Castration-resistant prostate cancer remains a major challenge to treat effectively. Now, results from a large phase 3 clinical trial provide hope that a novel combination therapy could offer significantly improved progression-free survival for men with advanced disease.
Understanding castration-resistant prostate cancer
Prostate cancer relies on the male hormone testosterone to stimulate growth. A standard treatment approach is therefore, androgen deprivation therapy (ADT), which aims to dramatically lower testosterone levels. However, some patients become castration-resistant [1]. This means their prostate cancer continues to grow, and spreads to other parts of the body, despite maintenance of castrate levels of testosterone.
Once prostate cancer becomes metastatic (spread to other parts of the body) and castration-resistant, treatment options are very limited. For those just beginning treatment of advanced disease, the androgen receptor inhibitor enzalutamide is one standard first-line therapy [2]. It blocks testosterone from binding to prostate cancer cells. However, resistance to enzalutamide inevitably develops after around 2 years, allowing the cancer to circumvent the drug's effects.
More effective treatment options are urgently needed for metastatic castration-resistant prostate cancer. The outlook for patients remains poor, highlighting the need for clinical trials of new approaches.
The TALAPRO-2 phase 3 clinical trial
While the latest research has shown that PARP inhibitors alone are effective in castration-resistant prostate cancer, their combination with current therapies holds even greater promise [3]. Researchers conducted a large multinational phase 3 trial called TALAPRO-2 to test such a combination for men with metastatic castration-resistant prostate cancer [4]. The study enrolled over 800 patients across 26 countries in North America, Europe, Israel, South America, South Africa, and the Asia-Pacific region.
The trial compared treatment with the androgen receptor inhibitor enzalutamide plus either the PARP inhibitor talazoparib or a placebo. PARP inhibitors are a relatively new class of drugs that block the repair of cancer cell DNA, causing DNA damage and eventually cancer cell death.
Patients in this clinical trial had the following characteristics:
All patients had metastatic castration-resistant prostate cancer.
None had yet received chemotherapy.
All were starting first-line treatment for advanced disease.
Some had previously received ADT or newer anti-androgens like abiraterone while their cancer was still castration-sensitive.
After enrolling, patients were randomly assigned to receive daily oral doses of either enzalutamide plus talazoparib or enzalutamide plus a placebo. This allowed researchers to directly compare outcomes from adding the PARP inhibitor versus standard care alone.
Significantly improved progression-free survival
The trial results were very encouraging. Those men receiving the combination of talazoparib plus enzalutamide had a significantly longer progression-free survival (time without disease worsening) compared to the placebo group receiving enzalutamide alone.
Average progression-free survival was not reached after 2 years of follow-up in the talazoparib combination group. However, for the placebo group receiving only enzalutamide, the average progression-free survival was just 21.9 months.
This represents a highly clinically meaningful improvement from adding talazoparib. The risk of disease progression was reduced by 37% compared to the current standard of care.
Managing side effects of talazoparib
The addition of talazoparib did increase the risk of certain side effects like fatigue, neutropenia (deficiency of white blood cells), and anemia (deficiency of red blood cells). However, these side effects were manageable in most patients through talazoparib dose reductions when needed.
Only 8% of patients had to discontinue talazoparib entirely due to the side effects. The most common grade 3-4 side effect was anemia, occurring in 46% of the talazoparib group. But this was readily managed with dose adjustments. No treatment-related deaths occurred in the talazoparib group.
Next steps for combination therapy
The TALAPRO-2 trial provides strong clinical evidence that adding the PARP inhibitor talazoparib to standard enzalutamide therapy extends progression-free survival in metastatic castration-resistant prostate cancer. This is a very encouraging finding, as current treatment options beyond enzalutamide are limited.
Researchers will continue to follow patients in the trial to confirm if the progression-free survival benefit also translates into an overall survival advantage. Additional data on long-term safety will also further define the ideal talazoparib dosage and management of side effects.
If results remain positive, the combination of enzalutamide and talazoparib could soon offer fresh hope to patients with advanced castration-resistant prostate cancer.
References
1. J. Morote, A. Aguilar, J. Planas, and E. Trilla, “Definition of Castrate Resistant Prostate Cancer: New Insights,” Biomedicines, vol. 10, no. 3, p. 689, Mar. 2022, doi: 10.3390/biomedicines10030689.
2. L. J. Scott, “Enzalutamide: A Review in Castration-Resistant Prostate Cancer,” Drugs, vol. 78, no. 18, pp. 1913–1924, Dec. 2018, doi: 10.1007/s40265-018-1029-9.
3. K. Fizazi et al., “Rucaparib or Physician’s Choice in Metastatic Prostate Cancer,” N Engl J Med, vol. 388, no. 8, pp. 719–732, Feb. 2023, doi: 10.1056/NEJMoa2214676.
4. N. Agarwal et al., “Talazoparib plus enzalutamide in men with first-line metastatic castration-resistant prostate cancer (TALAPRO-2): a randomised, placebo-controlled, phase 3 trial,” The Lancet, vol. 402, no. 10398, pp. 291–303, Jul. 2023, doi: 10.1016/S0140-6736(23)01055-3.
