Lynparza Plus Zytiga Boosts PFS, Response Rates in Metastatic Prostate Cancer

The drug combination of Lynparza (olaparib), Zytiga (abiraterone) and prednisone led to better progression-free survival outcomes and responses compared to either Lynparza or Zytiga alone plus prednisone, according to findings from a phase 2 study presented at the 2024 Genitourinary Cancers Symposium.

Of note, progression-free survival (PFS) is the time patients live without their disease getting worse.

The study included several arms: patients in arm 1 received Zytiga and prednisone; arm 2 received 300 mg of Lynparza; and arm 3 received 300 mg of Lynparza plus Zytiga and prednisone.

The median PFS was 39 months in arm 3 compared with 8.4 months in arm 1 and 14 months in arm 2.

Study highlights:

  • The combination of Lynparza, Zytiga and prednisone demonstrated better outcomes in terms of progression-free survival and response rates compared to using Lynparza or Zytiga alone along with prednisone.
  • A total of 33% of patients in the combination arm responded to treatment — a higher percentage of those in the Lynparza/prednisone and Zytiga/prednisone arms.
  • The prostate-specific antigen (PSA) response rate in the combination arm was notably higher at 95% compared to 61% in the Zytiga/prednisone arm and 67% in the Lynparza arm. Additionally, the rate of undetectable PSA was 33%, 17% and 14% in the combination, Zytiga/prednisone, and Lynparza arms, respectively.
  • The study involved 165 patients with metastatic castration-resistant prostate cancer, and the combination therapy showed manageable side effects, with grade 3 side effects affecting 19% of patients in the combination arm, 21% in the Zytiga/prednisone arm and 14% in the Lynparza arm. Common grade 3 side effects included anemia and fatigue.

Additionally, the objective response rate (ORR; percentage of patients whose disease shrunk or disappeared from treatment) in each respective arm was 33%, 2%, and 14%. Moreover, the prostate-specific antigen (PSA) response rate in arms 3, 1 and 2, respectively, was 95%, 61% and 67%. The rate of undetectable PSA was 33%, 17% and 14%.

A total of eight patients crossed over from Zytiga/prednisone to Lynparza, and eight crossed over from Lynparza to Zytiga. The median PFS from crossover was 8.3 months with crossover to Lynparza and 7.2 months with crossover to Zytiga. Additionally, the median PFS from randomization was 16 months and 16 months. The ORR to and PSA response rate to crossover treatment was 38% and 25%, as well as 50% and 63%, respectively.

“2023, as you are all aware, was a really dynamic year for the PARP pathway,” lead author Dr. Maha Mussain, the Genevieve E. Teuton Professor of Medicine at Northwestern University’s Feinberg School of Medicine, said in a presentation on the data. “The FDA approved the combination of Lynparza and (Zytiga)/prednisone for frontline patients with castration-resistant disease and BRCA1/2 alterations. “

To be included in the study, patients needed to have an mCRPC diagnosis and no previous exposure to PARP or androgen receptor inhibitors or chemotherapy, washout of antiandrogen for metastatic hormone-sensitive prostate cancer, radiation and other investigational agents. Those who enrolled received next-generation sequencing and germline testing. Those with inactivating BRCA1/2 and/or ATM alterations were randomly assigned to one of the three arms. Those in arms 1 and 2 were able to cross over to Lynparza and Zytiga/prednisone, respectively, upon progressive disease.

The study’s primary end point was radiographic PFS, with key secondary end points including ORR, PSA response rate and toxicity.

A total of 165 patients were included in the study and received somatic/germline testing. Of these patients, 61 were randomly assigned to arms 1 to 3, including 19 in arm 1, 21 in arm 2, and 21 in arm 3. The median age in each respective cohort was 63, 68 and 69. Additionally, the baseline PSA in each respective group was 14 ng/mL, 14 ng/mL and 15 ng/mL. Patients in each respective cohort had bone metastases (84% versus 57% versus 76%), lymph node metastases (47% versus 57% versus 48%) and visceral metastases (11% versus 14% versus 33%).

In total, 47% of those in arm 1, 62% in arm 2 and 52% in arm 3 had germline alterations, and 53% versus 38% versus 48%, respectively, had somatic mutations. The most common genetic mutation was BRCA2 (68% versus 90% versus 71%, respectively).

“(In terms of) declines from baseline (PSA) to the lowest PSA, the combination arm does better than the single-agent arm,” Hussain noted.

Grade 3 side effects impacted 21% of patients in arm 1, 14% in arm 2 and 19% in arm 3. Common grade 3 side effects in each arm, respectively, included anemia (0% versus 4.8% versus 4.8%) and fatigue (5.3% versus 4.8% versus 4.8%).

Among those who crossed over to receive Lynparza and Zytiga/prednisone, respectively, one patient in the latter arm experienced grade 3 hyperglycemia.

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