Addition of New Androgen Receptor Pathway Inhibitors to Docetaxel and Androgen Deprivation Therapy in Metastatic Hormone-Sensitive Prostate Cancer: A Systematic Review and Metanalysis

Round 1

Reviewer 1 Report

The meta analysis of the outcomes of mHSPC patients from combination of therapeutic agents is well written and has enough scientific weight and novelty to be accepted for publishing. My only minor concern is that all the figures in the manuscript are not sharp enough and are hard to read in a current way.

Author Response

The meta analysis of the outcomes of mHSPC patients from combination of therapeutic agents is well written and has enough scientific weight and novelty to be accepted for publishing. The study is well written and balance, so far it should be published after minor revisions: 

• We thank the reviewer for the comment.

My only minor concern is that all the figures in the manuscript are not sharp enough and are hard to read in a current way.

We thank the reviewer for the suggestion. We improved the figures quality.

Reviewer 2 Report

In the manuscript entitled with “Addition of new androgen receptor pathway inhibitors to docetaxel and androgen deprivation therapy combination in metastatic hormone-sensitive prostate cancer: a systematic review and a meta-analysis  ”, the authors give an attempt to evaluate the activity of the triplet therapy(ARPI+ADT+chemotherapy) in mHSPC by applying meta-analysis with data from multiple clinical trials, which may benefit the treatment of the prostate cancer. The manuscript is well written, and the drawbacks of this study is well discussed in the discussion part of the manuscript.

I have the comments as following:

1.     In the introduction part, the sentence located between line 45 and line 47 is confusing, not sure what the authors want to explain.

2.     In the introduction part, line 69 to line 71, the authors mentioned that adding abirartorone improves OS by 16.8-33.6 months, but for enzalutamide, no statistic is presented for the increased OS.

3.     For the result part, line 164-165, “The mean patient age was xx years and ranged from x to xx years. 164 The performance status defined with the ECOG scale went from xx to xx.”, it is confusing what those xx means.

4.     The quality of the chart in the figures needs to be improved.

5.     Line 197, “the other two a no statistically significant benefit…. ”, it is hard to read.

Author Response

In the manuscript entitled with “Addition of new androgen receptor pathway inhibitors to docetaxel and androgen deprivation therapy combination in metastatic hormone-sensitive prostate cancer: a systematic review and a meta-analysis  ”, the authors give an attempt to evaluate the activity of the triplet therapy(ARPI+ADT+chemotherapy) in mHSPC by applying meta-analysis with data from multiple clinical trials, which may benefit the treatment of the prostate cancer. The manuscript is well written, and the drawbacks of this study is well discussed in the discussion part of the manuscript.

 

• We thank the reviewer for the comment and for the suggestions.

 

In the introduction part, the sentence located between line 45 and line 47 is confusing, not sure what the authors want to explain.

 

• We modified the text according with the reviewer suggestion: Despite the high probability of initial response, after a median time of about 20 months, the disease becomes resistant to ADT, with progression to the castration resistant prostate cancer (CRPC) [4].

 

 

In the introduction part, line 69 to line 71, the authors mentioned that adding abiraterone improves OS by 16.8-33.6 months, but for enzalutamide, no statistic is presented for the increased OS.

 

• We modified the text according to the reviewer suggestion: Initial findings showed that in de novo mHSPC patients, the addition of docetaxel to ADT significantly improved OS compared to ADT alone [16]-[18], especially in high-volume diseases (according to the CHAARTED criteria). More recently, also the addition of ARPI to ADT increased OS. Firstly, two large trials [19] [20] demonstrated that adding abiraterone to ADT significantly improved OS. Subsequently, the addition of enzalutamide or apalutamide demonstrated to increase the OS compared to ADT alone [21]-[23].

 

 

For the result part, line 164-165, “The mean patient age was xx years and ranged from x to xx years. 164 The performance status defined with the ECOG scale went from xx to xx.”, it is confusing what those xx means.

 

• The mean patient age was 68.2 years, ranging from 66 to 70. According to the ECOG scale, the performance status defined as “0” went from 64.3 to 77.5%.

 

The quality of the chart in the figures needs to be improved.

 

• As suggested by the reviewer, we improved the figures quality.

Line 197, “the other two a no statistically significant benefit…. ”, it is hard to read.

• We thanks reviewer for the suggestion. The sentence was modified: The treatment effect on OS favoured the triplet therapy in all but one RCTs [23]; a statistically significant difference was observed in only 2 RCTs [21] [22].

Reviewer 3 Report

1.      Figure 1a , the text is invisible. Improve the quality.

2.      Figure 2a, text is invisible.

3.      All the figures quality is very bad and can’t be read.

4.      Future direction need to be added.

5.      Rationale and importance of this must be highlighted in the last paragraph of introduction section.

Author Response

Figure 1a , the text is invisible. Improve the quality.

• We thank the reviewer for the suggestion. We improved the quality of the figures.

  Figure 2a, text is invisible

• We thank the reviewer for the suggestion. We improved the quality of the figures.

 All the figures quality is very bad and can’t be read.

• As suggested by the reviewer, we improved the figures quality.

      Future direction need to be added. Rationale and importance of this must be highlighted in the last paragraph of introduction section.

• We thank the reviewer for the suggestion. We added future direction, rationale and importance in conclusions paragraph:

Castration resistance is brought on by ADT's induction of adaptive alterations in PC cells and the selection of resistant clones. Minimizing this mechanism and delaying the onset of resistance is the clinical key to improving survival in mHSPC. All these novel synergic approaches show significant improvement in outcomes and can be used in clinical practice. Further clinical trials must be developed to increase these results combining local treatment as radiotherapy and therapeutic agents acting on androgen receptor dependent and independent mechanisms of neoplastic progression.    . 

Reviewer 4 Report

Dear editor,

 

Thank you for having me review this manuscript. In my opinion, meta-analysis for this topic seems to be too early to be written, and this can also be reflected in the Line “no head-to-head trials compare ARPI and chemotherapy in mHSPC” by authors themselves. The details of my comments are listed below:

 

Introduction

1.        Line “While localised prostate cancer is generally associated with more favourable outcomes, metastatic prostate cancer is currently considered incurable. The 5-year relative survival rate is nearly 100% in patients with localised PC” should be more specific. Localized prostate cancer (PCa), according to NCCN guideline, could be categorized into six risk groups, and not all of them can be monitored only or performed with radical prostatectomy. I suggested the author modify this description according to the risk groups of localized PCa.

Method:

1.        Providing PRISMA flowchart for literature selection process

2.        The databases used for literature retrieval are so few.

Results

1.        The figures are so vague. Must be improved

2.        Providing the way that the authors used to judge the selection bias.

3.        Like what I said, this topic is too soon to be analyzed with meta-analysis. The data of progression-free survival used in analysis are not distributed equally in each included literature, and similar problems are observed in every included parameter. The results of all parameters are basically in line with the most weighted literature. So, what is the point doing such a meta-analysis? Our readers can just simply refer to each RCT for their answers of each parameter. The main purpose of doing meta-analysis is to make a conclusion for a topic with heterogeneous results in literature. As we can see, this topic is not such one.      

Conclusion

1.        I would like to review this part when the authors resolve the above-mentioned problems.

Besides, the citation numbers in text can be re-arranged more concisely. For example, changing [16] [17] [18] [19] [20] [21] [22] [23] into [16-23]. Also, the length of the text and the citation are obviously few for an article of meta-analysis.

Author Response

In my opinion, meta-analysis for this topic seems to be too early to be written, and this can also be reflected in the Line “no head-to-head trials compare ARPI and chemotherapy in mHSPC” by authors themselves.

 

We thank the reviewer for the comment. There are no head-to-head trials comparing ARPI and CT. However, the triplet therapy is a new challenge for oncologist. We performed this meta-analysis in order to evaluate the best patient for this therapeutic option. We have demonstrated a significant impact on PFS and OS with the concomitant administration of docetaxel, ARPI and ADT in mHSPC patients, in particular in de-novo and high-volume metastatic disease patients.

 

 

Line “While localised prostate cancer is generally associated with more favourable outcomes, metastatic prostate cancer is currently considered incurable. The 5-year relative survival rate is nearly 100% in patients with localised PC” should be more specific. Localized prostate cancer (PCa), according to NCCN guideline, could be categorized into six risk groups, and not all of them can be monitored only or performed with radical prostatectomy. I suggested the author modify this description according to the risk groups of localized PCa.

 

 

• We thank the reviewer for the suggestion. We modified the sentence:

 

While, in localized prostate cancer, a personalized treatment approach according to the patient’s class of risk can allow a cure (active surveillance, prostatectomy, radiotherapy +/- ADT), a patient with metastatic prostate cancer is often considered incurable [2].

 

 Providing PRISMA flowchart for literature selection process

 

• We thank the reviewer for the suggestion. The flowchart was added as figure 1.

 

Providing the way that the authors used to judge the selection bias.

 

• We thank the reviewer for the suggestion; in the statistical method, we have added the following sentence:   Begg's funnel plots were generated, and Egger's regression asymmetry test was used to examine potential publication bias related to PFS and OS.

 

Furthermore, we added the chapter 4 publication bias and the figure 6.

 

 

Like what I said, this topic is too soon to be analyzed with meta-analysis.

 

• We agree with the reviewer comment; however the topic of our work is an urgent actual unmet need.

 

The data of progression-free survival used in analysis are not distributed equally in each included literature, and similar problems are observed in every included parameter. The results of all parameters are basically in line with the most weighted literature.

 

• We thank the reviewer for the comment. The data of PFS and OS are shown for all RCT. The effect of triplet therapy on PFS favoured the combination in all RCTs reaching statistically significant differences in 3 studies. The meta-analysis reinforces the estimated effect and reduces the interval confidence of each study. Triplet therapy favoured an OS improvement also in all but one RCT reaching statistically significant differences in only 2 RCTs. Also, here the pooling produces a reduced CI. The data of OS for subgroup analysis reinforces the evidence of benefit in high volume and de novo metastatic patients. We believe these results can be a backbone for further investigations.  

So, what is the point doing such a meta-analysis? Our readers can just simply refer to each RCT for their answers of each parameter. The main purpose of doing meta-analysis is to make a conclusion for a topic with heterogeneous results in literature. As we can see, this topic is not such one.  

 

• We thank the reviewer for the comment. There is no quantitative heterogeneity (I2= 16% in PFS and 0% in OS), so we could not explore and analyse it. However, we believe this meta-analysis is helpful because it improves and reinforces the estimation of the impact of triplet therapy in mHSPC and reduces the confidence interval in OS analysis and PFS.