Synthetic Lethality by Co-Inhibition of Androgen Receptor and Polyadenosine Diphosphate-Ribose in Metastatic Prostate Cancer

Round 1

Reviewer 1 Report

Authors in the review entitled “Synthetic Lethality By Co-Inhibition Of Androgen Receptor And PARP in Metastatic Prostate Cancer” documented one the very interesting class of drugs in PARPi as chemotherapeutic agent in prostate cancers. Authors detailed mechanisms of action, PARPi to analyze the biological mechanisms behind the interplay between the androgen receptor and PARPi system. Furthermore, authors summarize the preliminary results of the ongoing studies on ARPI + PARPi combinations and discuss its clinical implications. Overall, review is well written and authors efforts are commendable to address one of the pressing questions in prostate cancer biology. The review might contribute to improving better understanding of treatment outcomes in prostate cancer for better survival of cancer patients.

 However, there are few major comments as following:

1. Castration resistant prostate cancer (CRPCs) are often resistant to enzalutamide as well as arbitone. Authors need to discuss the role/limitation of ARPI + PARPi combination therapy in such cases.

2. Mot all prostate cancers are AR dependent. In fact, most aggressive PCas (including CRPCs) are AR independent. Authors need to discuss the such scenarios in context of ARPI + PARPi combination therapy.

3. PARPi works by enhancing the general toxicity inside the cell. Authors need to incorporate discussion where they need to detail effects of PARPi on immune cells. I believe this is an important aspect which authors are missing in current review. Also, can PARPi can be conjugated to other cancer cell specific chemotherapeutic agents to provide better overall survival?

minor comments:

4. Please provide detailed legends for all figures.

5. Please provide tables in better resolution. Currently they are bit pixilated.

Author Response

Orbassano, December 17th 2023

Title: Synthetic Lethality by Co-Inhibition of Androgen Receptor and PARP in Metastatic Prostate Cancer

Manuscript ID: ijms-2697735

To

Reviewer #1

International Journal of Molecular Sciences

Dear Reviewer,

Thank you for your precious comments to our manuscript entitled “Synthetic Lethality by Co-Inhibition of Androgen Receptor and PARP in Metastatic Prostate Cancer” on International Journal of Molecular Sciences. Your suggestions allowed us to improve the quality of our manuscript. As requested, we addressed your comments in the manuscript, and you can find the changes detailed on a point-by-point basis.

1. Castration resistant prostate cancer (CRPCs) are often resistant to enzalutamide as well as abiraterone. Authors need to discuss the role/limitation of ARPI + PARPi combination therapy in such cases.

We really appreciated this comment. It is well known that a percentage of PC shows an early resistance to ARPI. In these cases the combination with PARPi could increase the sensitivity to AR inhibition. In paragraph 5 we discuss in detail the biological rationale for the combination of ARPI and PARP inhibitors. As suggested, we added a comment in the discussion section (lines 496-500) to highlight the role of ARPI + PARPi in patients resistant to ARPI.

2. Not all prostate cancers are AR dependent. In fact, most aggressive PCs (including CRPCs) are AR independent. Authors need to discuss such scenarios in context of ARPI + PARPi combination therapy.

AR is one of the most studied target in PC, although in a minority of cases tumor growth is not driven by AR. This concept is closely related to the previous one discussed, as in such cases PC is usually resistant to ARPIs. In this context targeting an additional pathway other than AR such as PARP could be a winning strategy. We thank you for highlighting these two notions that we tried to cover altogether in the discussion section (lines  482-486 and 496-500).

3. PARPi works by enhancing the general toxicity inside the cell. Authors need to incorporate discussion where they need to detail effects of PARPi on immune cells. I believe this is an important aspect which authors are missing in current review. Also, can PARPi can be conjugated to other cancer cell specific chemotherapeutic agents to provide better overall survival?

Thank you for this useful comment. Ongoing trials are also examining the potential synergistic lethality that could arise from combining PARPi with other agents, for example  immunotherapy. There is strong biological evidence about co-inhibition of PARP and immunocheckpoint. We added a comment about this topic in the future perspective section (lines 464-478).

Further minor comments:

4. Please provide detailed legends for all figures.

According to this suggestion, we added detailed captions for the figures.

5. Please provide tables in better resolution. Currently they are bit pixilated.

As suggested, we increased the resolution of the tables.

We thank you once again for your suggestions.

In addition to the changes suggested by reviewers we also made minor adjustments that you will find highlighted in the final version of the manuscript. We added some new references so you will find the updated bibliography.

We hope that the revised manuscript will be suitable for publication on International Journal of Molecular Sciences.

With best regard,

Consuelo Buttigliero on behalf of all authors

Reviewer 2 Report

This manuscript presents a comprehensive review of the synergistic effects of co-inhibiting the AR and PARPi in the treatment of metastatic PC. The paper is well-structured, providing a clear overview of the current state of research, along with insightful discussions on the potential clinical implications of these findings. 

Specific Comments:

• Introduction Section: The paper would benefit from a brief introduction of the concept of Synthetic Lethality to provide a better context for readers who may not be familiar with this term. 
• Line 67-68:Reference/s is/are missing.
• Tables 1 and 2: Including Clinical Trial IDs in Tables 1 and 2 would be highly beneficial for readers interested in further exploring the discussed trials. 

Overall, this manuscript is a valuable contribution to the field of prostate cancer research.

Author Response

Orbassano, December 17th 2023

Title: Synthetic Lethality by Co-Inhibition of Androgen Receptor and PARP in Metastatic Prostate Cancer

Manuscript ID: ijms-2697735

To

Reviewer #2

International Journal of Molecular Sciences

Dear Reviewer,

Thank you for your precious comments to our manuscript entitled “Synthetic Lethality by Co-Inhibition of Androgen Receptor and PARP in Metastatic Prostate Cancer” on International Journal of Molecular Sciences. Your suggestions allowed us to improve the quality of our manuscript. As requested, we addressed your comments in the manuscript, and you can find the changes detailed on a point-by-point basis.

1. Introduction Section: the paper would benefit from a brief introduction of the concept of Synthetic Lethality to provide a better context for readers who may not be familiar with this term.

Although we explained the concept of synthetic lethality in paragraph 4, we agree that it would be useful to give a hint of its meaning in the introduction section. Therefore we added a brief definition of synthetic lethality also in the introduction when talking about PARP inhibitors mechanism of action (lines 67-70).

2. Line 67-68: Reference/s is/are missing.

We added some references as suggested (please note that after the previous correction the lines we are referring to are now 70-71).

3. Tables 1 and 2: Including Clinical Trial IDs in Tables 1 and 2 would be highly beneficial for readers interested in further exploring the discussed trials.

We thank you for the suggestion. We added Clinical Trial IDs in all tables.

We thank you once again for your suggestions.

In addition to the changes suggested by reviewers we also made minor adjustments that you will find highlighted in the final version of the manuscript. We added some new references so you will find the updated bibliography.

We hope that the revised manuscript will be suitable for publication on International Journal of Molecular Sciences.

With best regard,

Consuelo Buttigliero on behalf of all authors

Reviewer 3 Report

Calabrese et al. present an elaborate overview, discussing the mechanistic basis as well as past/ ongoing clinical trials exploring co-perturbation of the Androgen receptor pathway with PARP as a promising therapy for metastatic prostate cancer. The review appropriately covers outcomes of both mono- and combined therapies in PrCa. However, this topic has already been extensively covered by others and published elsewhere, in fact till very recently (Taylor et al. Frontiers in oncology 2023; Giorgi et al, Annals of oncology, 2023; Messina et al. Eur Urol Oncol., 2023, as examples). It therefore becomes a little redundant to keep the same discussion in the form of another review. A review must ideally be a significantly extended coverage of this topic beyond what is already known.

Author Response

Orbassano, December 17th 2023

Title: Synthetic Lethality by Co-Inhibition of Androgen Receptor and PARP in Metastatic Prostate Cancer

Manuscript ID: ijms-2697735

To

Reviewer #3

International Journal of Molecular Sciences

Dear Reviewer,

Thank you for your precious comment to our manuscript entitled “Synthetic Lethality by Co-Inhibition of Androgen Receptor and PARP in Metastatic Prostate Cancer” on International Journal of Molecular Sciences, which we really appreciated and tried to address as follows:

“This topic has already been extensively covered by others and published elsewhere, in fact till very recently (Taylor et al. Frontiers in oncology 2023; Giorgi et al, Annals of oncology, 2023; Messina et al. Eur Urol Oncol., 2023, as examples). It therefore becomes a little redundant to keep the same discussion in the form of another review. A review must ideally be a significantly extended coverage of this topic beyond what is already known.”

We agree that ARPI-PARPi combination is currently a well-discussed and covered topic. In our review, we began by analyzing the biological rationale behind the use of the combination ARPI + PARPi, then we explored current studies using the combination and finally we tried to identify the subset of patients in whom there may be most benefit.

We believe our review sets itself apart from the cited articles. Messina et al. conducted a meta-analysis of randomized combination studies, systematically screening literature across various databases, and analyzing the meta-analysis data. De Giorgi et al. wrote an editorial aiming to provide an overview of studies without analyzing the biological mechanisms of the combination.

Lastly, Taylor et al.'s review described PARPi as an emerging therapeutic option for the treatment of prostate cancer; however its primary focus was to identify other agents that induce synergistic lethality with PARPi (including ARPI, as well as immunotherapy, chemotherapy, and radiotherapy). As a result, it did not discuss extensively the biological evidence of combining ARPI and PARPi, focusing on different responses based on HRR mutations and mechanisms of resistance to PARPi.

Our review instead aims to transversally explore the theme of ARPI-PARPi combination, starting from the biological rational, passing through the scientific evidence of the available clinical trials and finally discussing its application in clinical practice.

We thank you once again for your comment.

In addition to the changes suggested by reviewers we also made minor adjustments that you will find highlighted in the final version of the manuscript. We added some new references so you will find the updated bibliography.

We hope that the revised manuscript will be suitable for publication on International Journal of Molecular Sciences.

With best regard,

Consuelo Buttigliero on behalf of all authors