Vogelzang: Rucaparib Approval Raises New Hope in mCRPC

Nicholas J. Vogelzang, MD, a TRITON2 clinical trial investigator; medical oncologist, cancer researcher, and clinical professor of medicine at the University of Nevada School of Medicine; and clinical professor at UNLV School of Medicine

Nicholas J. Vogelzang, MD

Rucaparib (Rubraca) is an important new drug for patients with BRCA-mutant, metastatic castration-resistant prostate cancer (mCRPC), according to Nicholas J. Vogelzang, MD, and its recent accelerated approval from the FDA further underscores the need to test for these mutations in this patient population.

“It opens up a whole new opportunity for life extension for these patients, as well as disease control,” said Vogelzang. “In some patients, the benefit with the agent could last for years. As such, every man with a BRCA1/2-mutant metastatic prostate cancer needs to be on these drugs; that also implies that every one of these patients need to be tested for those mutations.”

Rucaparib was granted approval from the FDA on May 15, 2020, for the treatment of adult patients with BRCA mutation—positive mCRPC who had been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.¹

The regulatory decision was based on data from the ongoing phase 2 TRITON2 trial (NCT02952534), which showed that the agent led to a 44% confirmed objective response rate (ORR) in 62 evaluable patients with mCRPC harboring BRCA1/2 mutations.

Preliminary findings from 85 patients enrolled on the trial through June 29, 2018, with a median follow-up of 5.7 months showed that the PARP inhibitor resulted in a 44% confirmed ORR (95% CI, 24.4%-65.1%) per investigator assessment among evaluable men with BRCA1/2-mutated mCRPC.² Notably, among those whose tumors harbored these mutations, 51.1% experienced a confirmed prostate-specific antigen (PSA) response to the agent.

All 11 investigator-assessed radiographic responses in those with the BRCA­­­-mutant tumors were partial responses; 9 (36.0%) of these patients had stable disease. The median duration of response had not been reached.

Updated data presented at the 2019 ESMO Congress showed that at a median follow-up of 13.1 months, rucaparib induced a 43.9% confirmed ORR and a confirmed PSA response of 52.0% in patients with BRCA1/2-mutant mCRPC.³ The responses observed proved to be durable, with more than half (60%) lasting ≥24 weeks.

With regard to safety, all-grade treatment-emergent adverse events (AEs) reported in >20% of patients included asthenia/fatigue (55.3%), nausea (49.5%), anemia/decreased hemoglobin (37.9%), decreased appetite (27.9%), transient increased aspartate transaminase/alanine aminotransferase (24.7%), constipation (24.7%), vomiting (22.1%), and diarrhea (21.1%).

The continued approval of the agent for use in this setting remains contingent on data from a confirmatory trial. Currently, the randomized phase 3 TRITON3 trial (NCT02975934) is examining rucaparib monotherapy in comparison with physician’s choice of abiraterone acetate (Zytiga), enzalutamide (Xtandi), or docetaxel in men with mCRPC and homologous recombination deficiency who experienced disease progression on previous treatment.⁴

In an interview with OncLive, Vogelzang, a TRITON2 clinical trial investigator; medical oncologist, cancer researcher, and clinical professor of medicine at the University of Nevada School of Medicine; a clinical professor at UNLV School of Medicine; and a 2018 OncLive Giant of Cancer Care^® in Genitourinary Cancers, discussed the significance of the rucaparib approval for this patient population.

OncLive: Could you provide a bit of background on rucaparib and what makes the approval such a novelty for patients?

Vogelzang: We've known for 4 or 5 years that BRCA-mutant prostate, breast, and ovarian cancers could be treated with PARP inhibitors. I won't go into all the mechanisms, but the benefit in ovarian cancer has been great. As such, these agents have been approved for many variants of the disease. The same mechanism that drives ovarian and breast cancer BRCA mutations, [drives] the BRCA mutations in prostate cancer.

Knowing this, you have to test for patients’ germline or somatic mutational status. I’ve been doing that testing on almost all my patients with metastatic prostate cancer for the past year anticipating that this day would come.

The drug does have some degree of AEs. Each patient needs to be monitored for white count, hemoglobin, and liver and kidney [function], but compared with chemotherapy, it's not even [close] to those AEs seen with [the latter approach].

This [approval] is a big deal; however, it's only available for patients with those mutations; that's a limitation, but you can't get around it. That being said, we are studying the agent in other patients, but we don't have any indication yet that it will be effective.

Could you expand on the data reported from the TITON2 trial that served as the basis for this approval?

The approval is based on data from the phase 2 TRITON2 trial, which was a several-hundred patient trial of men with a variety of DNA repair enzyme deficiencies. The major degree of benefit [with rucaparib] occurred in the patients whose tumors harbored BRCA1/2 mutations. Notably, some benefit [was observed with the agent] in other subtypes, and that is still being further explored.

What is your take-home message regarding this approval?

It's great. We need it badly; it was really desperately needed. One patient I saw today is dying of his BRCA2-mutated prostate cancer; he's 50 years old, an African American man with terrible bone pain. He has just terrible, terrible cancer. I've gotten him a few samples here and there, but now I have the drug. I'm hoping that within the next day or 2 he can get started on it. This is really a very important new drug for our patients with BRCA1/2-mutated prostate cancer.

References

1. Rubraca (rucaparib) approved in the U.S. as monotherapy treatment for patients with BRCA1/2-mutant, metastatic castration-resistant prostate cancer (MCRPC) who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy. News release. Clovis Oncology: Boulder, CO; May 15, 2020. bit.ly/2z0rMrK. Accessed May 15, 2020.
2. Clovis Oncology highlights Rubraca (rucaparib) updated data from the ongoing TRITON2 clinical trial in patients with mCRPC and exploratory and integrated analyses in recurrent ovarian cancer at the ESMO Congress 2019. News release. Clovis Oncology: Boulder, CO; September 29, 2019. bit.ly/2u4iEPS. Accessed January 15, 2020.
3. Abida W, Bryce AH, Vogelzang NJ, et al. Preliminary results from TRITON2: a phase 2 study of rucaparib in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) associated with homologous recombination repair (HRR) gene alterations. Ann Oncol. 2018;29(suppl_8):viii271-viii302. doi:10.1093/annonc/mdy28
4. A Study of Rucaparib Versus Physician’s Choice of Therapy in Patients With Metastatic Castration-Resistant Prostate Cancer and Homologous Recombination Gene Deficiency (TRITON3). https://clinicaltrials.gov/ct2/show/NCT02975934?term=NCT02975934&draw=2&rank=1. Updated March 31, 2020. Accessed May 15, 2020.