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Jingsong Zhang, MD, PhD, discusses his vision for treating patients with metastatic castration-resistant prostate cancer.
Jingsong Zhang, MD, PhD
With a half-dozen newly approved therapeutics, the treatment options for metastatic castration-resistant prostate cancer (mCRPC) have greatly expanded since 2010. Researchers are now looking to refine use of these agents and expand into new therapeutic areas.
Jingsong Zhang, MD, PhD, discussed these advancements in his lecture during the 2016 OncLive State of the Science Summit on Genitourinary Cancers. Zhang covered sequencing, the pathophysiology of the androgen receptor, the expanding array of hormonal approaches, strategic timing for cytotoxic therapy, and PARP inhibition and other appealing targets.
OncLive: Please provide an overview of how advanced prostate cancer has been an exciting field in recent years.
In an interview with OncLive during the meeting, Zhang, a medial oncologist at Moffitt Cancer Center, discussed the key takeaways from his talk and his vision for treating patients with mCRPC.Zhang: Since 2010, there are 6 drugs approved for treating this disease where the cancer becomes late stage IV, and patients no longer respond to hormonal therapy, such as androgen-deprivation therapy (ADT), and things such as leuprolide acetate for depot suspension (Lupron). Five of [these agents] are based on an improvement of overall survival.
After that, the field is wondering how to sequence them, and perhaps, for some patients, we need to [look at combinations]. In the past 2 years, there have not really been any advancements in terms of how to sequence these treatments.
One important trial is the CHAARTED study, which was published last year for high-risk patients with high-volume disease. There is a [reason] to give upfront chemotherapy when patients first start ADT. That has been shown to be beneficial, in terms of improvement in survival.
Later on, in terms of the tumor markers, there is AR-V7—which shows a pretty good predictive marker in terms of response to newer androgen-deprivation agents such as abiraterone acetate (Zytiga) and enzalutamide (Xtandi).
There are phase III trials ongoing right now that are specifically targeting this patient population, but they have positive AR-V7 in their circulating tumor cells (CTCs). There are a lot of efforts to try to understand the underlying biology of this disease; that is really from the tremendous efforts of just doing next-generation sequencing of the prostate cancer. Many trials mandate biopsy for patients with metastatic disease. In the past, not many patients with metastatic prostate cancer got a biopsy. That’s kind of the hurdle to learn about this disease when they progress to late stage.
Therefore, a lot of sequencing works. We found biomarkers. We found out there is enrichment of DNA damage repair deficiency proteins, and that there are agents to explore such as PARP inhibitors. There is a phase III trial planned for patients with stage IV prostate cancer using the PARP inhibitor and conducting biomarker studies.
You discussed the pathophysiology of the androgen receptor, as well as an expanding array of hormonal approaches. What were the main points of this portion of the lecture?
Those are the exciting things in the field of prostate cancer. It keeps evolving. First, we have new agents; then, we try to figure out how to sequence these agents. Perhaps for some patients, we need to combine these different agents. All of this is based on understanding the biology, and we are learning more about the biology of this disease when patients progress to late stage IV. It’s definitely a different disease compared with initial prostate cancer presentation.The key point is to bring up to date the AR-V7 and the qRT-PCR assay platform. It is not really 100% that, if patients are positive for AR-V7 on the qRT-PCR assay, they will have no response to treatment. What is more important is that the same AR-V7 prognostic predictive value is also confirmed with another platform.
What is important to know about strategic timing of cytotoxic therapy?
AR-V7 is certainly a step in that direction of using a target for therapy. What is the prevalence of it?
What potential do PARP inhibitors have in this field?
Additionally, some prostate cancer cells may carry positive AR but not V7, and other prostate cancer cells may have AR-V7 dominance.This stems from the CHAARTED trial. That is probably one of the most important findings in the past 3 years. Again, the field is moving to really [understand] patient selection. In the future, the prostate cancer cells will no longer be an all-comers trial. One must select specific patient testing, and specific hypotheses based on the biology of that will be applicable to this patient population. The CHAARTED trial is now widely adopted as a standard of care for patients with high-volume metastases. There is a sure survival benefit of giving upfront docetaxel.AR-V7 is more often tested in the late stage. Even in the late-stage, castration-resistant form, there is only about a 10% chance the patient may have detectable AR-V7 based on the qRT-PCR assay. It is not really a big population. For patients who are positive for AR-V7, one can certainly make the case to start on docetaxel as a frontline treatment for this group of patients, because we do know docetaxel has activity for AR-V7—positive patients. These patients tend to do worse than those who are AR-V7–negative.PARP inhibitors have actually been well started in prostate cancer. In a New England Journal of Medicine paper in 2009, there was a study that included 2 patients with prostate cancer who had a BRCA2 mutation. One patient actually has a durable response.
I believe Dr. Johann de Bono is kind of pioneering this field. He led a phase I PARP inhibitor trial for prostate cancer that was published a few years ago in The Lancet Oncology, looking at CTCs, loss of PTEN, and the TMPRSS2-ERG gene. It documented activity, but it didn’t show much association between PTEN loss and TMPRSS2-ERG fusion status; therefore, the most recent trial from his group was published in The New England Journal of Medicine last year. The beauty of that study is they mandated biopsy of every patient enrolled into the study. They biopsied the metastatic lesions and really demonstrated the point for patients with DNA-repair deficiency—not necessarily limited to double-strand repair. Even if patients have mismatch-repair deficiency, they can still respond to PARP inhibition.
Most recently, Dr. Maha Hussain presented a University of Michigan trial combining a PARP inhibitor with abiraterone. The initial idea is that the TMPRSS2-ERG gene fusion may sensitize patients to this strategy because PARP also functions as a transcription factor. This trial stratified based on the fusion gene status, and based on the data presented, they did not see much correlation between the gene fusions. Therefore, gene fusion cannot predict better responses to PARP inhibitors, which is consistent with de Bono’s findings early on with a smaller scale phase I study. However, Hussain’s group did show that, for patients with DNA-repair deficiency, the time to response to PARP inhibition is better.