Alexandra Sokolova, MD, Oregon Health and Science University Knight Cancer Institute, Portland, Oregon, shares her thoughts on the most compelling research in prostate cancer presented at the 2024 ASCO Genitourinary Cancers Symposium. 

Transcript: 

Alexandra Sokolova, MD: My name is Alexandra Sokolova. I'm a medical oncologist focusing on prostate cancer at Oregon Health and Science University Knight Cancer Institute at Portland, Oregon.

Can you share your key takeaways from ASCO GU 2024? Did any groundbreaking developments or advancements in prostate cancer treatment stand out to you?

Dr Sokolova: There was a lot of exciting data presented at GU ASCO of 2024. From the prostate cancer world, I would like to highlight three studies that had their data presented at GU ASCO 2024. We'll start with the BRCAAWAY trial presented by Dr. Hussein on prostate cancer day. So BRCAAWAY is a randomized phase two trial of abiraterone, olaparib, or combination of abiraterone and olaparib in patients with metastatic, hormone-resistant prostate cancer with homologous recombination mutations. What's different about this trial compared to some other trials in a similar space that they had this olaparib monotherapy arm that was not evaluated in prior PARP inhibitor studies in that space. So patients enrolled in this study were metastatic castration-resistant prostate cancer patients with no prior exposure to PARP inhibitors or pathway inhibitors or chemotherapy in hormone-resistant prostate cancer space.

It is worth mentioning that this patient population is not large. It doesn't currently represent the landscape of treatment because most of those studies were planned and designed a while ago. So those would be the patients who kind of had chemotherapy only or ADT chemotherapy only in their hormone sensitive space without ARP inhibitors or were treated only with EDT, and they’re hormone sensitive, and now they’re progressing without exposure to ARP inhibitors, or PARP inhibitors. And so those patients were enrolled in randomized one-to-one to abiraterone monotherapy, olaparib monotherapy, or combination. And so primary endpoint was radiographic progression-free survival or clinical assessment or death. The baseline characteristics were more or less balance between three arms. It is worth mentioning that ARM two, which was olaparib monotherapy arm, had a higher percentage of BRC2-mutated cases. So they had 90% of BRC2 cases compared to 68 in arm one and 78 in arm three, which is this such small study with BRC2 probably being the high driver, could potentially represent some bias.

The adverse events were very similar to what we would expect. There was nothing unexpected. Talking about efficacy, the median progression-free survival was longest in a combination arm—was 32 months compared to 8.4 in abiraterone monotherapy, or 14 months in olaparib monotherapy. Objective response was, again, higher in arm three with a combination 33% compared to 22 in arm one and 14 in arm two. PSA response was higher in a combination arm. 95% had a PSA response compared to 61 in abiraterone, in 67% in olaparib monotherapy. And undetectable PSA again, was higher in combination, 33% compared to 17 and 14%. It was a really nice separation of the curve and progression-free survival. Importantly, they also looked at crossover. So they looked at what percent of patients crossed over to olaparib and what percent of patients crossed over to abiraterone. It was not a high number: only eight patients crossed over to olaparib and only eight patients crossed over to abiraterone.

The PFS was eight to seven months in either arm. And if you compare the PFS from the randomization to the progression of the second drug, it was 16 months in both arms, which is still shorter than a combination of olaparib plus abiraterone. The study wasn't designed to compare this PFS 2 endpoint, but I think out of all the data that came out, this might be the first one that is actually suggesting a synergy, a true synergy between those two drugs, the abiraterone and PARP inhibitor. We're gonna have to wait for overall survival data to mature before we can actually use it in the clinic, but I think it's a really exciting look into potential synergy between those two drugs that has been really discussed and debated in the field. 

The second study we highlight is a CONTACT-02 study, which was presented by Dr. Agarwal, which is a study of cabozantinib plus atezolizumab versus second novel hormonal therapy in patients with metastatic castration-resistant prostate cancer. And they presented a primary analysis from this phase 3 study. Both studies, both agents have been studied in prostate cancer and haven't been as effective as we hoped they would be. There have been several studies of immunotherapy in combination monotherapy that haven't gained the meaningful response rate in all commerce population. There has been a study of cabozantinib in a phase one that had an exciting RPFS, but then resulted in no OS benefit.

So it's really exciting to see this combination kind of come back and have some promising data. In CONTACT-02, enrolled patients with metastatic castration-resistant prostate cancer, who progressed on one prior neurohormonal agent, they must have had measurable extra pelvic soft-tissue disease. So visceral or extra pelvic lymph node metastasis per RESIST 1.1. The must have had a progressive disease PC soft tissue progression, ECOG 021, and docetaxel was allowed in hormone-sensitive setting. Patients were randomized to cabo plus atezo or second new hormonal agent, and there was a combined primary endpoint, combined dual primary endpoint: PFS in PFS intention to treat population per RESIST. So bone metastasis were not included in this PFS or overall survival intention to treat population.

And 253 patients were included in cabo plus atezo. 254 was included in a control arm of second new hormonal agent. The baseline characteristics were very well balanced—it was a high-risk patient population with 40% having a visceral metastasis in both groups, and about quarter of patients had liver metastasis in both groups. So the patient population enrolled in this trial was a high-risk patient population, which we know usually don't do well and have worse overall survival. They presented at GU ASCO PFS data and PFS in cabo and atezo was 6.3 months compared to 4.2 months in second new hormonal agent, with hazard ratio of 0.65, which statistically significant. When you look at subgroup analysis, most groups benefited, patients with liver metasasis benefited, patients with prior docetaxel, patients with bone disease only have benefited with cabo and atezo.

And when you look at PFS per specified subgroups, that looked at liver metastasis, prior docetaxel and bone metastasis, all three benefited with hazard ratio being the most promising in a liver metastasis subgroup. The overall survival data is immature and it's too early to comment on it. There might be some trend for improved OS in cabo plus atezo. There might be some early separation of the curves, but it is too early to comment on it. We need more events to comment on it. The tumor response, overall response, was 14% in cabo plus atezo, and it was 4% in second new hormonal agent subgroup. So if you looked at kind of key endpoints, secondary endpoints, the median time to skeletal events was 16 versus 13 in cabo plus atezo versus second neuro hormonal. Time to pain progression was 4.3 in both arms and time to deterioration of quality of life was 2.2 months. So it was similar in in both arms.

So key secondary end points. The time to skeletal events was a little better in cabo plus atezo, but hazard ratio was crossing 1 and median time to pain progression and quality of life was the same in both arms, so there was no benefit in that. I was quite short for 4.3 months for pain progression and 2.2 months for quality of life decrease. Not a lot of patients got subsequent treatment in this patient population. So 19% of patients from cabo-atezo got subsequent chemotherapy and 28 in control arm got subsequent chemotherapy trying this another NHT almost 6% in cabo plus atezo, and only 1% in second new hormonal agent. That makes the think that a lot of patients don't get more than one or two lines in mCRPC.

And are those patients potentially missing their opportunity to get a more effective treatment, especially those in a new hormonal agent control arm. But the baseline, I think, that's promising PFAS data, too early to use it in practice. We really need this OS data to mature and show benefit. The PFAS data was exciting and promising. Time to pain progression and time to quality of life degeneration was quite short and was the same between two arms. So I think we really need more data to understand how that's gonna impact our treatment in patients. But that could potentially be a treatment option for those patients with high-risk disease with visceral metastasis that really don't do well. So it would be great to have an additional treatment options for those patients. 

So the third study I would like to highlight is a early study, it's phase 1/2 study, but I think it's quite exciting target. It could potentially bring new treatment options to a patient population that doesn't do well and has poor prognosis, which is neuroendocrine prostate cancer. Dr. Beltran presented interim results from phase 1/2 study of HPN328, a three-specific DLL3-targeting T-cell engager in patients with neuroendocrine neoplasms. So DLL3 is expressed in neuroendocrine cancers including neuroendocrine prostate cancer and it almost not expressed at all on any healthy tissues. So that makes it a very promising therapeutic target. And so this is a T-cell engager targeting DLL3 that engages CD3s. And the patients including the studies were patients with neuroendocrine cancers. In this particular cohort there was a small cell lung cancer patients, 62%.

Other neuroendocrine cancers was 12%, and 24% were GU cancers including 17% of neuroendocrine prostate cancer. So 15 patients with neuroendocrine prostate cancer were included in this cohort that was presented at GU ASCO. It was, they mostly focused on its tolerability and side effects. It was relatively well tolerated. There was total of two DLTs. Most of the DLTs were seen kind of early priming doses and not in subsequent dosing. No DLTs were, so there were two DLTs seen at priming dose at two grams, a two milligram dose. And so it was deescalated to one milligram. No DLTs were observed at target doses. And target dose in maximum tolerated dose was not reached. The most common DLT was cytokine release syndrome, seen at 58%. It was mostly seen kind of early on in treatment initiation. Dyscrasia was also seen in 35 patients, fatigue in 32, diarrhea in 18, and nausea and 17. Anti-tumor activity at one milligram was also somewhat promising. The oral response was 56% with confirmed response of 32%. If we, that's for all tumor types. If we focus on GU neuroendocrine cancers, the oral response was 58% with confirmed response of 25%, which is quite exciting for this high-risk patient population. The duration of response and treatment, some of the patients were in treatment for quite a long time, up to 50 weeks of treatment. 

So HPN328 is a novel DLL3 T-cell engager that is well tolerated and demonstrates some promising clinical activity in endocrine carcinomas including neuroendocrine prostate cancer. The adverse events were manageable with CRS being the most common or occurring with the first dose, but most of them were grade one or two. Monotherapy dose optimization is ongoing and the data is maturing for kind of a some dosing cohorts and we're excited to see more data on this promising agent and hopefully it can bring additional treatment options to our patient population.

Based on the conference insights, do you foresee any emerging trends in prostate cancer treatment that may enhance patient outcomes or lead to adjustments in your approach or treatment recommendations?

Dr Sokolova: There was a lot of exciting data presented to ASCO, a lot of promising preliminary data, preliminary kind of outcomes. However, I don't think any of it is ready for prime time to change treatment or practice in prostate cancer world. I think we'll need to wait a little bit of more mature data for our kind of olaparib combinations, for DLL3 neuroendocrine prostate cancer, for cabo plus atezo. I think we need more data to use it in practice. So the short answer is no. I don't think any of it is ready for prime time to change, but I think there's a lot of excitement happening in prostate cancer world. We didn't have as much of PSMA-related updates, but I think that's what everyone is watching and that's what everyone's following, PSMA path and lutetium 177 has significantly changed the landscape of prostate cancer.

So we're anticipating more data on our alpha meter trials, on timing alpha versus beta meters, on timing of the lutetium 177, and kind of where it will fall in our landscape, early versus late. I think it would've been trend of moving it earlier with some data presented at ESMO with PSMA 4 to trial. So I think we're all kind of eagerly waiting on all this data to come up. There are other targets that have been explored using rider ligands such as as sT1, as potential new targets. So I think there's a lot of excitement, a lot of exciting research. We also didn't talk a lot about the ER degraders, which is also in another exciting avenue in prostate cancer development. We didn't have any kind of big breakthrough data on that end, but we are anticipating more data, hopefully coming, maybe at big ASCO or next ESMO, but also potentially could be practice changing. But unfortunately none of it is ready for prime time yet.