Umang Swami: Thanks, Dr. Agarwal, and you have always been so gracious, and thanks for having me.
Neeraj Agarwal: So Umang, we have seen so many registration trials, which happen fortunately for our patients in metastatic hormone-sensitive prostate cancer with overall survival dramatically improving. It used to be two to two and a half years, now is in the range of five-year-plus, which is fantastic news for our patients. But we continue to treat every patient in a very similar fashion. We start them on ADT plus an ARPI, androgen receptor pathway inhibitor such as enzalutamide, apalutamide, darolutamide, or abiraterone, or even triplet therapy with docetaxel chemotherapy. We saw more recent data from ESMO that adding lutetium therapy may be an option in the near future for our patients. But all these patients are then treated indefinitely with these treatments, doublets or triplets. And we have heard data on PSA response being a reliable biomarker of survival in these patients, which can potentially allow us to personalize medicine in these patients.
So can you first, before we get to your presentation on the OPTIMAS trial, can you please tell us, share your experience with how you perceive PSA response after six to seven months as a biomarker, as a marker of survival in these patients from different trials and your own experience first?
Umang Swami: So thanks, Neeraj. You bring an excellent point. So right now we treat all the patients with metastatic prostate cancer, which are hormone-sensitive in the same way. We either use a doublet therapy or a triplet therapy. Either we use ADT with ARPI, or we use docetaxel in addition to ADT with ARPI. And when we treat these patients, we continue treating them the same way, regardless of how the PSA responds. But when we look, approximately 51% of patients or more, depending on what trial we look, we see patients achieving an undetectable PSA, which is defined usually in different trials by either 0.1 or 0.2 nanograms per milliliter and this-
Neeraj Agarwal: So 150, half of the patients-
Umang Swami: More than half of the patients-
Neeraj Agarwal: ... achieve a PSA level, which is undetectable, less than 0.2 or less than 0.1, depending upon the cutoff they use, but that's a pretty large number of patients.
Umang Swami: Yes. So more than half of the patients achieve this undetectable PSA, which we can also call as an optimal PSA. And these patients have a prolonged overall survival, which may be approximately seven years or more. And this has been seen across multiple clinical trials like the SWOG 1216 trial, ENZAMET, TITAN. It has been seen in ARASENS. It has been seen in the PEACE trial. It has been seen with LATITUDE. It has been seen with STAMPEDE so it's a consistent-
Neeraj Agarwal: So across the trials, across the ARPIs, we have seen consistent message.
Umang Swami: And there has been a meta-analysis looking at it, and the patients who achieve this optimal PSA have a 61% reduction in risk of death. The hazard ratio was 0.39 with a 95% confidence interval of 0.3 to 0.5. It means that these patients have a very prolonged overall survival. And when we keep on treating them with the same androgen deprivation therapy, along with ARPIs, these patients experience a lot of side effects. They are at increased risk of getting cardiovascular events, as well as skeletal-related events. They lose their muscle mass. They get prolonged fatigue. They get hot flashes. They have gynecomastia. They have a deterioration in their sexual function, and these things keep on worsening as the time progresses. So there's a possibility that we can de-intensify treatment. These patients who have achieved an optimal PSA response may get treatment breaks, which can help with mitigating the side effects, which they may get from continued androgen deprivation therapy with ARPIs.
Neeraj Agarwal: So based on your observation that these patients who achieve a PSA, very low PSA levels, less than 0.2, less than 0.1, they have a much higher survival, overall survival. But there's a potential in your mind to de-escalate treatment in these patients in order to not only allow recovery of testosterone, or recovery from all those side effects, but also allow them to live long while maintaining their quality of life.
Umang Swami: Yes. So keeping this in mind, we designed a clinical trial, a randomized clinical trial, which is trying to explore this finding, this observation.
Neeraj Agarwal: So please tell us more about this trial.
Umang Swami: So this is a phase 2 randomized investigator-initiated trial, which is looking at a de-intensification treatment regimen. So patients who are newly diagnosed with metastatic hormone-sensitive prostate cancer are enrolled in the study, and they get treatment with relugolix with an androgen receptor pathway inhibitor, and they can get any other standard-of-care treatment, which is currently available for patients with prostate cancer in this setting. And they are treated for six to 12 months. And if they achieve an optimal PSA response, which is again defined as 0.2 or less PSA, then they get randomized to either continuing the same treatment, or they get an intermittent treatment where they get treatment breaks and the treatment is re-initiated based on the PSA and patient and physician's choice and discussion. And the primary endpoint for this study is to evaluate the difference in fatigue after six months of randomization based on pre-fatigue inventory score.
Neeraj Agarwal: I find use of relugolix very interesting. Why did you choose relugolix as the treatment backbone here for ADT and not Eligard, or leuprolide, or other GnRH agonists, which are also available out there?
Umang Swami: So that's a great question. So we looked at the time to testosterone recovery with leuprolide. So previous studies have shown that if the leuprolide has been given, for example, for three years, then the recovery of testosterone may take one and a half years. And this recovery may be delayed in older patients and if they have received leuprolide for a longer duration. Relugolix, on the other hand, in the phase 3 HERO trial has shown a faster recovery time of testosterone. It has also shown that it has a better cardiovascular risk profile. We also looked at our own institutional dataset, which my colleague, Dr. Maughan, and you have published where the time of testosterone recovery with relugolix was 1.4 months, which is quite fast. And since the overall objective of our study was to help testosterone recovery, we felt that relugolix will be a better androgen deprivation therapy as compared to leuprolide.
Neeraj Agarwal: That's a brilliant point you made. We consistently see in our clinics that if you give GnRH agonist injections to our patients, even after discontinuing those injections, testosterone recovery takes a really long time. I have patients who have not recovered their testosterone even two to three years after stopping GnRH agonist injections if they have received this for more than six months to one year. And you are right. Stopping relugolix at a given point of time allows testosterone levels to recover very quickly. Based on HERO trial, we saw the data. It was in weeks. We had our own experience from Huntsman Cancer Institute in our patient population. The testosterone recovery was quite quick. Within six weeks, most of the patients were able to recover their testosterone. So definitely a very attractive option in those trials where we are pursuing de-escalation. What has been your experience so far? Not asking you for the results, but how easy it is to get relugolix, and what we should be concerned about combining relugolix with androgen receptor pathway inhibitors?
Umang Swami: So I found that we didn't face any hurdles with approval of relugolix with an ARPI. There has been some studies which may show some drug-drug interaction with apalutamide. There have been two contrasting studies. One study showed that we may need to use a higher dose, but the other study did not show such kind of drug-drug interaction. Apart from that, I found relugolix to be very well-tolerated and liked by the patients. I have patients who have taken it for years, and they really liked it.
Neeraj Agarwal: And copay issues with the new ... For Medicare patients, now copay is fixed at $2,000 per year. So you have not encountered any major financial issues regarding switching from Eligard to relugolix, for example?
Umang Swami: No, I haven't encountered because of the Medicare cap on the copay issues. And most of the patients are already eligible for Medicare, so I haven't encountered any financial barriers.
Neeraj Agarwal: So just to summarize for our audience out there, in this trial, patients with metastatic hormone-sensitive prostate cancer, patients are started on relugolix with an ARPI. After six to nine months of treatment with relugolix with ARPI, if patients achieve a PSA level, which is less than 0.2 or 0.2, then they are randomized to continuation of the same treatment versus stopping all treatment. Is that correct?
Umang Swami: Yes.
Neeraj Agarwal: Okay.
Umang Swami: And the treatment re-initiation happens based on patient and physician's wishes when they want to initiate and certain other criteria.
Neeraj Agarwal: And we hope that because of the rapid recovery of serum testosterone in these patients who are stopping relugolix, they will derive a meaningful improvement in quality of life and also alleviation of other side effects which are associated with GnRH agonist. Would you agree with that?
Umang Swami: Definitely. And to document that we are doing multiple patient-related outcome assessments, as well as ecological momentary assessments. And we are also then correlating them with the levels of testosterone and their overall quality of life along with various other biomarkers.
Neeraj Agarwal: So quite comprehensive assessment of quality-of-life measures.
Umang Swami: Yes, definitely.
Neeraj Agarwal: Well, congratulations on designing this study, Umang, and kudos to you for hopefully moving the field forward. We look forward to seeing the results of OPTIMAS trial in the near future, and hopefully we'll have bigger trial asking this question to allow us to change practice for these patients who have these optimal or exceptional PSA response, and to really answer the question whether these patients need to be on lifelong therapy with ADT plus ARPI, or they can take a break and allow their quality of life to recover.
Umang Swami: Thanks, Dr. Agarwal and UroToday team for providing me with this opportunity to discuss the OPTIMAS trial.