Educated Patient® Prostate Cancer Summit Novel Agents Presentation: May 21, 2022

Newly approved therapies such as PARP inhibitors and Lutetium are changing the trajectory of patients with metastatic castration-resistant prostate cancer, according to Dr. Tian Zhang.

Zhang, who is the associate professor of genitourinary oncology at the UT Southwestern Medical Center Harold C. Simmons Comprehensive Cancer Center, recently discussed these up-and-coming agents at the CURE® Educated Patient® Prostate Cancer Summit.

“So now in our landscape of disease continuum of prostate cancer, we are adding in (Lynparza [olaparib]) after hormonal treatments and before chemotherapy. (Rubraca [rucaparib]) had an accelerated approval in the post-chemotherapy setting,” Zhang said in her presentation. “And now we also have PSMA-targeted Lutetium that was just approved.”

PARP Inhibitors

In previous studies, researchers found that up to 20% of prostate cancer samples had mutations in the homologous recombination repair genes — most frequently the BRCA1, BRCA2 and ATM genes. These affect how a cell repairs the DNA once it is damaged.

PARP is also a protein that plays a role in DNA repair.

“So if I have an altered BRCA gene and an altered BRCA protein that does not repair the DNA, and then I go to block the PARP protein, then we don't have any ability of the (cancer) cells to fix DNA damage,” Zhang said. “And then downstream of that, if there's too much DNA damage, that cancer cell dies and cannot make more of itself. So we call this a mechanism of synergistic length lethality.”

The efficacy of PARP inhibitors has been proven in clinical trials, such as the phase 3 PROfound trial, which showed that Lynparza led to an improved overall survival duration in patients with metastatic castration-resistant prostate cancer that had BRCA1, BRCA2 or ATM mutations. Meanwhile, the PROPEL clinical trial examined Lynparza in combination with Zytiga (abiraterone), a hormone therapy. Again, outcomes favored the PARP inhibitor-containing group.

“So then the debate is whether the combination upfront is truly better than sequential treatment. We do have (Lynparza) approved on as a monotherapy on its own. And so is truly adding it to (Zytiga) upfront better than (Zytiga) followed by (Lynparza),” Zhang said. “And so we do need to wait to further follow up for those overall survival results.”

177Lutetium-PSMA-617

177Lutetium-PSMA-617 is a radioactive therapy that targets prostate-specific membrane antigen (PSMA) that is present on prostate cancer cells.

“For the first time, we’re able to use a radio-pharmaceutical, a radioactive treatment, to target both soft tissue and bone lesions expressing PSMA,” Zhang said.

The phase 2 TheraP clinical trial showed that 177Lutetium-PSMA-617 led to a higher reduction in PSA reduction (which can mean better outcomes) than those given Jevtana (cabazitaxel). Similarly, the phase 3 VISION trial analyzed 177Lutetium-PSMA-617 with Zytiga or Xtandi (enzalutamide) compared to standard of care (Zytiga or Xtandi alone). Again, the 177Lutetium-PSMA-617 group had improved outcomes, this time in both progression-free survival (time from treatment until the disease worsens) and overall survival (time from treatment until death of any cause).

In March of 2022, 177Lutetium-PSMA-617 was approved by the Food and Drug Administration for patients with metastatic castration-resistant prostate cancer with a positive Gallium-PSMA PET scan. However, a recent production shortage is limiting the amount of patients that can be treated with the therapy.

“As soon as we can, we will try to make it available to patients,” Zhang said.

Ultimately, these newly approved drugs continue to improve the outcomes of patients with metastatic castration-resistant prostate cancer.

“It’s certainly an exciting time for prostate cancer now, as we’re adding to the companion of treatment options for patients with metastatic castration-resistant disease.”

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