Primary Analysis of STARTAR: A Phase 2 Salvage Trial for High-Risk Prostate Cancer with Biochemical Recurrence - Tian Zhang

July 3, 2023

Alicia Morgans hosts Tian Zhang to present an update from her presentation on the STARTAR trial, focusing on treatment intensification for high-risk prostate cancer with biochemical recurrence. STARTAR builds on an earlier trial, STREAM, by combining hormone deprivation with apalutamide, salvage radiation, and six cycles of docetaxel. The study focused on patients with Gleason 7 with nodal positivity, Gleason 8 to 10 at prostatectomy, and PSA recurrence within three years post-prostatectomy. The trial, which concluded its last patient enrollment in 2019, found that the three-year PSA progression-free survival rate was 73%, and all but one patient had normal testosterone levels after three years. Dr. Zhang suggests that this intensive, yet short-term, treatment approach could be an alternative to prolonged hormone deprivation for motivated patients. However, she acknowledges the limitations of the trial and underscores the need for further investigation.


Tian Zhang, MD, MHS, Associate Professor, Department of Internal Medicine, UT Southwestern Medical Center, Dallas, TX

Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, MA

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Alicia Morgans: Hi, I'm so excited to be here with Dr. Tian Zhang, who is joining me from UT Southwestern to talk about her exciting ASCO presentation, the STARTAR trial. So tell me a little bit about this trial. It's a prostate cancer trial, so I love to see someone with a love for kidney cancer expanding her expertise into prostate cancer quality assurance for us.

Tian Zhang: Yeah, thanks, Alicia. That's really kind. So STARTAR was an investigator led trial that I did when I was early career faculty at Duke, but it was really based on the salvage setting, trying to intensify treatment for high risk prostate cancer with biochemical recurrence. And it was based on the earlier trial that we had run at Duke, which was called STREAM. And STREAM was a trial of hormone deprivation plus enzalutamide and salvage radiation. And for that trial, the three-year PSA progression-free survival was about 53%. So we said, could we improve that even more by adding other effective strategies in this biochemical recurrent setting? So with STARTAR, our premise was ADT with apalutamide salvage radiation followed by six cycles of docetaxel. So really intense treatment, but nine months of it. So a shortened course. And the patients we selected were patients who had Gleason 7 with nodal positivity at the time of prostatectomy. They were also Gleason 8 to 10 at the time of prostatectomy, and they had to have had PSA recurrence within a certain timeframe. So within the first three years after their prostatectomy.

So those higher risk patients who in this salvage setting, we thought needed more treatments upfront. And so we enrolled 39 patients. Last patient was enrolled around December of 2019, which means that this is our 3 year PSA time point. And so we were very excited to present that. And the 3 year PSA progression-free survival rate was 73%. So three out of four patients did not have PSA progression and everybody achieved PSA nadirs of undetectable levels. So these patients are PSA-free basically three years out. And the more exciting part I think is these patients, the vast majority of them had recovered their testosterone levels. Median time to testosterone recovery was about 15 months, but at 3 years, all but 1 had achieved normal testosterone levels. So of those patients, they're living with normal testosterone and they're PSA progression free. So if that's a surrogate for other outcomes like metastasis free survival and overall survival, then I think we're getting these patients to live longer without prostate cancer recurrence.

Alicia Morgans: That's fantastic. And so this really was sort of an intense combination of therapies, a multimodal treatment strategy that seems to have given us some durable effective disease control at the three-year time point. So that's great. So tell me a little bit about the chemotherapy. When did you give it? How many cycles? How was it tolerated?

Tian Zhang: Sure. So very similar to how we give docetaxel in the CHAARTED setting, we gave six cycles of docetaxel, and it was in the latter half of those nine months. So people started with ADT and apalutamide. They then got their salvage radiation therapy to the prostate bed, plus any nodes if they initially had nodal disease. And then after radiation, we gave the six cycles of docetaxel. So usually the first cycle of docetaxel started about four weeks after the radiation. So it's interesting in that setting, these patients technically are very healthy and so they can get through a lot of intense treatments. But to your point on toxicity, we did have some neutropenia, some anemia, and a couple of episodes of febrile neutropenia during chemotherapy. And I think that's the overlay of some bone marrow suppression from pelvic radiation plus then the docetaxel. But most people tolerated it well, and we went through this study without really any unexpected safety findings. Some rashes from apalutamide and some neutropenia, anemia, and some alopecia from the chemotherapy. But otherwise, everybody did great.

Alicia Morgans: That's wonderful. And it's really exciting to the point that you made earlier that all but 1 of these 39 patients had recovery of testosterone. I think we've seen some recent data that there can be prolonged suppression of testosterone as we're giving these systemic therapies. And even in this combination of systemic therapies, you did see the recovery of testosterone, which I think is very, very encouraging from a patient quality of life standpoint.

Tian Zhang: Absolutely. So I think, we always think about if we maintain long-term right androgen deprivation, will some of our patients actually recover their testosterone later on. So I think we're showing with nine months, people can still recover their testosterone and get back to normal, if you will. And they had to be a bit more motivated to accept more intensive treatments for nine months. But these folks were so appreciative of the patients who part of the trial, and I think we're learning a lot from them.

Alicia Morgans: Wonderful. So final question. If you're seeing a patient like this in the clinic and you think about the RADICALS-HD data, which is for higher risk patients kind of recommending potentially 24 months of ADT versus this more intensive approach, but a really kind of condensed timeline. Are you thinking about using this kind of an approach rather than a two year ADT approach in clinical practice? Is this something that you would think that you might use day to day?

Tian Zhang: Yeah, so I think that's a great question. When we're doing a single cohort phase two study, it may not be so practice changing, but in the select patient who is motivated to do a lot of treatment upfront and maybe not take two years of hormone deprivation, I think it's a consideration. And we've seen that with STARTAR also at GU ASCO, we saw Paul Nguyen's data on FORMULA-509, great trial name, but intensifying treatment upfront with AR targeted strategies on top of ADT really can achieve really good responses. And his 3 year PSA progression-free survival was somewhere around 74% too, if I remember correctly. So very similar rates. And so it says to me that in this biochemical recurrence setting, there's a patient population that will do well with more intense treatments, but more brief treatments upfront and hopefully that's meaningful and gets them to durable outcomes.

Alicia Morgans: Absolutely. And I do think that having the options for patients to kind of think through the data with the limitations in mind, as you said, single arm studies, phase twos, it really is important because you never know when a patient's preference will be to do more within a shorter period of time versus longer, but less intensive therapy. And patients need to be asked these questions to their point of view.

Tian Zhang: Yeah, it's a shared decision, but there is a limited cohort of patients, especially now that we have PSMA PET imaging. And so we only enrolled patients who were CT and bone scan negative, with true biochemical recurrence, PSA progression, but those are some of the patients who probably have PSMA positive disease on their PET scans. And so how do you factor that piece in? I think maybe those patients also are the ones who are at higher risk and need more intensification upfront. So I think we're all learning about that space right now of PSMA positive disease, but CT bone scan negative, and I'm looking forward to seeing some of the trials that really speak to that patient population readout.

Alicia Morgans: Well, I am too, and I so appreciate it, thank you and the team at Duke for putting this together. Certainly thank you to all the patients who took a chance because STARTAR seemed to be quite a winner, at least as we look at that three year progression free survival. I appreciate your time and your expertise.

Tian Zhang: Thanks Alicia. Great to be here.