Metastatic Prostate Cancer Paradigm Flourishes With Recent Progress

Michael Schweizer, MD

Data from 3 pivotal trials—PROfound, CARD, and HERO— have changed the standard of care for certain subsets of patients with metastatic prostate cancer, according to Michael Schweizer, MD.

The phase 3 PROfound trial (NCT02987543) underscored that PARP inhibitors represent an important option for patients with mutations in homologous recombination repair genes. Data showed that olaparib (Lynparza) resulted in a 66% reduction in the risk of disease progression or death versus abiraterone acetate (Zytiga) or enzalutamide (Xtandi; HR, 0.34; 95% CI, 0.25-0.47; P <.0001) in patients with BRCA1/2 or ATM-mutant metastatic castration-resistant prostate cancer. These results led to the May 2020 FDA approval of the agent.^1,2

Additionally, findings from the pivotal phase 4 CARD trial (NCT02485691) demonstrated that in patients who have progressed on androgen receptor (AR)–targeted therapy, cabazitaxel (Jevtana) represents a third-line standard of care. The median imaging-based progressionfree survival (PFS) was 8.0 months in those who received cabazitaxel versus 3.7 months in those given an antiandrogen on which they had not progressed (HR, 0.54; 95% CI, 0.40-0.73; P <.001).³

Most recently, in December 2020, the oral gonadotropin-releasing receptor antagonist relugolix (Orgovyx) joined the treatment arsenal for patients with advanced prostate cancer based on data from the phase 3 HERO trial (NCT03085095). The agent proved to be superior to leuprolide (Lupron) in terms of sustained testosterone (T) suppression through 48 weeks, fast T recovery after discontinuation, and a 50% reduction in major adverse cardiovascular effects (MACE).^4,5

“Many treatment options are expanding for patients with advanced and metastatic prostate cancer. It’s truly an exciting time for the field,” Schweizer said. “Looking forward, I believe there will be additional approvals in the near term. With the recent approval of agents such as olaparib, we are already seeing all of the hard work we have done come to fruition.”

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on prostate cancer, Schweizer highlighted data from pivotal trials that have advanced the metastatic prostate cancer paradigm. He is a physician of the Seattle Cancer Care Alliance; assistant professor in the Division of Medical Oncology at the University of Washington School of Medicine; and associate professor in the Clinical Research Division at the Fred Hutchinson Cancer Research Center.

OncLive^®: What lessons have we learned from the PROfound trial?

Schweizer: PROfound evaluated olaparib versus either enzalutamide or abiraterone in patients who had already progressed on one of the other drugs. Specifically, patients with alterations and at least 1 gene involved in homologous recombination repair [were enrolled]. The activity of olaparib was evaluated in 2 cohorts: cohort A and cohort B. Cohort A was the main focus of the primary analysis and included patients with mutations such as BRCA1/2 or ATM. Cohort B included patients with mutations in any of the other homologous recombination repair genes.

The primary end point of the trial was focused on cohort A and looked at imaging-based PFS. Results from the study showed that cohort A had a significant improvement in the primary end point with olaparib versus physician’s choice of AR-targeted therapy; this [benefit] was highly significant.

The secondary end points looked at both cohort A and B, which were combined into a single group. This also showed that olaparib was active in the entire study, with a median PFS of 5.8 months versus only 3.5 months, which was, again, significant. Importantly, when you look at cohort B alone, or [those with mutations] in genes that aren’t BRCA1/2, the PFS findings were not that impressive with olaparib. When you look at the BRCA cohort alone, we still see a significant improvement in PFS of 9.8 months [with olaparib] versus 3.0 months with control. When you look at the PFS for either [patients with] ATM-mutated disease or [those with] CDK12 mutated [disease], which were 2 other genes that were commonly altered in this study, no significant difference in PFS was observed between olaparib and the control.

The study was not designed to examine PFS by gene. Do you believe more work is needed to further evaluate by subgroup?

Ultimately, I believe the data just highlight the need for additional clinical trials to really understand the clinical activity of olaparib in non–BRCA-mutated subgroups. However, based on the current data, I don’t find it very convincing that olaparib has a lot of activity in non-BRCA cohorts. It’s still an option that we should potentially consider, but I would not write off more standard drugs that have a long track record of working across patients, regardless of any genomic alterations that may be present.

What was the rationale for the CARD trial?

The CARD study was designed as a response to several different retrospective analyses that showed that when drugs like abiraterone and enzalutamide are used sequentially, the second drug used does not work that well. This makes sense because these drugs, mechanistically, work very similarly to one another. They basically work to shut down the AR signaling program; as such, it makes sense that if you used one after the other, then you would see cross-resistance and diminished clinical activity.

What was the significance of this research?

CARD evaluated the use of cabazitaxel, a taxane chemotherapy agent, in patients who had already progressed on abiraterone or enzalutamide. Patients were then randomized to the other drug that they had [not] received. Patients who enrolled to this study had to have progressed within 12 months on the other AR-targeted therapy. [Investigators were] essentially selecting for patients who likely had some degree of de novo resistance to AR-targeted drugs given the fact that they really didn’t respond to the first-line AR-targeted agent for a long time.

Phase 3 studies have shown that, when it comes to abiraterone or enzalutamide, you would expect a median PFS that’s well beyond the 12-month landmark. Upon enrollment, patients were randomized 1:1 to receive cabazitaxel or AR-targeted therapy and the primary end point was PFS. This study was found to be positive. Results showed that the median PFS with cabazitaxel was superior to an AR-signaling drug, at 8.0 months versus 3.7 months. Cabazitaxel was also shown to have superior overall survival. Ultimately, this study really highlights that cabazitaxel is an important consideration for patients who have already progressed on AR-targeted therapies.

This was, again, a relatively high-risk population that was probably enriched for some degree of intrinsic resistance to AR-targeted drugs. The median time on the novel, next-generation AR-targeted drug was around 6 months across the study population. It's also worth noting that the patients enrolled to this trial had a relatively short response, even to first-line androgen deprivation therapy [ADT], with a median duration of treatment of only 12 to 13 months. As such, this underscores that cabazitaxel is an important option for patients in this setting.

Could you shed light on the HERO trial?

The HERO trial evaluated a novel, oral luteinizing hormone- releasing hormone [LHRH] agonist versus leuprolide, a more conventional form of ADT. Patients with advanced prostate cancer were enrolled. The study was quite large, with a total of 934 patients who were randomized 2:1. In terms of the trial definition for advanced disease, 50% of those enrolled had biochemically recurrent disease after definitive local treatment. About one-quarter of patients had metastatic disease, while a quarter had advanced localized disease.

The primary analysis looked at sustained castration through week 48 of the study. HERO was designed as a noninferiority trial and was also found to be positive. Results showed that relugolix led to a sustained castration rate of 96.7% through week 48, with 95% confidence intervals of 94.9% to 97.9%, which met the prespecified noninferiority boundary.

Some secondary analyses [indicated] that relugolix resulted in more rapid castration compared with leuprolide; this was sustained throughout the 48-week period. Interestingly, the results also showed that, upon discontinuation of relugolix, there was rapid T recovery; this was well in excess of what you would see after stopping leuprolide. In addition, relugolix was associated with lower rates of MACE compared with leuprolide, which is consistent with some of the findings using degarelix [Firmagon], another LHRH antagonist.

What is the clinical implication of rapid T recovery?

The authors of the paper indicated that faster T recovery is probably a good thing. I believe this is true in some contexts; however, as a cautionary measure, we shouldn’t necessarily assume that. I could imagine, for instance, if you had a patient population who started on a LHRH analogue after radiation therapy, and they were to stop it and have rapid T recovery, this could potentially mean a shorter duration of ADT compared with what has been studied in phase 3 trials. That may or may not be a good thing. It could be that a shorter duration of ADT means inadequate duration of therapy. I believe we’re going to need additional therapeutic studies to determine whether using drugs like this in that context makes sense.

References

1. Lynparza Highlights of Prescribing Information. FDA. Updated May 19, 2020. https://bit.ly/2WLJt7u. Accessed May 19, 2020.
2. Lynparza approved in the US for HRR gene-mutated metastatic castration-resistant prostate cancer. Published May 20, 2020. https://bit.ly/36eCJlP. Accessed January 20, 2021.
3. de Wit R, de Bono J, Sternberg CN, et al. Cabazitaxel versus abiraterone or enzalutamide in metastatic prostate cancer. N Engl J Med. 2019;381(26):2506-2518. doi:10.1056/NEJMoa1911206
4. 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 15):5602. doi:10.1200/JCO.2020.38.15_suppl.5602
5. Shore ND, Saad F, Cookson MS, et al. Oral relugolix for androgen-deprivation therapy in advanced prostate cancer. N Engl J Med. 2020;382(23):2187-2196. doi:10.1056/NEJMoa2004325