooperative Oncology Group Performance Status (ECOG PS), Gleason score, serum PSA, time to CRPC diagnosis, PSA nadir, CRPC-free survival, and OS. Metastatic status was evaluated via chest and body computed tomography and bone scintigraphy before initiating ADT. Bone metastatic volume was evaluated using the extent of disease (EOD) score on bone scintigraphy. CRPC-free survival was evaluated from the date of the initial diagnosis of mCSPC to the date of CRPC diagnosis following the recommendations of the Cancer Clinical Trials Working Group 2 28 . OS were evaluated from the date of the initial diagnosis of mCSPC to the date of any cause of death or nal follow-up.

Treatment protocol
Treatment was selected based on the decision of the attending physicians. Patients were initially treated with ADT alone or ADT plus bicalutamide before the approval of upfront intensive therapy. After June 2016, we started providing upfront intensive therapy in patients with high tumor burden. After the diagnosis of CRPC, patients underwent sequential therapy including taxane-based chemotherapy or second-generation androgen receptor-axis-targeted agents (ARATs) such as ABI, APA, or ENZ.

Primary purposes
The comparison of the rate of primary resistance between the ADT and upfront groups. The primary resistance was de ned as a PSA progression, radiologic progression, or any cause of death within 6 or 12 months.

Secondary purposes
The comparison of CRPC-free survival and OS between the ADT and upfront groups, and assessing safety in the upfront group. Adverse events (AEs) were evaluated using the Common Terminology Criteria for Adverse Events version 5.0.

Exploratory purposes
The exploratory purposes were to compare the CRPC-free survival and OS between the ADT group and patients treated with upfront DTX, and between the ADT group and patients treated with upfront ARATs (ABI/APA/ENZ). The achievement rate of PSA ≤ 0.2 ng/mL was also evaluated. Informed consent:

Statistical analysis
Pursuant to the provisions of the ethics committee and the ethics guideline in Japan, written consent was not required in exchange for public disclosure of study information (opt-out approach) in the case of retrospective and/or observational study using a material such as the existing documentation.

Consent to Participate:
Written consent was not obtained in exchange for the public disclosure of study information (opt-out approach).  Figure 1 Patient selection. Patients with high tumor burden (CHAARTED high-volume or LATITUDE high-risk) were selected in this study. Finally, we identi ed 206 and 126 patients in the ADT and upfront groups, respectively.

Figure 2
Primary outcomes. The comparison of the rate of primary resistance (CRPC progression < 6 months) between the ADT and upfront groups (A). The comparison of the rate of primary resistance (CRPC progression < 12 months) between the ADT and upfront groups (B). DTX: docetaxel, ABI: abiraterone, APA: apalutamide, ENZ: enzalutamide Secondary outcomes Unadjusted CRPC-free survival comparison between the ADT and upfront groups (A). Unadjusted OS comparison between the ADT and upfront groups (B). Multivariable Cox regression analysis using a propensity score-based inverse probability of treatment weighting (IPTW) method for CRPC-free survival after adjusting for potential confounders (age, ECOG PS, Gleason score, and EOD score for the upfront intensive therapy) (C). IPTW-adjusted multivariable Cox regression analysis for OS (D).

Figure 4
Safety pro le Safety pro le of upfront intensive therapies was shown using CTCAE v5.0 (A). Detailed adverse events (AEs) in the upfront DTX therapy (B), in the upfront ABI therapy (C), and in the upfront APA/ENZ therapy (D) were shown.

Supplementary Files
This is a list of supplementary les associated with this preprint. Click to download. v5Graphicabst.pdf