Practice-Changing Trials Pave the Way for Novel Approaches in Metastatic Prostate Cancer

Joseph Kim, MD

Data from pivotal trials such as CARD and PROfound have led to practice-changing shifts in the treatment of patients with metastatic prostate cancer, according to Joseph Kim, MD, who added that the HERO trial examining the oral gonadotropin-releasing hormone antagonist relugolix is also showing promise for patients with advanced disease and a history of major cardiovascular risk factors.

“Cabazitaxel in the third-line setting improves radiographic progression-free survival [rPFS] and overall survival [OS] in patients who have received prior docetaxel chemotherapy and progressed on a next-generation hormonal agent. Cabazitaxel is highly recommended and has been shown to improve survival compared with next-generation hormonal agents,” said Kim. “Also, PARP inhibitors are changing the whole landscape in terms of metastatic castration-resistant prostate cancer [mCRPC] management. Next-generation sequencing is now a standard of care for our patients and is highly recommended.”

Another agent that has generated excitement in the space is relugolix (Orgovyx), which was found to achieve superiority over leuprolide (Lupron) with regard to sustained testosterone suppression through 48 weeks, fast testosterone recovery after discontinuation, and a 50% reduction in major adverse cardiovascular events (MACE), according to data from the phase 3 HERO trial.^1,2 Based on these findings, the FDA granted approval to relugolix on December 18, 2020 for use in patients with advanced disease.

“We have to see what the FDA has to say but this drug will clearly serve a good number of our patients, including those with preexisting cardiovascular disease who are at risk of developing a major cardiovascular complication,” added Kim. “This may be a favored option for this group of patients.”

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on Prostate Cancer, Kim, an associate professor of Internal Medicine (Medical Oncology) at Yale School of Medicine discussed pivotal trials in metastatic prostate cancer, the rise of PARP inhibitors and novel combinations under investigation, and the promise of relugolix.

OncLive^®: Could you speak to the significance of the CARD trial? What were the key lessons learned from this research?

Kim: CARD was a randomized phase 3 study that compared cabazitaxel with next-generation hormonal agents in the third-line setting. The trial included patients who had received prior docetaxel chemotherapy and had recently progressed on a novel hormonal agent, either abiraterone [Zytiga] or enzalutamide [Xtandi]. Patients were randomized to receive either cabazitaxel chemotherapy or a subsequent novel hormonal agent of either abiraterone or enzalutamide. The trial was done in patients with mCRPC.

This is really an important study because we knew that using a subsequent novel hormonal agent in this setting in patients who had prior docetaxel and enzalutamide, that they were not going to do well with a subsequent next-generation hormonal agent. Thus, we were looking to prove that giving chemotherapy to this group of patients would be better than using subsequent, novel hormonal agents.

Of course, there is no question in terms of toxicities that the novel hormonal agent would be favored. However, study goes on to say that cabazitaxel does improve rPFS and OS. Thus, these data really prove that chemotherapy is favored in this setting, and in a way, it confirms what we usually do in practice for this patient population.

For example, I had a patient in this setting who had received prior docetaxel chemotherapy early on and he subsequently received abiraterone, but he experienced clinical progression. He needed radiation therapy and ended up having spinal cord compression. His disease was very rapid and aggressive. After he recovered from the radiation, he went on to receive cabazitaxel.

The CARD trial established cabazitaxel as a third-line standard of care. Are there any questions that remain regarding this research?

It depends on the clinical setting. With these data, I recommend cabazitaxel up front, [except for] patients who really can't receive chemotherapy. If you look at the control group in this study with abiraterone or enzalutamide, the efficacy is only modest, but at least we know the prospective data [so we are able] to counsel our patients. That was another important point to highlight. Patients who cannot receive cabazitaxel in this setting now can at least be consulted and receive either abiraterone or enzalutamide.

We know that the response rates and prostate-specific antigen response rate was approximately 12% to 13%. The median OS for the group of patients receiving abiraterone or enzalutamide was in the 10- to 11-month range.

How did the PROfound study impact clinical practice? How did this pave the way for the use of PARP inhibitors?

This was the study that demonstrated the efficacy of olaparib [Lynparza] in patients with mCRPC who harbor homologous recombination repair mutations. Olaparib was approved by the FDA in May 2020 based on the data, which showed an improvement in PFS. Also, with the updated survival data, we now know that olaparib improves survival compared with subsequent novel hormonal agents.

This research was practice-changing and really important because now we know that in patients who have this mutation, we can use a PARP inhibitor knowing this will benefit them in terms of response, PFS, and OS.

Another PARP inhibitor that is approved by the FDA is rucaparib [Rubraca]. This decision was based on data from a small phase 2 study that showed a 44% response rate in patients with a BRCA1/2 mutation. This was also practice-changing. It's really exciting to be able to treat our patients with PARP inhibitors.

What are some of the emerging PARP combination that are generating excitement in the field?

Now that we know that PARP inhibitors have an impact on the treatment landscape in metastatic prostate cancer, many ongoing studies are looking to improve upon that [benefit that we are seeing]. For example, I am a principal investigator on a trial using olaparib in combination with cediranib. I led a small, randomized phase 2 trial that evaluated the combination vs olaparib monotherapy in patients with mCRPC who had progressed on a previous line of therapy. I presented the data at the 2020 Genitourinary Cancers Symposium that showed an improvement in rPFS [with the combination].

I recently submitted an abstract for presentation at next year’s meeting, where we [will share] updated biomarker data. We continue to learn more about the patients who will derive benefit from this combination approach versus monotherapy.

Other combination approaches with PARP inhibitors [are being investigated]. Knowing that PARP inhibitors affect DNA damage, investigators are also combining [these agents] with radium-223 dichloride [Xofigo]; this is another very interesting combination. There is a lot to be done to improve upon what we already have.

How do you foresee relugolix impacting the treatment paradigm?

The oral gonadotropin-releasing hormone antagonist relugolix was evaluated in the HERO study. We know many of our patients have pre-existing cardiovascular disease and many retrospective studies suggest that luteinizing hormone–releasing hormone agonists may actually increase the risk of cardiovascular events. Some studies have shown that antagonists may be more protective in terms of these events.

Relugolix is an oral agent that was developed by Myovant Sciences. Investigators looked at sustained castration rates at week 48 and relugolix demonstrated superiority over leuprolide. Not only that, it also showed a favorable risk reduction of 54% with regard to MACE. This drug is still not approved by the FDA but is currently under priority review. We have to see what the FDA has to say, but if approved, this drug will clearly serve a good number of our patients.

Another very interesting aspect of this study is that there was a very short time to achieving effective castration of about 1 week or so. Then, when [a patient] stops this medication, [they] recover testosterone very quickly, as well. There is better control over castration status with the use of this medication.

For which patients do you feel this agent will be most beneficial?

Relugolix would be ideal for patients who have a history of major cardiovascular risk factors. Many of these patients have some degree of these factors, whether this is a lifetime risk factor or a history of major cardiovascular events. The fact that this agent had a favorable risk profile, [indicates that it] will serve a good number of our patients. Many of our patients are elderly and have either coronary heart disease or a history of chronic pulmonary aspergillosis, where we're really nervous about giving them a long-term androgen deprivation therapy.

This agent may be preferable in this group of patients along with those who experience severe AEs from castration therapy, such as hot flashes and mood swings. Especially when patients are receiving it in conjunction with radiation therapy, they really experience major AEs that affect their quality of life. Because this agent has a great time to recovery of the testosterone, I believe it will be beneficial to this group of patients.

Editor’s Note: This interview was conducted prior to the December 2020 FDA approval of relugolix for the treatment of patients with advanced prostate cancer.

References

1. Shore ND, George DJ, Saad F, et al. HERO phase III trial: results comparing relugolix, an oral GnRH receptor antagonist versus leuprolide acetate for advanced prostate cancer. J Clin Oncol. 2020;38(suppl; abstr 5602). doi:10.1200/JCO.2020.38.15_suppl.5602
2. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. doi:10.1056/NEJMoa2004325