Xiaolei Shi: Okay, great. Thank you so much for having me here, and thank you so much, Dr. Jia, for the introduction. Yeah, I would like to... It's my pleasure to share my study about the six androgen production uptake in conversion genes. We call that APUC-6 in the CHAARTED trial.
So as we know, prostate cancer is fundamentally driven by androgens. So androgen production uptake in conversion can play an important role in prostate cancer pathogenesis. And there are about greater than 20 genes that govern this complicated process. We call them APUC or APUC genes.
So clinically, we target this pathway at multiple steps. For example, abiraterone, it inhibits CYP17A1, it's right here. So preventing the testosterone and DHT synthesis. And it is currently the standard of care in both localized disease and advanced disease. And more recently, the novel agents like ODM-208, it is a selective inhibitor of CYP11A1, which is the very first rate-limiting enzyme in this whole process, are currently showing promise in MCRPC by blocking the first step. So, it is even in resistant AR mutant settings. And they're currently under investigation in phase 3 trials, OMAHA-003 and OMAHA-004 trials in those MCRPC patients. And another one is the inhibitor right here to block the 3β-hydroxysteroid dehydrogenase, is also currently under investigation. So given the importance of these genes in prostate cancer development and progression, the investigation of APUC genes may lead to new therapeutic targets and inform future clinical design.
So, our collaborator from University of Minnesota, Dr. Wang and Dr. Ryan's group, they identified a subset of six key genes as listed here. And they named the gene APUC-6. As so you can see here they exhibited concordant behavior on this heat map. And also, I didn't show there, but interestingly, they also found that in APUC-6 is high, the AR expression tends to be low and vice versa. So because of these findings, they stratified the patients from CARIS cohort and HSPC cohort into four subgroups, based on their APUC-6 and AR expression. And they found that APUC-6 high or low patients actually had better overall survival, compared to the APUC-6 low and AR high tumors in those mHSPC patients. So these findings suggest that APUC-6 and AR signature may define distinct subsets of prostate cancer patients with differential clinical outcomes. Therefore, we're trying to have a better understanding of the APUC-6 genes expression on prostate cancer trajectory, because we think it's of significant clinical interest.
So there are a couple questions remaining or we're interested in, for example, whether APUC-6/AR has any prognostic value, whether it can predict the response to the treatment, and how this signature is associated with a high-risk markers. Or can we use this as a biomarker to get prostate cancer treatment.
So for this purpose, we have purposes that APUC-6/AR expression may refine clinical outcomes in mHSPC and predict treatment response. So we use the CHAARTED trial, which is a randomized phase 3 trial in mHSPC patients. They have two treatment arms, ADT plus docetaxel, and the other one is ADT alone. So we analyzed a whole transcriptomic data from a total 160 patients. In the majority of the cases, about 70% they're synchronized high volume disease similar.
Similarly to Dr. Wang's paper, these patients were stratified into four subgroups based on their APUC-6 and a AR expression. And the high expression was defined as APUC-6 or AR expression in the top 25%, while the remaining 75% were classified as a low expression level.
So, our first question is whether this APUC-6/AR signature has differential clinical outcomes. As you can see here, there's a significant differences in the clinical outcomes observed across the four subgroups. The APUC-6 high/AR low subgroup, which is the green line right here, it shows overall median overall survival 58.1 months compared to, for example, APUC-6 low/AR high 29.4 months. So it has the best survival compared to other subgroups. So, we think this results suggested that there is a potential role of APUC-6 high/AR low as a prognostic biomarker for the favorable survival.
Interestingly, when we take a look at outcomes in the two treatment arms, for patients with APUC-6 high/AR low expression, adding docetaxel to ADT, which is a dotted line here, did not prolong overall survival compared to the ADT alone group, as shown in the solid line. And in contrast, if you take a look at APUC-6 low/AR low group, for those patients, they demonstrated a significant improved overall survival after the received docetaxel plus ADT compared to the ADT alone. So, if we compare to the whole CHAARTED cohort, which has a median overall survival 57.6 months, so you can clearly see there is a differential outcomes if we stratify by those APUC-6/AR signature.
So, we also take a look at all the APUC-6 low patients regardless of their AR expression. And as shown here for those patients, the docetaxel ADT group shows significantly improved overall survival compared to the ADT alone group. So, our next question is that whether this APUC-6 low/AR low can predict the response to docetaxel. So to answer this question, we performed interaction analysis to evaluate. As you can appreciate on this table, I had it here. So the interaction P value 0.001, and the HR is 0.36, which is suggested that APUC-6 low/AR low is a significant predictor of improved survival from docetaxel.
So, to summarize what I've shown you for patients with APUC-6 high/AR low, they had a favorable overall survival. However, no additional survival benefits from adding docetaxel to ADT. For patients with APUC-6 low/AR low, they significantly benefit from adding docetaxel to ADT, and with this signature predicts docetaxel benefits. So, our study highlighted the potential of using APUC-6/AR expression to identify patients who are more or less likely to benefit from docetaxel, which can lead to more personalized treatment option. Thank you.
Angela Jia: That was wonderful. Thank you so much for sharing that. That's really great. That's very interesting. One of the first slides you showed that heat map where those six genes were initially identified. Any surprise to see that the APUC-6 and AR expression are inversely correlated?
Xiaolei Shi: Yeah. So interestingly, so we take a look at both us and Dr. Wang's group would take a look at a different cohort. Actually, we do see there is a negative correlation between APUC-6 and androgen receptor and AR expression. For example, I didn't show that, but the paper, when patient have a little bit higher APUC-6 expression, they tend to have low AR. And also in our CHAARTED cohort we do see a significant negative correlation between APUC-6 and AR expression.
Angela Jia: Okay, that's great. In the slides you also showed that the APUC-6 high and AR low had the better prognosis. And it seemed like if you were APUC-6 low, regardless of what the AR status was, it seemed to benefit, patients seemed to benefit from the docetaxel from addition of chemo to the ADT. That's very intriguing. Any thoughts on what the biology might be here to explain this?
Xiaolei Shi: Yeah. So definitely the results may reflect the end underlying tumor biology. So, the APUC-6 high or low tumor seems more like a ligand driven, or traffic enough ligands. So they don't rely really on AR amplification, and they're highly ADT sensitive. So, once ADT removes the ligand pressure, chemotherapy doesn't offer much more benefit. But in contrast to the APUC-6 low tumors may be less hormone dependent, and they shift towards the androgen independent pathway. So, they respond better to another mechanism of treatment, cytotoxic therapy, which explains why docetaxel helps most in that group. So this hypothesis definitely worries further magnetic validation.
Angela Jia: Yeah. And that would totally make sense to why they're inversely correlated, why APUC-6 high is correlated with a lower AR expression, right? That makes sense. So looking ahead, do you think that APUC-6 status alone would be sufficient to guide clinical decision-making or does it always need to be interpreted alongside with the AR expression?
Xiaolei Shi: Yeah, that's a good question. So, the APUC-6 tell us a lot, but pairing it with the AR really sharpens the picture. So the combination is more informative than using the APUC-6 alone. For example, it has shown the APUC-6 low/AR low identifies patients with longer median overall survival like 69.5 months, and a better HR 0.39. Receiving docetaxel plus ADT versus for the APUC-6 low patients, regardless of their expression, their median overall survival is about 53.9 months, which is shorter than the APUC-6 low AR location population. And their HR is 0.43 in docetaxel plus ADT group. So, that pattern says APUC-6 status really matters, and adding AR sharpens the address of the decision boundary. So, we have ongoing work to further validate this hypothesis.
Angela Jia: That's great. And so what are those next steps of prospective validation?
Xiaolei Shi: Yeah, thanks for mentioning that. So first, we would like to integrate the DECIPHER score into our analysis. So both post hoc analysis of CHAARTED by Dr. Hamid published in 2021, and the recently published analysis on STAMPEDE by Dr. [Inaudible] group, I'll suggest that patients with high DECIPHER score were more likely to benefit from docetaxel. So we looked at a high DECIPHER score patients in our CHAARTED cohort, and we found the patients actually with high APUC-6 and AR low still did not benefit from docetaxel even with the high DECIPHER score. So it gave us a signal that the potential of using APUC-6 AR in combination with the DECIPHER score may be able to better stratify patients who are more or less likely to benefit from docetaxel, which can lead to more personalized treatment decision. So, definitely this hypothesis also need to be further validated in prospective trials.
So, we would like to validate this signature in the setting of today's MHSPC backbones ADT plus ARPI and/or docetaxel. So from CHAARTED our hypothesis is pretty clear. Patients with APUC-6 high AR low may actually do very well with hormone therapy alone. So that is a potential D intensification group. On the other hand, those patients with APUC-6 low, especially when AR is also low, seems to gain the most from adding docetaxel to their hormone therapy. And it can be the intensification group. So these were the hypothesis generating findings from our current analysis, and our goal is to test them prospectively in larger and more than trials to see if they really hold up.
Angela Jia: That's wonderful. Thank you so much for taking the time and going over these results. This is super exciting, and I can't wait to see the future validations in prospective trials.
Xiaolei Shi: Thank you so much. Thank you.