Triplet Therapy in Metastatic Castrate Sensitive Prostate Cancer (mCSPC)—A Potential New Standard of Care

Round 1

Reviewer 1 Report

Dear Authors, I read with interest your paper. The article is well written and clear, giving a general overview on the topic.

In this field, research is focusing on new treatment strategies based on a proper selection of patients suffering from metastatic castrate resistant PCa. However, a strong bias relies on the classification of metastatic disease burden and risk, which is based on conventional imaging (CT and bone scan). Since PSMA-PET has dramatically changed the detection rate of new metastasis, should we still select the metastatic patient in the same way? I think this point should be better discussed in your paper.

Author Response

Reviewer 1

Dear Authors, I read with interest your paper. The article is well written and clear, giving a general overview on the topic.

In this field, research is focusing on new treatment strategies based on a proper selection of patients suffering from metastatic castrate resistant PCa. However, a strong bias relies on the classification of metastatic disease burden and risk, which is based on conventional imaging (CT and bone scan). Since PSMA-PET has dramatically changed the detection rate of new metastasis, should we still select the metastatic patient in the same way? I think this point should be better discussed in your paper.

Author Reply:

Thank you for the thoughtful review of the manuscript and overall positive comments.

We appreciate the reviewer for raising the important question regarding the use of PSMA PET imaging to help with treatment selection. This is not routinely recommended in the guidelines due to lack of data. However more studies are underway to help address this question.

We have included a discussion of this point at the end of section 5. Clinical Practice Points (page 8, lines 483-492):

“Currently the presence of metastases and definitions of disease volume for treatment intensification for mCSPC are based on conventional imaging (CT and bone scan). PSMA PET imaging is not approved in this setting as none of the landmark trials included this in their protocols. PSMA PET imaging is anticipated to detect more metastases than conventional imaging (42,43), however there is no data to suggest their use for staging mCSPC can improve outcomes. There is also potential risk for classifying low volume to high volume disease which can lead to both over-treatment (adding docetaxel) and under-treatment (omit prostate primary radiation which is associated with overall survival benefit). Therefore, this approach cannot be recommended at this time, without further supporting prospective data.”

We also highlighted upcoming trials incorporating the use of PSMA PET in Section 6 Future Directions (page 9-10, lines 542-546)

“Trials incorporating PSMA-PET imaging to detect lesions occult on conventional imaging and to intensify treatment in the castrate sensitive setting are also ongoing (57,58).”

Reviewer 2 Report

First of all congratulations to the authors because the manuscript is written in an orderly and complete way, and deserves to be published. I would like to point out only this: along the manuscript there are many errors in the spacing of the words, so I recommend a re-reading of the text to make the appropriate changes. After which the manuscript can be published 

Author Response

Reviewer 2:

First of all congratulations to the authors because the manuscript is written in an orderly and complete way, and deserves to be published. I would like to point out only this: along the manuscript there are many errors in the spacing of the words, so I recommend a re-reading of the text to make the appropriate changes. After which the manuscript can be published 

Author reply:

Thank you for the comment. We have proof-read the manuscript and edited it

Reviewer 3 Report

This review article summarized the first-line treatments for mCSPC.

Clinical trials and real-world data on triplet therapy for CSPC are still insufficient. As authors mentioned in conclusion, many unanswered questions remain about upfront triplet therapy. Under these circumstances, it may be too early to mention that triplet therapy is “ A New Standard of Care” in the title.

Fig1

For high-volume cancer either synchronous or metachronous, not only ADT+ARPI, but ADT+docetaxel should be an option.  

Table 1  “OS:0.65” mat be “OS:HR 0.65 (TAITAN primary end point)

         “OS:0.68” mat be “OS:HR 0.68 (ARCHES  High-risk/…)

         “OS:0.66” mat be “OS:HR 0.66 (ARCHES  Low-risk/…)

Author Response

Comment 1

This review article summarized the first-line treatments for mCSPC. 

Clinical trials and real-world data on triplet therapy for CSPC are still insufficient. As authors mentioned in conclusion, many unanswered questions remain about upfront triplet therapy. Under these circumstances, it may be too early to mention that triplet therapy is “ A New Standard of Care” in the title. 

Author reply:

We thank the reviewer for highlighting the uncertainties regarding the use of triplet therapy. We believe given the existing data, there are multiple standard of care therapies which can be considered for patients with mCSPC, which are ADT + ARPI, and triplet therapy. We have revised the title to better reflect this.

“Triplet Therapy in Metastatic Castrate Sensitive Prostate Cancer (mCSPC) – A Potential New Standard of Care”

Comment 2:

For high-volume cancer either synchronous or metachronous, not only ADT+ARPI, but ADT+docetaxel should be an option.  

Author reply:

Thank you for the opportunity to clarify this point regarding the use of ADT + docetaxel. We believe for patients who are planned to receive docetaxel, there is now level I evidence for adding an ARPI (Peace 1, Arasens, and Enzamet) given improvement in OS compared to ADT + docetaxel. As such ADT + docetaxel should no longer be recommended.

We added the following in Section 5 Clinical Practice Points (page 7, lines 452-456)

“For patients who are planned for docetaxel, triplet therapy with the addition of either AAP or darolutamide should be used given improved overall survival, and ADT + docetaxel can no longer be considered a standard of care.”

Comment 3:

Table 1  “OS:0.65” mat be “OS:HR 0.65 (TAITAN primary end point)

         “OS:0.68” mat be “OS:HR 0.68 (ARCHES  High-risk/…)

         “OS:0.66” mat be “OS:HR 0.66 (ARCHES  Low-risk/…)

Author reply:

Thank you. We have made these suggested changes in Table 1.

We have also added a few new references which have now been published, and made a few other minor changes in the manuscript for the reviewer’s approval.

Round 2

Reviewer 1 Report

Dear Authors, thank you for have considered my suggestion.