“Metastatic prostate cancer is a complex cancer with marked inter- and intrapatient heterogeneity; therapy development must focus on the totality of disease biology,” said Maha Hussain, MD.
At the 38th Annual CFS meeting, Maha Hussain, MD, hailed 2020 as the year “we have finally reached the era of precision medicine in prostate cancer.”1
She said the era was launched by the FDA’s approval this year of the PARP inhibitors olaparib (Lynparza) and rucaparib (Rubraca) for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) whose tumors harbor specific genetic alterations.
“Metastatic prostate cancer is a complex cancer with marked inter- and intrapatient heterogeneity; therapy development must focus on the totality of disease biology,” said Hussain, Genevieve Teuton Professor of Medicine and Deputy Director of the Robert H. Lurie Comprehensive Cancer Center.
In her presentation at CFS, Hussain highlighted the pivotal data that led to the approval of olaparib and rucaparib in prostate cancer.
The FDA approved olaparib in May 2020 for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic mCRPC who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone acetate (Zytiga).
The approval was supported by the phase 3 PROfound trial, in which the risk of death was reduced by 31% with olaparib compared with abiraterone or enzalutamide (HR, 0.69; P <.0001) in patients with mCRPC harboring an alteration in BRCA1, BRCA2, or ATM.2 Olaparib also reduced the risk of disease progression or death by 66% (HR, 0.34; P <.001).
The PROfound trial enrolled patients with mCRPC who had alterations in at least 1 of 15 prespecified genes with a direct or indirect role in HRR and whose disease had progressed during previous treatment with a next-generation hormonal agents.
Cohort A (n = 245) consisted of patients with at least 1 alteration in BRCA1, BRCA2, or ATM, while cohort B (n = 142) comprised patients with at least one alteration in any of the other 12 prespecified genes.
Patients were randomly assigned 2:1 to receive either olaparib or the physician’s choice of enzalutamide or abiraterone. The study allowed patients to cross over from the control arm to receive olaparib at disease progression. In cohort A, 162 patients received olaparib and 83 patients were assigned to control therapy. In cohort B, 94 patients received olaparib while 48 patients were in the control arm.
The median OS was superior with olaparib compared with control therapy in cohort A (19.1 months vs 14.7 months; HR, 0.69; P = .02) and cohort B (14.1 months vs 11.5 months; HR, 0.96). Also of note, in cohort A the median PFS was 7.4 months with olaparib compared with 3.6 months in the control arm (HR, 0.34; P <.001)
Hussain noted that in cohort A, 67% (56/83) of patients on the control arm crossed over at progression, and a crossover-adjusted analysis showed an even greater survival benefit for olaparib, with a hazard ratio for OS of 0.42.
Hussain also shared the findings from a posthoc analysis examining the impact of prior chemotherapy. Among the subgroup of patients with a BRCA1 or BRCA2 alteration, the OS benefit for olaparib versus the control arm was greater among patients who had no prior taxane-based therapy (HR, 0.30), but there was still a benefit for the PARP inhibitor among those who had received prior taxane-based treatment (HR, 0.64). In the subgroup of patients with a CDK12 alteration, the olaparib benefit primarily occurred among patients with no prior taxane (HR, 0.72) compared to those with prior taxane (HR, 1.01).
What was interesting, Hussain said, was that in patients with ATM alterations, there was no olaparib benefit in those who were taxane-naïve (HR, 2.82), while the PARP inhibitor had an OS benefit in patients who had previously received a taxane (HR, 0.45).
Across the study, the most common adverse events among patients receiving olaparib group were anemia (39%), nausea (36%), and fatigue or asthenia (32%). Treatment with olaparib was discontinued because of anemia in 7% of patients and because of neutropenia, thrombocytopenia, nausea, vomiting, or fatigue or asthenia in 1% of the patients for each.
Also in May 2020, the FDA approved rucaparib for the treatment of patients with BRCA mutation (germline and/or somatic)—associated mCRPC who have been treated with androgen receptor–directed therapy and a taxane-based chemotherapy.
The approval was based on findings from the phase 2 TRITON2 trial, in which the PARP inhibitor induced a 44% confirmed objective response rate (ORR) in 62 evaluable patients with BRCA1/2-mutant mCRPC.3
In the international, multicenter, open-label TRITON2 study, investigators enrolled male patients with mCRPC associated with 1 of 13 HRR gene alterations. Patients had disease progression on androgen receptor—directed therapy and 1 prior taxane-based chemotherapy. Patients were treated with single-agent rucaparib until radiographic progression or treatment discontinuation.
The preliminary results included data from 85 patients enrolled through June 29, 2018, with a median follow-up of 5.7 months (range, 2.6-16.4). These data showed that rucaparib demonstrated a 44% confirmed ORR by investigator assessment among evaluable men with BRCA1/2-mutated mCRPC. Among those with BRCA1/2 alterations, 51.1% had a confirmed PSA response to rucaparib.
All 11 investigator-assessed radiographic responses in the patients with BRCA-mutated tumors were partial responses; 9 patients (36.0%) had stable disease. The median duration of response had not been reached.
Updated findings were presented at the 2019 ESMO Congress, with a median follow-up of 13.1 months (range, 4.1-28.5).4 Results showed that rucaparib elicited a 43.9% confirmed ORR and a confirmed PSA response of 52.0% in patients with mCRPC and a BRCA1/2 mutation. Responses were durable, with 60% of responses lasting ≥24 weeks.
Regarding safety, all-grade treatment-emergent adverse events occurring in >20% of patients were 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%).
Looking forward, Hussain said researchers are continuing to study the optimal use of PARP inhibitors in prostate cancer with studies such as the phase 3 PROpel trial of olaparib plus abiraterone as frontline therapy for men with mCRPC (NCT03732820) and the phase 2 CheckMate 9KD trial of rucaparib plus nivolumab (Opdivo) in men with mCRPC (NCT03338790).
1. Hussain, M. Optimizing Use of PARP Inhibition for Prostate Cancer. Presented at: 38th Annual CFS. November 4-6, 2020.
2. Hussain M, Mateo J, Fizazi K, et al. Survival with olaparib in metastatic castration-resistant prostate cancer [published online September 20, 2020]. N Engl J Med. doi:10.1056/NEJMoa2022485
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/mdy284
4. 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]: Boulder, CO. Clovis Oncology, Inc. Published September 29, 2019. https://bit.ly/2u4iEPS. Accessed November 6, 2020.