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Prostate Cancer Enters a New Era of Precision Medicine

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With the emergence of molecular biomarkers, prostate cancer has entered a new era, according to Daniel P. Petrylak, MD, who added that DNA repair mutations, prostate-specific membrane antigen (PSMA), and androgen receptors have been shown to be versatile targets that are beneficial in terms of selecting optimal therapies.

“Prostate cancer is now entering a new era. In lung and breast cancer, we use molecular markers to select treatment. Historically, we were using a one-size-fits-all approach for prostate cancer; however, we now have molecular biomarkers of the DNA repair. If [we see those] mutations, then we know that it’s appropriate to go forward with a PARP inhibitor,” Petrylak explained. “For immunotherapy, microsatellite instability and mutational burden also are pan-tumor indications for the use of checkpoint inhibitors. We also now have androgen receptor targeted therapies that are being used.”

One novel approach under investigation are proteolysis targeting chimera (PROTAC) protein degraders, which induce selective degradation of targeted protein by engaging the ubiquitin proteasome system. ARV-110, an orally bioavailable PROTAC, has been shown to degrade androgen receptor of 95% or greater and to exhibit antitumor activity in enzalutamide (Xtandi)-naïve and -resistant prostate cancer preclinical models.

Results of a first-in-human study of ARV-110 presented during the 2020 ASCO Virtual Scientific Program showed that the agent was potent, selective, and showcased encouraging clinical activity in heavily pretreated patients with mCRPC. Moreover, the safety and pharmacokinetic data were found to support further dose escalation. In May 2019, ARV-110 was granted fast track designation from the FDA for use in patients with mCRPC with disease progression following 2 or more systemic therapies.

In an Interview with OncLive, Petrylak, a professor of medicine and urology and coleader of Cancer Signaling Networks at Yale Cancer Center in New Haven, Connecticut, discussed the ever-changing prostate cancer armamentarium, as well as the role of biomarkers and new diagnostic methods in the space. 

OncLive: Could you expand on some of the pivotal research that has led to the regulatory approvals of novel PARP inhibitors in mCRPC and DNA repair mutations?

Petrylak: Several key trials have examined PARP inhibitors. The PROfound trial looked at olaparib (Lynparza) in men with metastatic castration-resistant prostate cancer (mCRPC). were 2 different cohorts in the study, one looked at those patients who had BRCA1/2 or ATM mutations and the other looked at all DNA repair mutations.

For the first group, a significant difference in radiographic progression-free survival was observed in favor of olaparib compared with investigator’s choice of therapy, which included abiraterone (Zytiga) or enzalutamide.

Rucaparib (Rubraca) was also examined in the phase 2 TRITON2 trial. Here, the agent showed [just under a] 50% objective response rate in patients with mCRPC who also had DNA repair mutations, whether it be ATM or BRCA1/2.

These studies have led to the approvals of olaparib and rucaparib in men with mCRPC and DNA repair mutations.

How have these regulatory decisions impacted the paradigm?

They have impacted the treatment landscape for prostate cancer from the standpoint that we now have to look at these markers. We didn’t have to check molecular markers before. Every man who has mCRPC should have sequencing performed on their tumor tissue or a liquid biopsy to determine whether they have DNA repair mutations.

What novel targets are currently being explored in prostate cancer?

We’ve been working with PROTAC, which is a molecule that will help mark proteins that are involved in degradation. The PROTAC that we’re working with is ARV 110, which targets the androgen receptor; the proteasome can then digest the androgen receptor.

We presented data during the 2020 ASCO Virtual Meeting and showed that we had some responses in refractory patients. We’re now moving forward with this approach and we’re extremely excited about it.

Beyond DNA repair mutations, what other biomarkers are under investigation?

PSMA is going to be an important biomarker for targeted therapy that involves tissue-labeled antibodies or small molecules. The androgen receptor is another target. Looking at different antigen receptor mutations may actually help us select different treatments.

What role does PSA screening play?

PSA screenings are useful in helping us determine whether a patient may have prostate cancer. There’s been a lot of controversy around the role of PSA and whether someone should receive a screen or not. Originally, the preventative task force, several years back, said that it had a D rating in terms of whether this should be done or not; that

Clearly, in the past 10 years, there has been a reduction in mortality in prostate cancer and this may be due to PSA screening. Certainly, if a patient is high risk, screening should be discussed. The old adage says that we should not draw a test unless we’re really going to act on it; it’s the same thing with PSA. You don’t draw the PSA unless you really want to move forward and consider local therapy or other options.

What challenges remain with testing?

The main challenge right now is getting adequate tissue. We need the right tissue and the right test to correlate with outcomes.

How do you decide between the use of a liquid versus a tissue biopsy in your own practice?

I personally like the tissue biopsy the best, since you can actually look at the architecture and can see where the different mutations are, if its heterogenous or not. In comparison, the liquid biopsy may be a little bit more homogeneous; it’s either normal or it’s not. Both have their values, the issue really is, whether it is possible to get [adequate] tissue from patients with prostate cancer.

Where is future research in this space headed?

I see future research efforts in prostate cancer further refining these targeted therapies and tests to determine whether a patient is eligible [to receive such treatments]. For example, we know that [those with] ATM mutations don’t particularly do well with BRCA-targeted therapies like olaparib or rucaparib. 

Ultimately, we are going to try to look for other combinations to expand out “BRCA-ness.” For example, at our institution, we have been looking at using anti-angiogenesis agents to induce hypoxia and then potentially make patients more sensitive to PARP inhibitors. I believe novel combinations could be moving forward in this disease.

Reference

  1. Petrylak DP, Gao X, Vogelzang NJ, et al. First-in-human phase I study of ARV-110, an androgen receptor (AR) PROTAC degrader in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) following enzalutamide (ENZ) and/or abiraterone (ABI. J Clin Oncol. 2020;38(suppl 15):3500. doi:10.1200/JCO.2020.38.15_suppl.3500

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