Armamentarium Continues to Evolve Across Metastatic Prostate Cancer

Manish Kohli, MD, discusses the agents that have redefined the treatment paradigm of metastatic prostate cancer and details ongoing work to elucidate genomic classifiers.

Manish Kohli, MD

The therapeutic arsenal for men with metastatic hormone-sensitive prostate cancer (mHSPC) continues to expand with targeted agents, such as enzalutamide (Xtandi) and apalutamide (Erleada), explained Manish Kohli, MD.

Both androgen receptor (AR) inhibitors have shown promising activity against placebo/androgen deprivation therapy (ADT) in hormone-sensitive disease. However, longer follow-up will reveal how these agents fare against more established regimens, Kohli said.

In August 2019, the FDA granted a priority review designation to a supplemental new drug application for enzalutamide for men with mHSPC, based on data from the phase III ARCHES and ENZAMET trials. Data from the ARCHES trial1 showed that at a median follow-up of 14.4 months, the median radiographic progression-free survival in this population was not reached in those who received enzalutamide versus 19.45 months in those who were given placebo. This translated to a 61% reduction in the risk of radiographic progression or death with enzalutamide (HR, 0.39; 95% CI, 0.30-0.50; P <.0001).

In ENZAMET,2 the 3-year overall survival (OS) rate with enzalutamide plus standard of care in this population was 80% compared with 72% in those who received a different nonsteroidal antiandrogen (HR, 0.67; 95% CI, 0.52-0.86; P = .002).

Furthermore, in the metastatic castration-resistant prostate cancer (mCRPC) setting, next steps in research include novel combination strategies.

“The combinations in mCRPC have yet to show promise, whereas in the hormone-sensitive setting we have a plethora of new drugs which have given us ‘analysis paralysis,’” said Kohli. “If we are to meet some of these challenges, the most conceivable way to go forward would be to look at liquid biopsies in different states of progression before and after treatments to understand the molecular classifiers in the context of one drug over the other.”

In an interview during the 2019 OncLive® State of the Science Summit™ on Genitourinary Cancers, Kohli, vice chair, Department of Genitourinary Oncology, Moffitt Cancer Center, discussed the agents that have redefined the treatment paradigm of metastatic prostate cancer and detailed ongoing work to elucidate genomic classifiers.

OncLive: Could you discuss recent shifts in the treatment of metastatic prostate cancer?

Kohli: Metastatic prostate cancer is typically divided into 2 states: hormone-sensitive and castration-resistant disease. Until a few years back, patients with mHSPC were treated with ADT alone. In mCRPC, first-line hormonal therapy has failed. However, we now have a slew of other new drugs. I tried to crystalize the novel therapeutics that have come on board since 2013 for the treatment of patients with mHSPC, as well as the novel combinations that have been explored in mCRPC [in my presentation].

What agents have shown a benefit in combination with ADT in the hormone-sensitive setting?

Typically, we [have treated] these patients with ADT and docetaxel, which is a systemic chemotherapy that was previously approved for use in castration-resistant disease. We also have the option of treating patients with ADT, abiraterone acetate, and prednisone. We also have the combination of ADT and apalutamide, which is an androgen receptor (AR) inhibitor. The fourth option is the combination of ADT and enzalutamide.

However, I would hasten to add that the last 2 options have yet to show the maturity of data we have seen [with docetaxel and abiraterone]. We need to wait a little more on those last 2 drugs. We have good level 1 evidence for docetaxel and abiraterone, with the caveat that we limit these combinations to patients with high-volume, high-risk metastatic hormone-sensitive disease. We are splitting hairs within the hormone-sensitive state of progression.

What are your thoughts on utilizing enzalutamide or apalutamide in the hormone-sensitive setting?

Enzalutamide and apalutamide are going to be competitors, but we have to see the mature data. We only saw interim results at 2 and 3 years. These are cut-offs as opposed to the long-term data we have from the CHAARTED, LATITUDE, and STAMPEDE trials. I'm a little guarded as to what [the long-term data for enzalutamide and apalutamide will] show.

In the ENZAMET study, investigators evaluated the combination of enzalutamide with docetaxel. The seizure rates were higher with the combination; the neuropathy rates and the fatigue rates were also higher. It makes me wonder whether an additional agent is going to add anything meaningful in terms of benefit-risk ratios.

We know apalutamide is another option based on data from the TITAN trial. We have interim results that are comparable with the other 2 options. There were some extra adverse events (AEs), such as pruritus and rash, which were not seen with the other drugs. However, they each have a different set of AEs. We'll have to decide which one to use based on tolerability profiles for individual patients as we go forward.

Could you shed light on sequencing concerns?

We have so many options. Some patients with hormone-sensitive disease receive docetaxel within the first 6 months of starting ADT. If they progress, we can re-challenge with docetaxel, or use abiraterone or enzalutamide. On the other hand, if you give upfront enzalutamide or AR inhibitors, such as apalutamide or abiraterone, with ADT and they progress—which they will—you've knocked off all the AR pathway inhibitors. Now, you’re just looking at docetaxel.

We need to figure out the best way to sequence these agents on an individualized basis. We will also have to look at how many patients are going to have access to these drugs because they're costly. A cost analysis was done between abiraterone and docetaxel in the hormone-sensitive setting, and it was clear that docetaxel is cheaper.

However, the toxicity profile is perhaps a little more toxic with docetaxel compared with abiraterone. We’ll have to weigh those factors as we go forward. We don't have good biomarkers; it would be really helpful to have biomarkers that could teach us how to sequence these agents.

Could you shed light on the drugs that have been explored in the castration-resistant setting?

From 2012 to 2017, we have had a slew of new drugs enter the space. The next step was to look for novel combinations. Thus far, there have been 2 combination trials that have not shown the promise we hoped they would.

For example, radium-223 dichloride (Xofigo) was combined with abiraterone in the phase III ERA 223 trial. However, the combination did not meet the primary endpoint of the trial, which was a delay in skeletal-related complications. We believed the combination could work better than the [current standard], which is to give radiotherapy for pain palliation in the presence of a fracture, spinal cord compression, etc.

The other combination, which was discussed at the 2019 ASCO Annual Meeting, was the combination of enzalutamide with abiraterone. We believed the total annihilation that could be achieved with the combination would be superior compared with just blocking the receptor. However, that was not seen either.

Could you discuss any emerging molecular classifications in advanced prostate cancer?

Broadly speaking, genomic classifiers of tumor biology from The Cancer Genome Atlas concentrated on 333 patients with localized disease. In the advanced stages, tumor profiling has been done in mCRPC. We published a study in 2018 in the Annals of Oncology, in which we profiled metastases before and after patients received abiraterone. Stand Up to Cancer has done a wonderful job in this area. We have a broad sense of agreement regarding which pathways are implicated as either prognostic or predictive.

The challenge is how to translate that to individual patients where the heterogeneity is so tremendous. We are constantly under the threat of clonal evolution because of treatment selection pressure. In metastatic hormone-sensitive disease, we don't profile patients with metastatic biopsies.

Should this methodology be incorporated into ongoing clinical trials?

The National Cancer Institute has done a wonderful job in getting correlative sciences into phase II/III trials. Liquid biopsies are very much a part of that architecture now; the trials are ongoing. Liquid biopsies can be done with circulating tumor DNA, micro-RNA profiling, or proteomic profiling. They are part of the ongoing research that is taking place right now. In pre-analytical evaluations, we need to have a uniform way of collecting and processing blood samples because we can lose or get false-positive signatures otherwise. That part has yet to be standardized.

The platforms themselves are varied. You can look at one signature of one gene, you can take multiple [genes], or you can take a whole genome-wide approach; that, too, is evolving. In the post-analytical evaluation, the challenge is how to apply the information to the individual patient who has a heterogeneous tumor. Only then may we understand whether that signature is predictive or prognostic for monitoring disease, evaluating minimal residual disease, and so forth. The data are being collected at this point in time. I'm confident [we’ll get those answers].


  1. Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. Phase 3 study of androgen deprivation therapy (ADT) with enzalutamide (ENZA) or placebo (PBO) in metastatic hormone-sensitive prostate cancer (mHSPC): The ARCHES trial. J Clin Oncol. 2019;37(suppl 7, abstr 687). doi: 10.1200/JCO.2019.37.7_suppl.687.
  2. Sweeney C, Martin AJ, Zielinski RR, et al. Overall survival (OS) results of a phase III randomized trial of standard-of-care therapy with or without enzalutamide for metastatic hormone-sensitive prostate cancer (mHSPC): ENZAMET (ANZUP 1304), an ANZUP-led international cooperative group trial. J Clin Oncol. 2019;37(suppl 18; abstr LBA2). doi: 10.1200/JCO.2019.37.18_suppl.LBA2.