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A phase II randomised trial of abiraterone acetate plus prednisone in combination with docetaxel or docetaxel plus prednisone after disease progression to abiraterone acetate plus prednisone in patients with metastatic castration-resistant prostate cancer: The ABIDO-SOGUG trial

Published:September 10, 2022DOI:https://doi.org/10.1016/j.ejca.2022.08.002

      Highlights

      • Docetaxel plus abiraterone acetate plus prednisone (AAP) versus docetaxel plus prednisone after progression to AAP in metastatic castration-resistant prostate cancer.
      • The 12-month radiographic progression-free survival rates did not differ (34.9% versus 33.9%).
      • No differences in the time to radiographic progression and overall survival.
      • Higher frequency of grade 3–5 and serious adverse events with the intervention.
      • Maintaining AAP added to docetaxel after progression to AAP is not an option.

      Abstract

      Background

      We aimed to compare the efficacy and safety of maintaining or withdrawing abiraterone acetate plus prednisone (AAP) in patients with metastatic castration-resistant prostate cancer who had experienced cancer progression to this treatment and were beginning a docetaxel-based therapy.

      Patients and methods

      Phase II, randomised, open-label study conducted in patients with metastatic castration-resistant prostate cancer who were asymptomatic or mildly symptomatic. After open-label treatment with AAP, patients who had experienced cancer progression to AAP were randomised to 75 mg/m2 of docetaxel plus AAP or to receive 75 mg/m2 of docetaxel plus 10 mg of prednisone orally daily. The primary outcome was the radiographic progression-free survival rate at 12 months as evaluated by the investigators in all randomised patients.

      Results

      A total of 148 patients were included in open-label treatment with AAP, and of them, 94 patients were randomised to receive either docetaxel plus AAP (intervention group; n = 47) or docetaxel plus prednisone (control group; n = 47). The 12-month radiographic progression-free survival rates did not differ between the intervention group (34.9%; 95% CI 20.7–49.2) and the control group (33.9%; 95% CI 19.5–48.3). There were no significant differences in the time to radiographic progression and the overall survival between the intervention and control groups. Grade 3–5 neutropenia with the combination of docetaxel plus prednisone and AA was more frequent than with docetaxel plus prednisone (59.6% versus 27.7%).

      Conclusion

      Our results indicate that the therapeutic strategy of maintaining AAP added to docetaxel in chemotherapy-naïve patients who have experienced cancer progression to AAP treatment should not be further evaluated and should be avoided in clinical practice.

      Clinical trials

      Keywords

      1. Introduction

      The first-line treatment of asymptomatic or mildly symptomatic patients with metastatic castration-resistant prostate cancer (mCRPC) consists of next-generation androgen receptor-signalling inhibitors, either abiraterone acetate plus prednisone (AAP) or enzalutamide [
      • Parker C.
      • Castro E.
      • Fizazi K.
      • Heidenreich A.
      • Ost P.
      • Procopio G.
      • et al.
      Prostate cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.
      ]. In patients with mCRPC who have shown cancer progression to an ARSi, a combination of docetaxel-prednisone is recommended [
      • González Del Alba A.
      • Méndez-Vidal M.J.
      • Vazquez S.
      • Castro E.
      • Climent M.A.
      • Gallardo E.
      • et al.
      SEOM clinical guidelines for the treatment of advanced prostate cancer (2020).
      ,
      • Cornford P.
      • Bellmunt J.
      • Bolla M.
      • Briers E.
      • De Santis M.
      • Gross T.
      • et al.
      EAU-ESTRO-SIOG guidelines on prostate cancer. Part II: treatment of relapsing, metastatic, and castration-resistant prostate cancer.
      ]. In the first-line treatment with AAP, a post hoc analysis of the pivotal trial evaluating AA in asymptomatic or mildly symptomatic patients with chemotherapy-naïve mCRPC (COU-AA-302) indicated that docetaxel was the most common subsequent therapy and showed meaningful antitumour activity [
      • de Bono J.S.
      • Smith M.R.
      • Saad F.
      • Rathkopf D.E.
      • Mulders P.F.A.
      • Small E.J.
      • et al.
      Subsequent chemotherapy and treatment patterns after abiraterone acetate in patients with metastatic castration-resistant prostate cancer: post hoc analysis of COU-AA-302.
      ]. In addition, some retrospective studies suggest that androgen deprivation treatment should be maintained in chemotherapy-treated patients [
      • Min K.
      • Chung J.W.
      • Ha Y.S.
      • Lee J.N.
      • Kim B.S.
      • Kim H.T.
      • et al.
      Efficacy of androgen deprivation therapy in patients with metastatic castration-resistant prostate cancer receiving docetaxel-based chemotherapy.
      ], and it has been suggested that the combination of docetaxel and AAP may have a synergistic effect [
      • Thadani-Mulero M.
      • Nanus D.M.
      • Giannakakou P.
      Androgen receptor on the move: boarding the microtubule expressway to the nucleus.
      ]. Therefore, another option after progression with AAP is continued AAP in combination with docetaxel. In a phase 1 B study, the combination of AAP plus docetaxel showed a prostate-specific antigen (PSA) decline rate and PSA response duration that compared favourably with historical controls [
      • Tagawa S.T.
      • Posadas E.M.
      • Bruce J.
      • Lim E.A.
      • Petrylak D.P.
      • Peng W.
      • et al.
      Phase 1b study of abiraterone acetate plus prednisone and docetaxel in patients with metastatic castration-resistant prostate cancer.
      ].
      The objective of this study was to compare the efficacy and safety of maintaining or withdrawing AAP in patients with mCRPC who had experienced cancer progression to this treatment and were initiating a docetaxel-based therapy.

      2. Material and methods

      The ABIDO-SOGUG trial we are presenting herein was a phase II, randomised, open-label study conducted in 16 centres in Spain that included two periods: period 1 with the open-label treatment of AAP and period 2 (randomised period), where patients who had experienced cancer progression to AAP were randomised to docetaxel plus AAP or docetaxel plus prednisone alone. The study was approved by the Ethics Committee Hospital Clínic de Barcelona (Barcelona, Spain) and was conducted following the principles contained in the Helsinki Declaration. Patients provided their written informed consent. The study was registered at ClinicalTrials.gov (NCT02036060).

      2.1 Subjects

      Eligible patients for period 1 of the study were 18 years of age or older, had a histologically or cytologically confirmed adenocarcinoma of the prostate, with radiological evidence of metastatic disease other than the liver or visceral metastasis, and had PSA progression to a previous castration treatment documented according to the Prostate Cancer Trials Working Group 2 (PCWG2) [
      • Scher H.I.
      • Halabi S.
      • Tannock I.
      • Morris M.
      • Sternberg C.N.
      • Carducci M.A.
      • et al.
      Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
      ] or radiographic progression according to modified RECIST criteria or bone scan progression. Patients had to be asymptomatic or mildly symptomatic according to the Brief Pain Inventory Short Form (i.e. a score of 0–1 or 2–3, respectively), be surgically or medically castrated with testosterone levels of <50 ng/dL, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and have a life expectancy of at least 6 months. Moreover, they had to meet prespecified criteria for laboratory parameters. Patients were excluded if they had liver, visceral, or known brain metastasis or had been treated with ketoconazole for prostate cancer for more than 7 days. To be included in period 2, patients had to show a radiological and/or clinical progression to the AAP treatment, have an ECOG PS of 0–2 and continue to meet the prespecified criteria for laboratory parameters. Patients were excluded from the randomised period if they had any contraindication to the use of prednisone, had uncontrolled hypertension or any clinically relevant cardiovascular disease, had severe hepatic impairment, or had any malignant neoplasia with a foreseen recurrence rate >30% within 24 months after inclusion.

      2.2 Design and treatment

      Patients who met the eligibility criteria for period 1 received 1000 mg/day of AA as four 250 mg tablets once daily plus 10 mg of prednisone orally daily until radiological and/or clinical progression. Patients who had shown disease progression to AAP and met the eligibility criteria for period 2 were randomised via the electronic case report form at a ratio of 1:1 to either receive 75 mg/m2 of docetaxel plus 10 mg of prednisone orally daily and 1000 mg of AA daily (intervention group) or 75 mg/m2 of docetaxel plus 10 mg of prednisone orally daily without AA (control group). In the intervention group, treatment with AAP was continued until unequivocal progression or unacceptable toxicity. Docetaxel was administered at a dose of 75 mg/m2 as a 1-h intravenous infusion on Day 1 and readministered every 21 days. Treatment was continued until reaching 10 cycles of docetaxel, unequivocal progression, or unacceptable toxicity. Treatment delays of up to two weeks and a maximum of two dose reductions of docetaxel were allowed with specified criteria for haematological and non-haematological toxicity. In the AAP group, if significant toxicity occurred, two dose reductions of AA were allowed (i.e. down to 750 mg and 500 mg once daily); if toxicity recurred despite optimal medical management and two dose level reductions, AA was discontinued.

      2.3 Follow-up and outcomes

      During period 1, ECOG, vital signs and haematological and biochemical parameters were evaluated on Day 1 of the first cycle and every two weeks during the first three cycles of AAP; the PSA and the Brief Pain Inventory Short Form were evaluated on Day 1 of every cycle. During period 2, ECOG, vital signs, haematological and biochemical tests, PSA and the Brief Pain Inventory Short Form were evaluated on the first day of every cycle; in the intervention group, ECOG, vital signs and haematological and biochemical tests were also evaluated on Day 7 during the first two cycles. In both periods, quality of life as assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P), computed tomography, magnetic resonance imaging and bone scanning were evaluated every 12 weeks. All evaluations were performed at the end of the study visit, which took place after either 15–28 days of therapy completion, evidence of disease progression, the occurrence of unacceptable toxicity, or consent withdrawal. After the end of the study visit, ECOG, PSA, computed tomography, magnetic resonance imaging and bone scanning were performed every 12 weeks.
      The primary outcome studied was the radiographic progression-free survival (rPFS) rate at 12 months as evaluated by the investigators. rPFS was defined as the time from randomisation to the occurrence of radiographic progression based on parameters suggested by the PCWG2 and modified RECIST, i.e. the occurrence of one of the following: 1. A patient was considered to have shown cancer progression by bone scan if they met the criteria of the PCWG2 [
      • Scher H.I.
      • Halabi S.
      • Tannock I.
      • Morris M.
      • Sternberg C.N.
      • Carducci M.A.
      • et al.
      Design and end points of clinical trials for patients with progressive prostate cancer and castrate levels of testosterone: recommendations of the Prostate Cancer Clinical Trials Working Group.
      ], 2. Progression of soft tissue lesions measured by CT or MRI as defined in the modified RECIST criteria and 3. Death from any cause.
      Secondary outcomes evaluated included PSA PFS defined as the time from randomisation to the occurrence of PSA progression (see below), rPFS, or death; the PSA progression rate where progression was defined as an increase of 25% or more and absolute increase of 2 ng/mL or more from the nadir was documented and confirmed by a second value (in the absence of documentation of a decrease in PSA at baseline in period 2, PSA progression was defined as an increase of 25% from the baseline together with an absolute increase of more than 2 ng/mL after 12 weeks of treatment); overall survival, defined as the time from randomisation to the date of death from any cause; PSA response rate, defined as the proportion of patients achieving a PSA decline ≥50% according to PCWG2 criteria; objective response rate in patients with measurable disease (RECIST); time to the first skeletal event; worsening of pain defined as an increased total score ≥2 points in item #3 of the BPI-SF (worst pain in the last 24 h) over the lowest score during the period; time to opiate use for cancer pain; QoL total score and each subscale score as assessed by the FACT-P.

      2.4 Statistical analysis

      The sample size was calculated using the Fleming method for phase II studies with the docetaxel plus prednisone rPFS rate at 12 months expected to be 10%. Assuming that we would accept the efficacy of the experiment if the rPFS rate at 12 months was at least 25%, with a power of 80% and a two-tailed significance level of 5%, we would require 49 patients per treatment; the sample size was increased to 54 patients to take into account a drop-out rate of 10%. Assuming a drop-out rate of 30–35% during period 1, we would require 160 patients in period 1.
      All efficacy analyses for period 2 were performed in the intent-to-treat population defined as all randomised patients regardless of whether they actually received the treatment assigned. The distributions of time-to-event variables were estimated using the Kaplan–Meier product-limit method. The median times to event with two-sided 95% confidence intervals (CIs) were estimated. rPFS and PSA progression rates at 12 months and the corresponding 95% CI were estimated from the Kaplan–Meier analysis. Response rates were calculated as the proportion of patients fulfilling the respective criteria for response and compared using the chi-square statistic or Fisher's exact test. Mean changes from the baseline in the FACT-P scores were calculated and compared using Student's t test.
      Safety analyses are summarised with absolute and relative frequencies using the safety population (i.e. all randomised patients who received at least one dose).
      All analyses were performed using the SPSS Statistics software package, version 22.0 (IBM Corp., Armonk, NY, USA).

      3. Results

      3.1 Patient disposition and characteristics

      From February 2014 to July 2016, 148 patients were included in period 1, and of them, 94 were randomised from July 2014 to February 2019 to receive either docetaxel plus AAP (intervention group; n = 47) or docetaxel plus prednisone (control group; n = 47) (Fig. S1). The baseline demographic and clinical characteristics of the patients entering in the randomised period were generally well-balanced between the two study groups (Table 1).
      Table 1Demographic and clinical characteristics.
      Docetaxel + AAP

      N = 47
      Docetaxel + Prednisone

      N = 47
      Total

      N = 94
      Age (years)
      These characteristics were those at the time of study inclusion; the remaining characteristics were at the time of randomisation.
      , median (IQR)
      70.0 (63.0–74.0)68.0 (61.0–73.0)69.5 (62.0–74.0)
      Gleason score at initial diagnosis
      Missing data: n = 2 and n = 8 for docetaxel + AAP and docetaxel + prednisone, respectively.
      , n (%)
       <819 (42.2)19 (48.7)38 (45.2)
       ≥826 (57.8)20 (51.3)46 (54.8)
      Previous local therapy
      These characteristics were those at the time of study inclusion; the remaining characteristics were at the time of randomisation.
      , n (%)
       Radical prostatectomy14 (29.8)10 (21.3)24 (25.5)
       Radical radiotherapy11 (23.4)14 (29.8)25 (26.6)
      ECOG, n (%)
       023 (48.9)16 (34)39 (41.5)
       121 (44.7)26 (55.3)47 (50.0)
       23 (6.4)5 (10.6)8 (8.5)
      Time from initial diagnosis (months)
      These characteristics were those at the time of study inclusion; the remaining characteristics were at the time of randomisation.
      , median (IQR)
      48.8 (26.4–86.6)39.6 (21.2–104.1)47.3 (23.5–91.2)
      Time from diagnosis of metastatic disease (months)
      These characteristics were those at the time of study inclusion; the remaining characteristics were at the time of randomisation.
      , median (IQR)
      11.7 (3.4–26.6)14.9 5.4–30.914.2 (4.4–27.1)
      Metastatic locations
      Missing data: n = 1 and n = 2 for docetaxel + AAP and docetaxel + prednisone, respectively.
      , n (%)
       Bone40 (87.0)40 (89.9)80 (87.9)
       Lymph nodes27 (58.7)30 (66.7)57 (62.6)
       Liver4 (8.7)4 (8.9)8 (8.8)
       Other4 (8.7)7 (15.6)11 (12.1)
      Baseline PSA (ng/ml), median (IQR)73 (32–295)34 (8–86)50 (19–218)
      AAP, abiraterone acetate plus prednisone; IQR, interquartile range.
      a These characteristics were those at the time of study inclusion; the remaining characteristics were at the time of randomisation.
      b Missing data: n = 2 and n = 8 for docetaxel + AAP and docetaxel + prednisone, respectively.
      c Missing data: n = 1 and n = 2 for docetaxel + AAP and docetaxel + prednisone, respectively.
      During period 1, among the 94 patients who were subsequently randomised, there were 2 patients who required AAP dose reductions, and the dose intensity for AA was 980.7 mg/day. The median time to progression among these patients was 12.1 months (95% CI 9.3 to 14.9) (Fig. S2).
      During the randomised period, the median number of docetaxel cycles was 8.0 in both study groups, the proportion of patients requiring at least one dose reduction was higher in the intervention group than in the control group (38.3% versus 29.8%, p = 0.384), and the proportion of patients with 1 or more infusion delays was 21.3% in the intervention group and 29.8% in the control group (p = 0.344). The median dose intensity of docetaxel was 21.8 mg/m2/week in both study groups. The median dose intensity of AA was 940 mg/day.

      3.2 Efficacy

      The median duration of the follow-up was longer in the intervention group (15.0 months) than in the control group (11.4 months). The 12-month rPFS rates did not differ between the intervention group (34.9%; 95% CI 20.7 to 49.2) and the control group (33.9%; 95% CI 19.5 to 48.3). The time to radiographic progression did not significantly differ between the two study groups (Fig. 1), with median times of 8.8 and 9.8 months for the intervention and control groups, respectively.
      Fig. 1
      Fig. 1Radiographic progression-free survival.
      There were no significant differences in the overall survival between the intervention (median 17.4 months) and the control group (median 16.9 months) (Fig. S3). With the exception of the PSA PFS, which was significantly longer among patients in the intervention group (log-rank test p = 0.038) (Fig. S4), there were no significant differences between the two study groups in any other secondary end-points, including the PSA response rate, the RECIST objective response rate, the proportion of patients with worsening pain, the time to opiate initiation (Fig. S5), the time to a skeletal event (Fig. S6) and the mean change from the baseline in the FACT-P total score (Table 2).
      Table 2Secondary end-points.
      Docetaxel + AAP

      N = 47
      Docetaxel + Prednisone

      N = 47
      p value
      PSA response rate, n (%)30 (63.8)22 (46.8)0.097
      RECIST objective response, n (%)7 (14.9)3 (6.4)0.181
      Worsening of pain according to BPI-SF, n (%)25 (53.2)26 (55.3)0.836
      Time to opiate initiation (months), medianNRNR0.994
      Time to a skeletal event (months), medianNRNR0.785
      Mean change from baseline in the FACT-P total score (SD)
      Calculated over 26 and 31 patients treated with docetaxel +AAP and docetaxel+prednisone, respectively. The baseline visit refers to the randomization visit.
      −6.6 (24.9)−1.3 (15.7)0.334
      AAP, abiraterone acetate plus prednisone; BPI-SF, Brief Pain Inventory Short Form; FACT-P, Functional Assessment of Cancer Therapy-Prostate; NR, not reached; SD, standard deviation.
      a Calculated over 26 and 31 patients treated with docetaxel +AAP and docetaxel+prednisone, respectively. The baseline visit refers to the randomization visit.

      3.3 Safety

      Information on adverse events is summarised in Table 3. Patients in the intervention group had a higher frequency of grade 3–5 adverse events and serious adverse events. Adverse events leading to death occurred in 6 patients in the intervention group (i.e. one case each of spinal cord compression, septic shock, sudden cardiovascular event, stroke, mesenteric ischaemia and acute respiratory distress) and 1 patient in the control group (i.e. a case of septic shock). Most treatment-related adverse events showed a higher frequency in the intervention group than in the control group, reaching statistical significance for neutropenia, decreased appetite, conjunctival toxicity, and pyrexia.
      Table 3Adverse events.
      Docetaxel + AAP

      N = 47
      Docetaxel + Prednisone

      N = 47
      Any adverse event, n (%)47 (100)44 (93.6)
      Grade 3-5 adverse event, n (%)39 (83.0)32 (72.7)
      Any serious adverse event, n (%)10 (21.3)7 (14.9)
      Adverse event leading to death, n (%)6 (12.8)1 (2.1)
      Most common (≥10% in either group) treatment-related adverse events, n (%)
      Docetaxel + AAP

      N = 47
      Docetaxel + Prednisone

      N = 47
      p value
      Comparison of the overall proportion of the corresponding adverse events.
      Grade

      1–2
      Grade

      3–4
      Grade

      5
      TotalGrade

      1–2
      Grade

      3–4
      Grade

      5
      Total
      Asthenia28 (59.6)5 (10.6)33 (70.2)27 (57.4)4 (8.5)31 (66.0)0.658
      Neutropenia1 (2.1)28 (59.6)29 (61.7)4 (8.5)13 (27.7)17 (36.2)0.013
      Diarrhoea18 (38.3)3 (6.4)21 (44.7)17 (36.2)4 (8.5)21 (44.7)>0.999
      Alopecia18 (38.3)1 (2.1)19 (40.4)18 (38.3)1 (2.1)19 (40.4)>0.999
      Neurological toxicity
      Neurological toxicity includes paraesthesia, polyneuropathy, peripheral neuropathy, and sensitive peripheral neuropathy.
      16 (34.0)1 (2.1)17 (36.2)17 (36.2)1 (2.1)18 (38.3)0.831
      Nail toxicity
      Nail toxicity includes nail disorder, nail toxicity, nail dystrophy, and onycholysis.
      16 (34.0)1 (2.1)17 (36.2)13 (27.7)13 (27.7)0.376
      Decreased appetite14 (29.8)14 (29.8)3 (6.4)1 (2.1)4 (8.5)0.009
      Mucosal inflammation11 (23.4)1 (2.1)12 (25.5)9 (19.1)2 (4.3)11 (23.4)0.810
      Nausea11 (23.4)1 (2.1)12 (25.5)11 (23.4)11 (23.4)0.810
      Dysgeusia8 (17.0)8 (17.0)10 (21.3)10 (21.3)0.600
      Peripheral oedema
      Peripheral oedema includes oedema, facial oedema, and peripheral oedema.
      10 (21.3)10 (21.3)5 (10.6)5 (10.6)0.159
      Constipation10 (21.3)10 (21.3)8 (17.0)8 (17.0)0.600
      Conjunctival toxicity10 (21.3)10 (21.3)3 (6.4)3 (6.4)0.036
      Anaemia7 (14.9)2 (4.3)9 (19.1)5 (10.6)5 (10.6)0.247
      Febrile neutropenia8 (17.0)8 (17.0)6 (12.8)6 (12.8)0.562
      Pyrexia6 (12.8)6 (12.8)1 (2.1)1 (2.1)0.049
      Limb pain5 (10.6)5 (10.6)1 (2.1)1 (2.1)0.091
      Musculoskeletal pain4 (8.5)4 (8.5)5 (10.6)5 (10.6)0.726
      Vomiting5 (10.6)5 (10.6)6 (12.8)6 (12.8)0.748
      AAP, abiraterone acetate plus prednisone.
      a Comparison of the overall proportion of the corresponding adverse events.
      b Neurological toxicity includes paraesthesia, polyneuropathy, peripheral neuropathy, and sensitive peripheral neuropathy.
      c Nail toxicity includes nail disorder, nail toxicity, nail dystrophy, and onycholysis.
      d Peripheral oedema includes oedema, facial oedema, and peripheral oedema.

      4. Discussion

      We found that maintaining AAP in patients with mCRPC who initiate a regimen of docetaxel after progression to AAP did not increase the 12-month rPFS rate. The results of this primary outcome were supported by all secondary outcomes, including the overall survival, the PSA response rate, the objective response rate, time to skeletal events, pain-related outcomes, and quality of life. Although phase 1 B of the docetaxel plus AAP treatment was not designed to evaluate the efficacy, the results of the pooled cohorts (n = 21) showed a PSA response rate of 85.7%, a median time to PSA progression of 22.9 months, and an objective response rate of 60%; all of these results compared favourably with the results of our cohort of patients who showed a PSA response rate of 63.8%, a median time to PSA progression of 5.4 months, and an objective response rate of 16.7% [
      • Tagawa S.T.
      • Posadas E.M.
      • Bruce J.
      • Lim E.A.
      • Petrylak D.P.
      • Peng W.
      • et al.
      Phase 1b study of abiraterone acetate plus prednisone and docetaxel in patients with metastatic castration-resistant prostate cancer.
      ]. However, this phase 1 B study was conducted in chemotherapy-naïve patients who had not received a previous treatment with AAP (first-line for CRPC), and patients in our trial were treated with docetaxel alone or in combination as a second-line treatment. More recently, Merseburger et al. have reported the results of the PRESIDE trial [
      • Merseburger A.S.
      • Attard G.
      • Boysen G.
      • Gourgioti G.
      • Martins K.
      • Chowdhury S.
      A randomized, double-blind, placebo (PBO)-controlled, phase 3b study of the efficacy and safety of continuing enzalutamide (ENZA) in chemotherapy-naïve, metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated with docetaxel (DOC) plus prednisolone (PDN) who have progressed on ENZA: PRESIDE.
      ], a randomised, double-blind, placebo-controlled phase III to evaluate the efficacy and safety of continued enzalutamide (160 mg/day) plus docetaxel (75 mg/m2) and prednisone (10 mg daily) after disease progression on enzalutamide alone in chemotherapy-naïve patients with mCRPC. Patients who continued with enzalutamide showed a statistically significant longer PFS (HR 0.72, 95% CI 0.53 to 0.96) than those randomised to placebo, and grade 3/4 treatment-emergent adverse events were reported by 84 (61.8%) patients on enzalutamide and 84 (62.2%) on placebo. In contrast to our design, the PRESIDE trial did not include patients who experienced cancer progression immediately to enzalutamide (i.e. primary resistant patients), a characteristic that could explain the differences in the results between the two trials. Interestingly, in a randomised, open-label phase 3 study using a 2 × 2 factorial design (PEACE-1 study), in patients with de novo metastatic castration-sensitive prostate cancer, the combination of ADT, docetaxel, and abiraterone was associated with an improved overall survival and rPFS without major safety concerns, except for an increased frequency of hypertension [
      • Fizazi K.
      • Foulon S.
      • Carles J.
      • Roubaud G.
      • McDermott R.
      • Fléchon A.
      • 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.
      ]. Similarly, in the ARASENS phase 3 trial, patients with metastatic hormone-sensitive prostate cancer who were randomised to the combination of darolutamide, ADT, and docetaxel showed a significant longer survival than those randomised to ADT and docetaxel alone (HR 0.68, 95%CI 0.57 to 0.80); toxicity was similar in the two groups [
      • Smith M.R.
      • Hussain M.
      • Saad F.
      • Fizazi K.
      • Sternberg C.N.
      • Crawford E.D.
      • et al.
      Darolutamide and survival in metastatic, hormone-sensitive prostate cancer.
      ]. Given the increased use of new hormonal treatments in patients with hormone-sensitive prostate cancer, maintaining them after progression and adding chemotherapy does not seem to be an effective strategy; as the PEACE-1 and ARASENS trial indicate [
      • Fizazi K.
      • Foulon S.
      • Carles J.
      • Roubaud G.
      • McDermott R.
      • Fléchon A.
      • 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.
      ,
      • Smith M.R.
      • Hussain M.
      • Saad F.
      • Fizazi K.
      • Sternberg C.N.
      • Crawford E.D.
      • et al.
      Darolutamide and survival in metastatic, hormone-sensitive prostate cancer.
      ], only the combination as initial therapy in patients with de novo tumours seems to be effective.
      Overall, the results of phase III studies of docetaxel-based combinations with antiangiogenic drugs, bone microenvironment agents, immune modulators, and other drugs in the first-line treatment of patients with mCRPC have been disappointing because they have failed to improve the overall survival compared to docetaxel alone [
      • Antonarakis E.S.
      • Eisenberger M.A.
      Phase III trials with docetaxel-based combinations for metastatic castration-resistant prostate cancer: time to learn from past experiences.
      ]. Moreover, in some cases, the results of the combination were worse [
      • Davis I.D.
      • Martin A.J.
      • Stockler M.R.
      • Begbie S.
      • Chi K.N.
      • Chowdhury S.
      • et al.
      Enzalutamide with standard first-line therapy in metastatic prostate cancer.
      ,
      • Petrylak D.P.
      • Vogelzang N.J.
      • Budnik N.
      • Wiechno P.J.
      • Sternberg C.N.
      • Doner K.
      • et al.
      Docetaxel and prednisone with or without lenalidomide in chemotherapy-naive patients with metastatic castration-resistant prostate cancer (MAINSAIL): a randomised, double-blind, placebo-controlled phase 3 trial.
      ]. The results of more recent trials were somewhat mixed. Thus, in the CHEIRON phase 2 randomised trial, among previously untreated patients with mCRPC, the combination of enzalutamide, docetaxel, and prednisone was more efficacious than docetaxel and prednisone alone in terms of investigator-assessed disease progression at month 6, with a progression rates of 12.5% and 27.8%, respectively; the combination with enzalutamide was associated with a higher frequency of grade III-IV fatigue, febrile neutropenia and neutropenia [
      • Caffo O.
      • Ortega C.
      • Nolè F.
      • Gasparro D.
      • Mucciarini C.
      • Aieta M.
      • et al.
      Docetaxel and prednisone with or without enzalutamide as first-line treatment in patients with metastatic castration-resistant prostate cancer: CHEIRON, a randomised phase II trial.
      ]; it is important to stress that, in contrast to our study, these favourable efficacy results were obtained with a first-line strategy. Other alternative combinations such as that of enzalutamide with abiraterone and prednisone in patients with chemotherapy-naïve mCRPC who had experienced cancer progression to enzalutamide treatment have not been associated with clinical benefit in terms of PFS in the PLATO study and have been associated with an increased frequency of grade 3 hypertension and increased of hepatic enzymes [
      • Attard G.
      • Borre M.
      • Gurney H.
      • Loriot Y.
      • Andresen-Daniil C.
      • Kalleda R.
      • et al.
      Abiraterone alone or in combination with enzalutamide in metastatic castration-resistant prostate cancer with rising prostate-specific antigen during enzalutamide treatment.
      ].
      Remarkably, in our study, the combination of docetaxel plus AAP was associated with relevant toxicity issues, including a higher frequency of grade 3–5 adverse events, serious adverse events, and adverse events leading to death. The frequency of grade 3–5 neutropenia in the combination of docetaxel plus AAP treatment was much higher than that observed with docetaxel plus prednisone treatment (59.6% versus 27.7%). This increased frequency is not explained by the characteristics of the patients or factors other than the combination itself; the frequency of grade 3–5 neutropenia observed in the docetaxel plus prednisone treatment was similar to that reported with 75 mg/m2 of docetaxel every 3 weeks plus prednisone in the TAX327 trial in patients with hormone-refractory prostate cancer (32%) [
      • Tannock I.F.
      • de Wit R.
      • Berry W.R.
      • Horti J.
      • Pluzanska A.
      • Chi K.N.
      • et al.
      Docetaxel plus prednisone or mitoxantrone plus prednisone for advanced prostate cancer.
      ]. In our trial, prophylactic use of the granulocyte colony-stimulating factor was highly recommended but not mandatory; the results of our study reinforce the recommendation of the prophylactic use of the granulocyte colony-stimulating whenever docetaxel is considered indicated.
      Our study has several limitations, including its open-label design and the exploratory nature of the phase II study. However, it reinforces the need reported by some authors [
      • Antonarakis E.S.
      • Eisenberger M.A.
      Phase III trials with docetaxel-based combinations for metastatic castration-resistant prostate cancer: time to learn from past experiences.
      ] to conduct phase II studies before proceeding with larger phase III studies in this clinical setting. Overall, our results indicate that the therapeutic strategy of maintaining AAP added to docetaxel in chemotherapy-naïve patients who have experienced cancer progression to AAP treatment should not be further evaluated and should be avoided in clinical practice.

      Funding

      This work was supported by Janssen-Cilag, S.A. (Madrid, Spain).

      Role of the funding source

      Janssen-Cilag, S.A. reviewed a draft of this manuscript and provided nonbinding comments to the authors.

      Data availability

      Data is available from corresponding author upon reasonable request.

      Author contribution

      Miguel A. Climent: Study conceptualisation, formal analysis, funding adquisition, investigation, methodology, project administration, resources, supervision, validation, visualisation, writing-original draft and writing - review & editing.
      Albert Font, Ignacio Durán, Javier Puente, María José Méndez-Vidal, María Isabel Sáez, Carmen Santander Lobera, José Angel ArranzArija, Aranzazu Gonzalez-del-Alba, Alfredo Sánchez-Hernandez, Emilio Esteban, Begoña Mellado Gonzalez, Pablo Maroto, Martín Lázaro-Quintela, Javier Cassinello-Espinosa, Begoña Pérez-Valderrama, Carmen Garcias and Daniel Castellano: Investigation and writing - review & editing.
      Maria Jose Juan-Fita: Study Conceptualisation, investigation and writing - review & editing.
      Teresa Alonso-Gardoa: Investigation, project administration and writing - review & editing.

      Conflict of interest statement

      The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M-AC: advisory role from BMS, MSD, Bayer, EUSA, Pfizer, Merck, Roche, Janssen, Ipsen, Astellas, Astra Zeneca; has received honoraria from Ipsen, Astella, Janssen, BMS, MSD, Pfizer, Merck, Roche, EUSA, AstraZeneca.
      AF: research grants from Astra-Zeneca, Pierre-Fabre; consulting honorarium from Astellas; advisory honorarium from Janssen, Eusa, Astellas, Sanofi, Roche, Astra-Zeneca; and travel grants from Roche, Sanofi, Astellas.
      ID: Astellas, Invited Speaker, Personal, I have participated in compensated educational activities for this company in the last two years. ASTELLAS, Advisory Board, Personal, I have participated in different compensated advisory boards over the last two years. Bristol Myers Squibb, Advisory Board, Personal, I have served as an advisor for this company in the last two years. Bristol Myers Squibb, Invited Speaker, Personal, I have participated in different compensated educational activities sponsored by this company over the last two years. EUSA PHARMA, Invited Speaker, Personal, I have participated in educational activities sponsored by this company in the last two years. Immunomedics, Inc., Advisory Board, Personal, I have collaborated as an advisor for this company over the last two years. IPSEN, Invited Speaker, Personal, I have participated in different compensated educational activities sponsored by this company over the last two years.
      Ipsen, Advisory Board, Personal, I have collaborated as an advisor in different occasions over the last two years. Jansen, Invited Speaker, Personal, I have participated in different compensated educational activities sponsored by Jansen over the last two years. Merck, Advisory Board, Personal, I have collaborated as an advisor for this company in the last two year. MSD, Advisory Board, Personal, I have served as an advisor for this company in the last two years. MSD, Invited Speaker, Personal, I have participated in educational activities sponsored by this company in the last two years. Novartis, Invited Speaker, Personal, I have participated in educational activities sponsored by Novartis in the last 2 years. PFIZER, Invited Speaker, Personal, I have participated in different compensated educational activities sponsored by Pfizer over the last two years.
      Roche Genentech, Advisory Board, Personal, I have served as an advisor for this company in the last two years. Astra Zeneca, Research Grant, Personal and Institutional, Financial interest, AZ has funded research conducted in my institution related to a project where I am the PI.
      Immunomedics, Inc., Steering Committee Member, Personal, Financial interest, I serve as a member of a SC for a trial sponsored by this company. ROCHE GENENTECH, Research Grant, Personal and Institutional, Financial interest, Roche has funded research in my institution to projects under my coordination. Non-Financial Interests ASEICA, Member of Board of Directors, I belong as a external advisor to the board of directors of the Spanish Association of cancer research since 2021. GO NORTE, Leadership Role, I am the president of an independent cooperative group of GU Oncologist from the north of Spain.
      JP: Honoraria for speaker engagements, advisory roles or continuous medical education: Astellas, Astra Zeneca, Janssen, MSD, Bayer, Pfizer, Eisai, Ipsen, Sanofi, Roche, BMS, Pierre Fabre, Merck; Research Funding: Astellas, Pfizer; Consultant: Astellas, Roche.
      MJM-V: Invited speaker from Janssen-Cilag, Bayer healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, Novartis, Pfizer, MSD; Advisory role from Janssen-Cilag, Bayer healthcare, Sanofi Aventis, Astellas Medivation, Roche, Ipsen, EISAI, Novartis, Pfizer, MSD; Travel support from Roche, Ipsen.
      JAAA: Advisory board: Janssen, Merck, MSD, BMS, Pfizer, Astellas; Speaker Honoraria: Merck, Pfizer, BMS; Travel accommodation: Merck, MSD, Janssen, Astellas.
      AG-D-A: has received research funding from Astellas, travel grants from Astellas, Jansen, Sanofi, BMS, Roche, Pfizer and Ipsen and honoraria for speaker engagements, advisory boards and continuous medical education from Janssen, Astellas, Sanofi, Bayer, Roche, Ipsen, BMS, MSD, Pfizer, Eusa Pharma, Eisai and Astra Zeneca.
      AS-H: Honoraria from BMS, MSD, AstraZeneca, Roche, Janssen, Sanofi, Pfizer, Lilly and Novartis; Consulting or advisory accommodations and expenses from BMS, MSD, AstraZeneca, Roche, Janssen, Sanofi, Pfizer, Lilly and Novartis; Speakers’ bureau from BMS, MSD, AstraZeneca, Roche, Janssen, Sanofi, Pfizer, Lilly and Novartis.
      MJJF: Advisory member from Janssen, BMS; Speaker honorarium from Janssen, Sanofi, BMS, GPPharm, Pierre-Fabre; Advisory honorarium from Novartis, Janssen, BMS.
      TA-G: Scientific Consultancy Role (speaker and advisory role) and travel grant: IPSEN, Pfizer, Roche, Bayer, Sanofi, Janssen, Astellas, Eisai, Adacap, Lilly, Novartis, BMS; Research grants: Roche, Pfizer, IPSEN.
      BMG: Speakers’ Bureau: Roche, Sanofi, Janssen, Astellas, Pfizer, Novartis, Bristol-Myers Squibb and Ipsen; Research Funding: Roche, Bayer and Janssen.
      PM: Research grant from Roche, Bayer; Speaker honorarium from Janssen; Advisory honorarium from Janssen, Bayer, Astellas, Pfizer, BMS.
      ML-Q: Consultant or Advisory Role: BMS, MSD, Takeda, Roche, Pfizer, Roche, Ipsen, Astra-Zéneca, Boehringer, Pierre-Fabré, Bayer; Speaking: Roche, Ipsen, Lilly, Astellas, Janssen, Novartis, Boehringer, BMS; Grant or travel support: MSD, Ipsen, Roche, Janssen, Pfizer, Astellas, Pierre-Fabré; Participation in clinical trials: Merck, Astellas, Pfizer, Ipsen, Roche, Mirati.
      JC-E: Advisory board member for ASTELLAS, JANSSEN, ASTRAZÉNECA, BRISTOL-MYERS, MSD; Speaker honorarium from ASTELLAS, JANSSEN, ASTRAZÉNECA, BRISTOL-MYERS, MSD IPSEN, PFIZER.
      BP-V: Consultancy from Astellas Parma; honoraria from Pierre Fabre; travel/accommodations expenses covered or reimbursed from Janssen-Cilag and Pfizer.
      CG: Speaker honorarium from Janssen, Pfizer, BMS, Astellas, Bayer; Consulting honorarium from Janssen, Pfizer, BMS, Astellas, Bayer; Advisory honorarium from Janssen, Astellas, Bayer, Sanofi, Roche; Travel grants from Pfizer, Roche.
      DC: ASTELLAS, Advisory Board, Personal; ASTRA ZENECA, Advisory Board, Personal; BMS, Advisory Board, Personal; GSK, Advisory Board, Personal; IPSEN, Advisory Board, Personal; JANSSEN, Advisory Board, Personal; MSD, Advisory Board, Personal; NOVARTIS, Advisory Board, Personal; Pfizer, Advisory Board, Personal; ROCHE, Advisory Board, Personal.
      ASTELLAS, Local PI, Institutional, No financial interest; ASTRA ZENECA, Local PI, institutional, No financial interest; BAYER, Local PI, Institutional, No financial interest; BMS, Local PI, Institutional, No financial interest; CLOVIS, Local PI, Institutional, No financial interest; EISAI, Local PI, Institutional, No financial interest; EXELISIS, Local PI, Institutional, No financial interest; GSK, Local PI, Institutional, No financial interest; IPSEN, Local PI, Institutional, No financial interest; JANSSEN, Local PI, Institutional, No financial interest.
      LILLY, Local PI, Institutional, No financial interest; MSD, Local PI, Institutional, No financial interest; PFIZER, Local PI, Institutional, No financial interest; QED Therapeutics, Local PI, Institutional, No financial interest; ROCHE, Local PI, Institutional, No financial interest.
      MIS, CSL and EE report no conflict of interest.

      Acknowledgements

      This study was sponsored by the Spanish Oncology Genitourinary Group (SOGUG). The authors also thank Juan Luis Sanz and Susana Vara (APICES, Madrid; Spain) for their support with the study design, setup, coordination and project management, monitoring, and statistical analysis and Fernando Rico-Villademoros (APICES, Madrid, Spain) for writing a draft of this manuscript.

      Appendix A. Supplementary data

      The following is the Supplementary data to this article:

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