FDA approves 2 PARP inhibitors for certain men with prostate cancer

The FDA has approved 2 poly (ADP-ribose) polymerase (PARP) inhibitors for men with metastatic castration-resistant prostate cancer (mCRPC) who have certain genetic mutations, marking the first approvals of this newer drug class in prostate cancer.

The FDA granted approval to rucaparib (Rubraca) tablets for the treatment of adult patients with a deleterious BRCA mutation (germline and/or somatic)-associated mCRPC who have been treated with androgen receptor-directed therapy and a taxane-based chemotherapy, Clovis Oncology announced. Four days later, AstraZeneca and Merck announced that the agency approved olaparib (Lynparza) for the treatment of adult patients with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated mCRPC who have progressed following prior treatment with enzalutamide (Xtandi) or abiraterone (Zytiga).

Coinciding with the olaparib approval, Foundation Medicine, Inc received FDA approval for its FoundationOne CDx test to be used as a companion diagnostic to identify patients with HRR-mutated mCRPC.

The FDA approved rucaparib under accelerated approval based on objective response rate (ORR) and duration of response (DOR) data from the multicenter, single-arm TRITON2 clinical trial (NCT02952534). The TRITON3 clinical trial is expected to serve as the confirmatory study for the rucaparib accelerated approval in mCRPC, Clovis Oncology said in a statement. Warning and precautions include myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and embryo-fetal toxicity.

“Rubraca is the first in a class of drugs to become newly available to patients with mCRPC who harbor a deleterious BRCA mutation,” said Wassim Abida, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center in New York, and principal investigator for the TRITON2 study. “Given the level and duration of responses observed with Rubraca in men with mCRPC and these mutations, it represents an important and timely new treatment option for this patient population.”

FDA approval for this indication is based on efficacy data from patients with mCRPC and a deleterious BRCA mutation enrolled in the TRITON2 trial. The major efficacy outcomes are confirmed ORR and DOR by modified RECIST version 1.1/PCWG3 criteria assessed by blinded independent radiologic review (IRR). Confirmed prostate-specific antigen (PSA) response rate is an additional prespecified endpoint.

Efficacy outcomes included a 44% ORR (n=62; 95% CI, 31, 57) by blinded-IRR assessment. ORR was similar in patients with a germline versus somatic BRCA mutation. A 55% confirmed PSA response rate (95% CI, 45, 64) was observed in an analysis of 115 patients with a deleterious BRCA mutation and measurable or nonmeasurable disease.

The most common adverse reactions (≥20% of patients; CTCAE Grade 1-4) occurring in the BRCA mutant population (n=115) were asthenia/fatigue, nausea, anemia, ALT/AST increased, decreased appetite, constipation, rash, thrombocytopenia, vomiting, and diarrhea. The most common laboratory abnormalities (≥35% of patients; CTCAE Grade 1-4) were increase in ALT, decrease in leukocytes, decrease in phosphate, decrease in absolute neutrophil count, decrease in hemoglobin, increase in alkaline phosphatase, increase in creatinine, increase in triglycerides, decrease in lymphocytes, decrease in platelets, and decrease in sodium.

The approval of olaparib was based on positive results from the phase 3 PROfound trial.¹ PROfound results showed olaparib reduced the risk of disease progression or death by 66% (HR, 0.34 [95% CI, 0.25-0.47], P < .0001) and improved radiographic progression-free survival (rPFS) to a median of 7.4 months versus 3.6 months with enzalutamide or abiraterone in men with mCRPC selected for BRCA1/2 or ATM gene mutations, the primary endpoint and a subpopulation of HRR gene mutations. Results also showed olaparib reduced the risk of radiographic disease progression or death by 51% (HR, 0.49 [95% CI, 0.38-0.63], P < .0001) and improved rPFS to a median of 5.8 months versus 3.5 months with enzalutamide or abiraterone in the overall trial population of men with HRR gene-mutated mCRPC.

“Prostate cancer has lagged behind other solid tumors in the era of precision medicine,” Maha Hussain, MD, a principal investigator of the PROfound trial and deputy director of the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago. “I am thrilled by the approval of Lynparza, which now brings a molecularly targeted treatment for this patient population in the U.S.”

Additional results announced in April showed a statistically significant improvement in the key secondary endpoint of overall survival (OS) with olaparib versus enzalutamide or abiraterone in men with mCRPC and BRCA1/2 or ATM gene mutations. Olaparib reduced the risk of death by 31% (HR, 0.69 [95% CI, 0.50-0.97], P = .0175) and improved OS to a median of 19.1 months versus 14.7 months for those treated with enzalutamide or abiraterone, results showed.

Venous thromboembolic events, including pulmonary embolism, occurred in 7% of patients with mCRPC who received olaparib plus androgen deprivation therapy (ADT) compared with 3.1% of patients receiving enzalutamide or abiraterone plus ADT in the PROfound study. Patients receiving olaparib and ADT had a 6% incidence of pulmonary embolism compared to 0.8% of patients treated with ADT plus either enzalutamide or abiraterone.

The most common adverse reactions in the PROfound trial greater than or equal to 10% for olaparib compared to enzalutamide or abiraterone were anemia (46% vs 15%), nausea (41% vs. 19%), fatigue (including asthenia) (41% vs. 32%), decreased appetite (30% vs. 18%), diarrhea (21% vs. 7%), vomiting (18% vs. 12%), thrombocytopenia (12% vs. 3%), cough (11% vs. 2%), and dyspnea (10% vs. 3%).

Fatal adverse reactions occurred in 4% of patients treated with olaparib. These included pneumonia (1.2%), cardiopulmonary failure (0.4%), aspiration pneumonia (0.4%), intestinal diverticulum (0.4%), septic shock (0.4%), Budd-Chiari Syndrome (0.4%), sudden death (0.4%), and acute cardiac failure (0.4%). Serious ARs occurred in 36% of patients receiving olaparib. The most frequent serious ARs (≥2%) were anemia (9%), pneumonia (4%), pulmonary embolism (2%), fatigue/asthenia (2%) and urinary tract infection (2%).

In a statement, Foundation Medicine said FoundationOne CDx is the only FDA-approved comprehensive genomic profiling test for all solid tumors that incorporates multiple companion diagnostic claims.

“This therapy [olaparib] and companion diagnostic approval underscores the value of comprehensive genomic profiling in advanced cancer patients as it validates our ability to identify alterations in the 14 HRR pathway genes within FoundationOne CDx’s 324 gene panel that indicate a patient may be eligible for treatment with olaparib, a process not possible through single gene or hot spot testing,” said Brian Alexander, MD, MPH, chief medical officer at Foundation Medicine. “This is an important advancement for patients with HRR-mutated metastatic castration-resistant prostate cancer, as there have previously been limited treatment options available for this specific condition.”

FoundationOne CDx is a next-generation sequencing-based in vitro diagnostic device for detection of substitutions, insertion and deletion alterations, and copy number alterations in 324 genes and select gene rearrangements, as well as genomic signatures including microsatellite instability and tumor mutational burden using DNA isolated from formalin-fixed paraffin embedded tumor tissue specimens. It is intended as a companion diagnostic to identify patients who may benefit from treatment with certain targeted therapies in accordance with their approved therapeutic product labeling.

Additionally, FoundationOne CDx is intended to provide tumor mutation profiling to be used by qualified health care professionals in accordance with professional guidelines in oncology for patients with solid malignant neoplasms.

1. de Bono J, Mateo J, Fizazi K, et al. Olaparib for metastatic castration-resistant prostate cancer. N Engl J Med. 2020 Apr 28. doi: 10.1056/NEJMoa1911440. Online ahead of print.