AstraZeneca (AZN) and its partner Merck (MRK) announced positive results from a phase 3 study using Lynparza in patients with metastatic castration-resistant prostate cancer (mCRPC). Specifically, in patients with BRCA mutations and for those with other homologous recombination repair (HRRm) genes. This specific biomarker population is good news for patients who need a specific target to be addressed by a therapy. Lynparza can now be the type of focused treatment approach that these patients need. The study is now validated and the next goal is for AstraZeneca to eventually speak with regulators to get this drug out to patients as quickly as possible.
Molecular Biomarker Treatment Approach Advances Therapy Forward
The first thing to note is that the positive results came from a phase 3 study known as PROfound. This late-stage study recruited a total of 387 men with metastatic castration-resistant prostate cancer. First and foremost, you must know that metastatic means a type of cancer that has spread to other parts of the body. Castration-resistant prostate cancer indicates a type of cancer that no longer responds to androgen deprivation therapy (ADT). In essence, ADT is used to lower the amount of hormones (testosterone) in hopes of stopping the cancer from spreading. That’s the first portion; however, the population treated goes a little bit more deeper than that. These mCRPC patients were those who had a mutation in their homologous recombination repair genes and whose disease had progressed on prior treatment with new hormonal agents (NHA). Examples of such treatments are Pfizer (PFE) and Astellas with Xtandi (enzalutamide) as one NHA and then Zytiga (abiraterone) from Johnson & Johnson (JNJ) as the other.
Xtandi blocks androgen receptor signaling and Zytiga inhibits synthesis of androgen. As you can see, both of these NHA attempt to block androgen from causing the cancer to progress further. Homologous recombination repair genes are those where the double-strand DNA breaks off and if left unrepaired, the double-strand breaks can cause a large amount of rearrangement of chromosomes in somatic cells that can possibly lead to cancer. Thus, these patients have germline or somatic mutations in BRCA1/2 or many other types of (15 or more) homologous recombination repair genes. Why is this detail important and how does Lynparza fall into treating this specific molecular biomarker patient population? That’s because the deficiencies in DNA damage repair (DDR) resulting from BRCA1 and BRCA mutations can lead to tumor mutations or tumor mutation burden (TMB). A specific biomarker on a tumor is a TMB. Thus, this leads to these specific types of tumors being highly sensitive to PARP inhibitors. As you know, Lynparza is a PARP inhibitor, which is likely the reason why it performed so much better than the NHA. Think of NHA acting in a broad sense of treating these patients, whereas Lynparza acts in terms of sensitivity to a specific molecular biomarker for these mCRPC patients. This is why AstraZeneca can make the claim that the PROfound trial is the first positive phase 3 study of its type using a molecular biomarker for targeted treatment of men with mCRPC.
Specific Targeting of Biomarker Pays Off In A Big Way
The positive results came about from the late-stage phase 3 study treating mCRPC that had two separate cohorts:
- One cohort analyzed the primary endpoint which was radiographic progression-free survival (rPFS) in patients with mutations in BRCA1/2 or ATM genes (some homologous recombination repair genes)
- Then, the rPFS endpoint (considered secondary endpoint) was analyzed for all homologous recombination repair genes (entire population) like: BRCA1/2, ATM, CDK12, and 11 others in the second cohort
The primary endpoint was met in that treatment with Lynparza which was statistically significant in terms of rPFS in BRCA1/2 or ATM genes compared to Xtandi and Zytiga. That is patients who took Lynparza lived without disease progression or death with a median rPFS of 7.4 months compared to 3.6 months for those who took one of the two NHA. This ended up being that treatment with the drug reduced disease progression or death by 66%. Then, when you take a look at the entire homologous recombination repair gene population, the rPFS still ended up with a strong showing of 51%. My takeaway is that the more targeted treatment approach on the first few HRRm genes, specifically BRCA1/2 or ATM focus, resulted in a superior rPFS number. Still, the entire HRRm population still greatly benefited and that’s why this study was highly successful. These results were presented at the 2019 European Society for Medical Oncology (ESMO) conference.
AstraZeneca taking the route of a targeted molecular biomarker treatment approach paid off in a big way. I dare to say that this creates a major advancement for patients with mCRPC. It is always keen to give these patients new treatment options and observing a big improvement in radiographic progression-free survival for these patients is highly welcomed. The last positive item to note is that both cohorts also showed an improvement in overall survival (OS) at an interim analysis as well. I believe that this number should improve as the study moves forward. This is very good news for AstraZeneca and these specific mCRPC patients that need new treatment options. This latest announcement of positive results should eventually build upon the profile of Lynparza. This drug has already been approved for multiple indications, and AstraZeneca has already generated $520 million in sales with it in the first half of 2019. There is no doubt that Lynparza is expected to reach blockbuster status soon. Matter of fact, AstraZeneca believes it could reach such status by the end of this year along with its other cancer drug Imfinzi.
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