Negative Delta-Prostate-Specific Antigen Time Ratio as Potential New Marker of Progression-Free Survival in Castration-Resistant Prostate Cancer Patients Treated With First-Line Enzalutamide or Docetaxel

Article information

J Urol Oncol. 2023;21(3):271-276
Publication date (electronic) : 2023 November 30
doi : https://doi.org/10.22465/juo.234600440022
Department of Urology, Ajou University School of Medicine, Suwon, Korea
Corresponding author: Sun Il Kim Department of Urology, Ajou University School of Medicine, 164 World cup-ro, Yeongtong-gu, Suwon 16499, Korea Email: sikimuro@aumc.ac.kr
Received 2023 September 5; Revised 2023 October 1; Accepted 2023 October 23.

Abstract

Purpose

We propose a new potential marker of progression-free survival (PFS) called negative delta-prostate-specific antigen (PSA) time ratio (NDPSATR) and compare it with conventional PSA response, defined as PSA decline ≥50% at 12 weeks from pretreatment baseline (PSAR50) in metastatic castration-resistant prostate cancer (mCRPC) patients treated with first-line enzalutamide (ENZ) or docetaxel (DTX).

Materials and Methods

All patients diagnosed as mCRPC at Ajou University Hospital from 2016 were included. Delta-PSA days is PSA change between 2 consecutive measurements during a regimen multiplied by interval days. A negative delta-PSA days value represents a positive PSA response. NDPSATR is calculated by dividing the sum of days on negative delta-PSA days by total days on the regimen. Student t-test was used to compare mean values and Kaplan-Meier survival curves for PFS were obtained.

Results

Of 57 patients identified, 22 and 35 were treated with ENZ and DTX, respectively. Rates of PSAR50 for ENZ and DTX were 72.7% and 20.6%, respectively. Mean NDPSATR for ENZ and DTX were 0.40 and 0.46, respectively and the difference was not statistically significant. For ENZ, median PFS (mPFS) of PSAR50 and non-PSAR50 were 14.3 and 4.8 months, respectively and there was significant difference in PFS (p=0.002). For DTX, mPFS of PSAR50 and non-PSAR50 were 15.0 and 6.5 months, respectively but there was no significant difference in PFS (p=0.055). At cutoff value of 0.4, rate of NDPSATR ≥0.4 for ENZ and DTX were 36.4% and 62.9%, respectively. For ENZ, mPFS of NDPSATR ≥0.4 and NDPSATR <0.4 were not achieved and 14.1 months, respectively and there was no significant difference in PFS (p=0.895). For DTX, mPFS of NDPSATR ≥0.4 and NDPSATR <0.4 were 9.7 and 6.3 months, respectively and there was a significant difference in PFS (p=0.045).

Conclusions

NDPSATR ≥0.4 may be a good marker of PFS in CRPC patients treated with DTX and may replace PSAR50.

INTRODUCTION

Serum prostate-specific antigen (PSA) is the most practical, if not the most reliable marker of response to therapy in prostate cancer patients. In castration-resistant prostate cancer (CRPC), PSA has been advocated as one of the markers of response to therapy along with radiologic response and symptomatic response. PSA response, defined as PSA decline ≥50% at 12 weeks from pretreatment baseline (PSAR50) is the most commonly used marker of progression-free survival (PFS) [1]. Landmark phase 3 studies that gave birth to current standard-of care CRPC regimen, such as docetaxel (DTX) and androgen-receptor targeting agents (ARTAs) all used the rate of PSAR50 as secondary endpoints [2-4]. In real-world, retrospective data, DTX achieved PSAR50 in 41%–56% of CPRC patients which is remarkable, and comparable to 50% observed in the landmark phase 3 study of DTX and estramustine combination [2,5-7]. However, PSA level checked at a predetermined time may not faithfully reflect the efficacy of treatment in all patients equally. Well recognized measures of PSA kinetics such and time to PSA nadir, PSA halving time, PSA doubling time, PSA at 12 weeks, and other PSA-based parameters have shown limited potential as novel predictive markers of progression in DTX-only era [8,9]. Moreover, these PSA-based markers assume that all responders will show initial decline of PSA, which is not always true. In the current era where DTX is not the stand-alone therapy for CRPC patients, timely transition from first-line DTX to an ARTA and vice-versa is important to optimize treatment and prolong patients survival. We introduce a potential new marker of response to therapy based on PSA kinetics named total negative delta-PSA time ratio (NDPSATR) that can be easily evaluated any time and could be used during the course of treatment in CRPC patients.

MATERIALS AND METHODS

Using the clinical data warehouse, all male patients >40 years of age who were prescribed any one of the standard-of care pharmacotherapy agents used in CRPC at Ajou University Hospital were searched. These agents included abiraterone, cabazitaxel, DTX, and enzalutamide (ENZ). Once patients were identified, their history of prescription of antineoplastic agents including hormonal agents along with dosing dates were searched and downloaded in a spreadsheet file. Also, their PSA values along with test dates were searched and downloaded in a spreadsheet file. Then, the 2 spreadsheet files were merged so that patient’s identification number and dosing/test dates are aligned in same reciprocal columns. Sorting the spreadsheet successively in an ascending order for dosing/test dates and for patient identification number gave a report form whereby treatment and response (PSA value) are arranged in a chronological order for individual patients. This allowed us to assess the date and value of initial PSA, treatment regimen used, date and value of nadir PSA during the initial androgen-deprivation therapy (ADT), date of CRPC according to the PSA definition of CRPC (>25% increase in serum PSA within 2 consecutive measurements separated by at least 1 week, and an absolute value >2.0 ng/mL) and the last follow-up date, which was usually the date of the last PSA or the date of the last drug prescription. Using appropriate spreadsheet functions, important periods were calculated such as duration of each therapeutic regimen that is equivalent to PFS, initial treatment duration, time to nadir PSA, duration of hormone-sensitive prostate cancer, duration of CRPC, and time to first metastasis if applicable. NDPSATR based on PSA kinetics during a certain regimen were calculated. Delta-PSA days is PSA change between 2 consecutive measurements during a regimen multiplied by interval days. This mimics the pack-year equation, which measures the relative amount of cigarettes smoked by a person over the entire time he/she smoked. A negative delta-PSA days value will represent a positive PSA response and a positive delta-PSA days will represent PSA unresponsiveness. NDPSATR is calculated by dividing the sum of days on negative delta-PSA days by total days on the regimen. PSAR was calculated by dividing PSA change at 12 weeks from the start of the regimen by the baseline PSA. Fig. 1 shows 2 representative examples of PSA kinetics after ENZ and DTX treatment, respectively. For ENZ case (orange line), NDPSATR is calculated as NDPSATR=t1/Σt=0.06. For DTX case (blue line), NDPSATR is calculated as NDPSATR=(t2+ t4+t6+t8+t9+t10+t12+t14)/Σt=0.56.

Fig. 1.

Two representative examples of PSA kinetics in long-term responders to ENZ and DTX treatment, respectively. PSA, prostate-specific antigen; t, time interval between 2 consecutive PSA measurements; 3M PSAR, 3-month prostate-specific antigen response; NDPSATR, negative delta-PSA time ratio; DTX, docetaxel; ENZ, enzalutamide.

Patients were divided into ENZ and DTX groups according to the first-line treatment given at CRPC. Bivariate correlation analysis was used to calculate Pearson correlation coefficient (PCC) between PSAR and NDPSATR. Kaplan-Meier survival curves for PFS were obtained and the difference was compared using log-rank test. IBM SPSS Statistics ver. 25.0 (IBM Co., Armonk, NY, USA) was used for statistical analyses.

RESULTS

Fifty-seven patients were identified, 22 in the ENZ group and 35 in the DTX group. Clinicopathological data are summarized in Table 1. Figs. 2 and 3 show waterfall plots of PSAR and NDPSATR of individual patients during ENZ and DTX treatment, respectively. In the ENZ group, there was moderate correlation between PSAR and NDPSATR, which was not statistically significant (PCC=0.337, p=0.125). In the DTX group, there was moderate correlation between PSAR and NDPSATR, which was statistically significant (PCC=0.389, p=0.023). The rate of PSAR50 for ENZ and DTX were 72.7% and 20.6%, respectively. Median NDPSATR for ENZ and DTX were 0.35 and 0.47, respectively. Figs. 47 show Kaplan-Meier curves for PFS in ENZ and DTX groups, and compare between PSAR50 and non-PSAR50, and between NDPSATR ≥0.4 and NDPSATR <0.4. In ENZ group, median PFS (mPFS) for PSAR50 and non-PSAR50 were 14.3 and 4.8 months, respectively and there was a statistically significant difference in PFS (p=0.002). In DTX group, mPFS of PSAR50 and non-PSAR50 were 15.0 and 6.5 months, respectively but there was no statistically significant difference in PFS (p=0.055). NDPSATR ≥0.4 for ENZ and DTX were 36.4% and 62.9%, respectively. In ENZ group, mPFS of NDPSATR ≥0.4 and NDPSATR <0.4 were not achieved and 14.1 months, respectively and there was no statistically significant difference in PFS (p=0.895). In DTX group, mPFS of NDPSATR ≥0.4 and NDPSATR <0.4 were 9.7 and 6.3 months, respectively and there was a statistically significant difference in PFS (p=0.045).

Clinicopathological characteristics of metastatic castration-resistant prostate cancer patients treated with enzalutamide or docetaxel as the primary therapy

Fig. 2.

Waterfall plot of PSAR and NDPSATR for individual patients during first-line ENZ treatment in ascending order for PSAR. ENZ, enzalutamide; NDPSATR, negative delta-PSA time ratio; PSAR, prostate-specific antigen response; PSA, prostate-specific antigen.

Fig. 3.

Waterfall plot of PSAR and NDPSATR for individual patients during first-line DTX treatment in ascending order for PSAR. DTX, docetaxel; NDPSATR, negative delta-PSA time ratio; PSAR, prostate-specific antigen response; PSA, prostate-specific antigen.

Fig. 4.

Meier curve for progression-free survival (PFS) in patients treated with first-line enzalutamide divided into PSAR50 and non-PSAR50. PSAR50, prostate-specific antigen response ≥50%.

Fig. 5.

Kaplan-Meier curve for progression-free survival (PFS) in patients treated with first-line docetaxel divided into PSAR50 and non-PSAR50. PSAR50, prostate-specific antigen response ≥50%.

Fig. 6.

Kaplan-Meier curve for progression-free survival (PFS) in patients treated with first-line enzalutamide divided into NDPSATR ≥0.4 and NDPSATR <0.4. NDPSATR, negative delta-PSA time ratio. PSA, prostate-specific antigen.

Fig. 7.

Kaplan-Meier curve for progression-free survival (PFS) in patients treated with first-line docetaxel divided into NDPSATR ≥0.4 and NDPSATR <0.4. NDPSATR, negative delta-PSA time ratio; PSA, prostate-specific antigen.

DISCUSSION

PSA will often rise initially with DTX treatment only to fall gradually, a phenomenon which is rarely seen with ARTA. This flare-up phenomenon has been observed in 11%–15% of CRPC patients on DTX [7,10]. However, most of the patients who showed initial PSA flare-up had their successive PSA decline and demonstrated similar oncological outcome with patients who showed initial PSA response. Other than this initial flare-up, PSA will often fluctuate going up and down during the treatment for a long stable period (Fig. 1). This particular PSA kinetics with DTX may make PSA response criteria of >50% decline often obsolete. This may also lead to premature termination of DTX when it is still effective. NDPSATR was discovered during an effort to compensate for the unsatisfactory performance of PSAR50 at the clinic. NDPSATR ranges from 0 meaning no PSA response at all to 1 meaning continuous and uninterrupted PSA decline during treatment. In real-world practice, NDPSATR value of 0 coupled with a negative PSAR will signify primary resistance to treatment. As all mCRPC patients will ultimately progress on a treatment, NDPSATR value of 1 signifies either the treatment was prematurely stopped for some reason during a responsive period, or the treatment is still ongoing. As PSA rise usually precedes radiologic progression that mostly determines the discontinuation of a treatment by a few months, it can be expected that NDPSATR value of most patients who had their diseases progressed after an initial response will fall somewhere between 0 and 0.5. Median NDPSATR values of 0.35 and 0.47 are in line with these observations. Cutoff value of 0.4 was set arbitrarily based on our patients’ data showing meaningful prognostic value at this level. Our results showed PSAR50 rate of 73% with ENZ which is comparable to 78% shown in the landmark phase 3 study [3]. However, our PSAR50 rate with DTX was only 21%, which is much lower than results from previous studies and not clearly explained. In addition, PSAR50 was predictive of PFS in ENZ, but not in DTX. On the contrary, NDPSATR ≥0.4 rate was 63% in DTX and only 36% in ENZ. Also, NDPSATR ≥0.4 was predictive of PFS.

Differences in PSA kinetics between ENZ and DTX shown in our study are not new; similar differences are found in the literature. With the advent of ARTAs in the treatment of CRPC, multiple real-world studies have consistently shown that PSA markers exhibiting earlier, and more profound PSA decline after initiation of treatment are strong predictors of good prognosis [11-13]. If the PSA kinetics during first-line ARTAs in CRPC are similar to those during ADT in the initial castration-naïve state, the behavior of PSA during DTX is in sharp contrast. In a retrospective single center analysis of 41 CRPC patients who received DTX as first-line therapy, time to nadir PSA of <16 weeks was an independent predictor of shorter duration of chemotherapy response and shorter time to PSA progression [8]. In another retrospective series, 52 CRPC patients who showed initial sensitivity to DTX were given median holidays of 16 to 18 weeks before initiating DTX retreatment which ranged from 2 to 8 series [9]. In this study, various PSA kinetics were calculated during on- and off-treatment periods of which absolute PSA decline and type I PSA progression (increase of ≥25% from the nadir) were the only independent predictors of survival. On the other hand, PSA decline >50% and absolute and relative PSA values were not independent predictors of survival. In addition, type II PSA progression based on a PSA value above the baseline level, was not predictive of survival.

There are several limitations in our study. The study population was small and there was a significant disparity in the number of patients between the ENZ and DTX groups, making the statistical power limited as a result. A multicenter study would be ideal to prove the usefulness of NDPSATR. Also, the mPFS values used in the study were relatively short. Longer-term observations may be necessary, and additional studies may be required to evaluate PFS over a more extended period. Cutoff value of 0.4 was arbitrary and may not apply universally. NDPSATR presented in this study is the sum of all delta-PSA day values from the start of a regimen to progression, which is not practical as a predicting marker on a par with PSAR50 which is usually obtained at 12 weeks of the start of treatment. An interim NDPSATR should be studied in the future.

CONCLUSIONS

NDPSATR ≥0.4 may be a good marker of PFS in CRPC patients treated with DTX and may replace PSAR50 in the future. Further studies should be performed to improve and validate NDPSATR in a larger multicenter cohort.

Notes

Conflicts of Interest

The authors have nothing to disclose.

Funding/Support

This study received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Author Contribution

Conceptualization: SIK; Data curation: THK, KHS; Formal analysis: SIK; Methodology: SIK; Project administration: KHS; Visualization: THK; Writing - original draft:THK; Writing - review & editing: SIK, SHC.

References

1. Sella A, Kilbourn R, Amato R, Bui C, Zukiwski AA, Ellerhorst J, et al. Phase II study of ketoconazole combined with weekly doxorubicin in patients with androgen-independent prostate cancer. J Clin Oncol 1994;12:683–8.
2. Petrylak DP, Tangen CM, Hussain MH, Lara PN Jr, Jones JA, Taplin ME, et al. Docetaxel and estramustine compared with mitoxantrone and prednisone for advanced refractory prostate cancer. N Engl J Med 2004;351:1513–20.
3. Beer TM, Armstrong AJ, Rathkopf DE, Loriot Y, Sternberg CN, Higano CS, et al. Enzalutamide in metastatic prostate cancer before chemotherapy. N Engl J Med 2014;371:424–33.
4. de Bono JS, Logothetis CJ, Molina A, Fizazi K, North S, Chu L, et al. Abiraterone and increased survival in metastatic prostate cancer. N Engl J Med 2011;364:1995–2005.
5. Song G, Lee C, You D, Jeong IG, Hong JH, Ahn H, et al. Prostate-specific antigen response rate of sequential chemotherapy in castration-resistant prostate cancer: the results of real life practice. Prostate Int 2013;1:125–32.
6. Miyake H, Sakai I, Terakawa T, Harada K, Fujisawa M. Oncological outcome of docetaxel-based chemotherapy for Japanese men with metastatic castration-resistant prostate cancer. Urol Oncol 2013;31:733–8.
7. Sella A, Sternberg CN, Skoneczna I, Kovel S. Prostate-specific antigen flare phenomenon with docetaxel-based chemotherapy in patients with androgen-independent prostate cancer. BJU Int 2008;102:1607–9.
8. Thomas BM, Smith C, Evans J, Button MR, Kumar S, Palaniappan N, et al. Time to prostate specific antigen (PSA) nadir may predict rapid relapse in men with metastatic castration-resistant prostate cancer (CRPC) receiving docetaxel chemotherapy. Med Oncol 2013;30:719.
9. Maj-Hes A, Szarvas T, Sevcenco S, Kramer G. Multiple docetaxel retreatments without prednisone for metastatic castration-resistant prostate cancer in the docetaxel-only era: effects on PSA kinetics and survival. Adv Ther 2021;38:3831–41.
10. Nelius T, Klatte T, de Riese W, Filleur S. Impact of PSA flare-up in patients with hormone-refractory prostate cancer undergoing chemotherapy. Int Urol Nephrol 2008;40:97–104.
11. Miyazawa Y, Sekine Y, Shimizu N, Takezawa Y, Nakamura T, Miyao T, et al. 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 2019;79:1462–70.
12. Buttigliero C, Tucci M, Sonetto C, Vignani F, Di Stefano RF, Pisano C. Prognostic role of early PSA drop in castration resistant prostate cancer patients treated with abiraterone acetate or enzalutamide. Minerva Urol Nefrol 2020;72:737–45.
13. España S, de Olza MO, Sala N, Piulats JM, Ferrandiz U, Etxaniz O, et al. PSA Kinetics as prognostic markers of overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate. Cancer Manag Res 2020;12:10251–60.

Article information Continued

Fig. 1.

Two representative examples of PSA kinetics in long-term responders to ENZ and DTX treatment, respectively. PSA, prostate-specific antigen; t, time interval between 2 consecutive PSA measurements; 3M PSAR, 3-month prostate-specific antigen response; NDPSATR, negative delta-PSA time ratio; DTX, docetaxel; ENZ, enzalutamide.

Fig. 2.

Waterfall plot of PSAR and NDPSATR for individual patients during first-line ENZ treatment in ascending order for PSAR. ENZ, enzalutamide; NDPSATR, negative delta-PSA time ratio; PSAR, prostate-specific antigen response; PSA, prostate-specific antigen.

Fig. 3.

Waterfall plot of PSAR and NDPSATR for individual patients during first-line DTX treatment in ascending order for PSAR. DTX, docetaxel; NDPSATR, negative delta-PSA time ratio; PSAR, prostate-specific antigen response; PSA, prostate-specific antigen.

Fig. 4.

Meier curve for progression-free survival (PFS) in patients treated with first-line enzalutamide divided into PSAR50 and non-PSAR50. PSAR50, prostate-specific antigen response ≥50%.

Fig. 5.

Kaplan-Meier curve for progression-free survival (PFS) in patients treated with first-line docetaxel divided into PSAR50 and non-PSAR50. PSAR50, prostate-specific antigen response ≥50%.

Fig. 6.

Kaplan-Meier curve for progression-free survival (PFS) in patients treated with first-line enzalutamide divided into NDPSATR ≥0.4 and NDPSATR <0.4. NDPSATR, negative delta-PSA time ratio. PSA, prostate-specific antigen.

Fig. 7.

Kaplan-Meier curve for progression-free survival (PFS) in patients treated with first-line docetaxel divided into NDPSATR ≥0.4 and NDPSATR <0.4. NDPSATR, negative delta-PSA time ratio; PSA, prostate-specific antigen.

Table 1.

Clinicopathological characteristics of metastatic castration-resistant prostate cancer patients treated with enzalutamide or docetaxel as the primary therapy

Variable ENZ group (n=22) DTX group (n=35)
Age (yr), mean (range) 70.3 (51.6–84.1) 68.2 (51.2–89.5)
Gleason score
 6 0 0
 7 1 3
 8 3 3
 9 16 22
 10 2 5
 Unknown 0 2
Mean follow-up (mo) 27.8 34.1
Status
 Ongoing 12 11
 Dead of disease 3 8
 Dead of other cause 0 1
 Follow-up loss 7 15

Values are presented as mean (range) or number unless otherwise indicated.

ENZ, enzalutamide; DTX, docetaxel.