Beyond BRCA-1 and 2: The Impact of the TALAPRO-2 Study on Prostate Cancer Care - Cora Sternberg

June 16, 2023

Alicia Morgans speaks with Cora Sternberg about precision medicine's transformative impact on prostate cancer treatment. A key topic is the TALAPRO-2 study, which examines the efficacy of the PARP inhibitor talazoparib in combination with enzalutamide in treating metastatic castration-resistant prostate cancer (CRPC). The study's positive findings suggest significant benefits for patients with BRCA-1, 2, and homologous recombination defects, challenging FDA regulations that only approve the treatment for patients with BRCA-1 and 2. Sternberg also emphasizes the importance of real-world data in complementing clinical trials. The conversation shifts to AI's potential in oncology, particularly the ARTERA study, which uses AI to predict patients who may not need long-term androgen deprivation therapy (ADT). Sternberg concludes by underscoring the need for germline and somatic testing in prostate cancer patients to ensure effective treatment with precision medicine.


Cora Sternberg MD, FACP, Professor of Medicine and Clinical Director of the Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY

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. Cora Sternberg, who's a professor of medical oncology at Weill Cornell, as well as being the clinical director of the Englander Institute of Precision Medicine. Thank you so much for being here with me today.

Cora Sternberg: Thank you. It's always a pleasure to be with you.

Alicia Morgans: It is always wonderful to be with you too, and I'm excited to talk with you at ASCO 2023 because I know you have such a passion and expertise for precision medicine and the way that it's really transforming the field of prostate cancer care. I know there were several presentations this year at ASCO that really piqued your interest. I know there were many actually, but-

Cora Sternberg: There were many.

Alicia Morgans: There were many, but let's talk about a couple that I think are really kind of focused on this precision medicine idea.

Cora Sternberg: One of them is the TALAPRO-2 study, which was actually presented recently, and it was published in The Lancet Today. And the TALAPRO-2 study is a study of patients who have metastatic CRPC, castration-resistant prostate cancer, randomized between enzalutamide and talazoparib versus enzalutamide and placebo. And in that study, it's a positive study in terms of radiologic progression-free survival. They don't have enough data in terms of overall survival, and it was published in The Lancet Today.

But Karim Fizazi presented biomarker data of a population that was pre-specified to look at biomarker data. And they looked not just at BRCA-1 and 2, but they also looked at homologous recombination deficiency, other markers of that mutations such as ATM and PAL-1, CHECK-2, several of the different homologous recombination deficiency markers. And when looking at that, they found important advantages for the combination of the PARP inhibitor talazoparib, not only in the BRCA-1, 2 patients, where definitely they had the most advantage, but all of the patients with homologous recombination defects as well, mutations, also had an advantage.

And that is very different than what's happened in the past, and most recently by the FDA, where the PROpel Study had a non-selected group of patients, and they only in the United States, only approved olaparib and abiraterone for patients with BRCA-1 and 2, and not for any of the patients with homologous recombination defects. In Europe, they have approved the olaparib and abiraterone based on the PROpel Study in unselected patients, for all people with homologous recombination defects and BRCA-1 and 2, so it was rather unusual that the FDA is being more conservative than the Europeans now. But I don't know if Emma has changed now that it's no longer in Britain or if it's different people. I don't know what happened. I'm not sure exactly what happened at the most recent ODAC. But the PROpel Study, which was the first study that had a trend also in overall survival, although the P value was I think 0.06 or 0.05, only got a label for the BRCA-1 and 2.

But listening to this TALAPRO data where they pre-specified and pre-selected and there was about 399 patients where they had the biomarker. It's clear that the patients with homologous recombination mutations and defects, not only those with BRCA-1 and 2, had an important advantage in radiologic progression free survival by blinded independent review, and also an advantage in terms of pain control, an advantage in terms of time to needing chemotherapy. So there were many, many advantages in that group of patients. So I'm not sure if the FDA will rethink the whole story or not. There's been such a controversy, I'm sure you've heard about it, among clinicians and among geneticists, about how we should handle these patients with homologous recombination deficiencies.

Alicia Morgans: Absolutely. I think this story is far from over, but as you said, it's really interesting and important to see this population, the HRR population, beyond BRCA-1, BRCA-2, and how that combination may be beneficial, whether synergistic or otherwise in that population in addition to that population only with BRCA-1, BRCA-2. So I do expect, and I hope that we'll see more information to come too, because as you said, it wasn't just disease control outcomes, but also some of these quality of life outcomes that can be so important to patients.

Cora Sternberg: In my hospital, we're doing a study, but we're doing clinical, whole genome sequencing, which is really incredible. I'm able to do that on patients, not just with prostate cancer, urothelial cancer, other cancers. And we find different kinds of homologous recombination defects, and if you find two or three of them, that you really want to treat these patients with a PARP inhibitor, which is not yet approved, obviously in other tumors either. But we'll see what happens. I think we're going more and more towards precision medicine, and many of the hospitals at least, have targeted sequencing, looking for BRCA, looking for homologous recombination defects. But if it's only going to be BRCA-1 and 2, so I don't know what's going to happen with the payers if that's all they're going to want to pay for. We'll see what happens.

Alicia Morgans: Yeah, we will definitely have to see what happens, and we'll see what happens not only here in the US but around the world, especially as maybe real world data will come out to help us understand how these additional populations may fare when they get the intensified treatments.

Cora Sternberg: Real world data is so important because we do all these registration studies with highly selective patients in universities, and then when you go and have real world data, you see what's going on in the real world. The performance status is often not as good, but patients can be treated in the real world, and you can find real world data in many different tumors that I think is very important. When I lived in Italy, it would often take me two years to have an approval of a drug. And so I published many studies over a thousand patients of real world data with abiraterone, with atezolizumab for urothelial cancer, showing that you can get really important information out of real world data.

Alicia Morgans: Absolutely. I could not agree more. Well, thank you for that. And I wonder, I know that you had another presentation that you really wanted to dig into, and this was the Artera presentation on AI.

Cora Sternberg: I loved this presentation today. I've been interested in AI and I really think that artificial intelligence is the future in many, many ways. I attended a meeting on artificial intelligence here on Thursday. I wrote one paper in which we've developed a tool for sequencing therapies of prostate cancer. It's going to be published soon, with artificial intelligence. But this was different. This was looking at NRG studies in which androgen deprivation therapy was given together with radiation therapy, either given short term or long term, long term in those patients that are at high risk. And they used artificial intelligence primarily on the biopsy specimens of the prostate, and were able to define a predictive biomarker via artificial intelligence that could predict those patients who may not need long-term ADT, along with radiation. When you look at the other biomarkers that have been approved for prostate cancer, such as the decipher score and others, I think that maybe the work wasn't as vigorous as what was done in this study.

I thought this study was very, very well done and validated on many different studies. And they show that about a third of the patients who seem to be at high risk, could actually do well, just as well, with short term ADT. And I think that this could change a lot for many men because we know that long term ADT has more side effects and it comes along with many different side effects that we'd like to avoid if we can. So I think that this is the beginning of the future and artificial intelligence will be helping us more and more, it's there in pathology. It's in radiology. It's making its way into our homes even. But I think that this was a very interesting study presented by Andy Armstrong today.

Alicia Morgans: Absolutely. Yeah. And this kind of study is different than some of the others that you may have mentioned because they have to use big data to train the AI and then to validate the AI so-

Cora Sternberg: And to validate, yeah.

Alicia Morgans: It's really fascinating the way that the number of data points that actually go into these models and so interesting that it was able to be predictive in a setting, like you said, where patients are really bearing the brunt of the treatment. And if they don't have to, if they can get that right sized treatment, it seems like it will be a big advance for them.

Cora Sternberg: I agree. And if you can get six months instead of two to three years of androgen deprivation therapy, I think that's a big deal for men.

Alicia Morgans: Absolutely, especially with some of the data that's come out at recent meetings and in publications, that suggests that the time to testosterone recovery is just longer and longer and longer with each longer duration of ADT-

Cora Sternberg: We know this from the old bolus studies when they got three years of hormonal therapy, some people didn't recover for at least five years. I think it depends upon the age of the patient, also, when they go in what the testosterone level is to start, but it's important if they can get six months instead of three years, it's a big deal.

Alicia Morgans: It is a really big deal. So as you think about these presentations and as you think about precision medicine generally in prostate cancer, what would your message be to listeners? Because it sounds like there's a lot to look forward to and certainly more to come.

Cora Sternberg: I think that precision medicine, it's the present and the future for prostate cancer. And I think that we need to look at our patients and any patient that has even localized disease, that's at high risk, who has a family history of prostate cancer, who's Ashkenazi Jewish, they all have to have germline testing. And I think we also need to do somatic testing on their tissue as well. And then with that information, we can treat our patients better with PARP inhibitors. We can know if we need to do cascade testing on their family members. So I think that it's so important that we know that in the prostate cancer community, that we do the germline and somatic testing whenever possible.

Alicia Morgans: I absolutely agree. And as these tests like from Artera and otherwise become commercially available and some already are, I do think that they'll inform our clinical decision making and certainly we look forward to more data when it comes to those PARP and ARSI combinations, because I think that we have so many more questions and a lot more to learn. But thank you so much for your time and for your expertise today.

Cora Sternberg: Pleasure to be here. Thank you.