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Rucaparib: A promising new treatment for advanced prostate cancer

Castration-resistant prostate cancer is difficult to treat. It is resistant to standard hormone therapy and has the ability to grow without testosterone. Recently, a new targeted therapy called rucaparib has shown promise for treating this condition.


This blog post will discuss the findings of a major clinical trial evaluating rucaparib in patients with castration-resistant prostate cancer.


Castration-resistant prostate cancer


Prostate cancer is a type of cancer in which the cells in the prostate gland (a part of the male reproductive system) start to multiply excessively. Prostate cancer cells require testosterone (the primary male sex hormone) to grow.


Therefore, a common management strategy in prostate cancer is to reduce the levels of testosterone, and the therapy is called androgen depletion therapy (ADT). However, some patients do not respond to ADT and their cancer continues to grow. Such patients are said to have castration-resistant prostate cancer [1].


Castration-resistant prostate cancer can be metastatic and non–metastatic. It is called non-metastatic when the cancer cells are restricted to their site of origin in the prostate gland, and metastatic when the cancer cells spread to the other parts of the body and establish secondary sites of proliferation.



Challenges and management of castration-resistant prostate cancer


Advanced prostate cancer

The first and most obvious challenge is that castration-resistant prostate cancer does not respond to ADT. In castrate-resistant prostate cancer patients whose cancer has not spread to the other parts of the body (non-metastatic), secondary manipulations to hormone therapy can be beneficial. Moreover, low-dose steroids are added to the therapy due to their palliative as well as direct anti-cancer effects for prostate cancer [2].


However, aggressive therapies are opted if the cancer has already spread to other parts of the body (metastatic). This usually includes a chemotherapy drug called docetaxel. Steroid therapy is also effective in metastatic prostate cancer. If the patient does not respond to docetaxel, mitoxantrone is given as second-line therapy. For pain management resulting from bone involvement, radiotherapy is an effective option.


Rucaparib – a new hope


Rucaparib is an anticancer drug that selectively kills cancer cells by breaking their DNA. It belongs to a class of drugs called PARP inhibitors. Other drugs from this class have shown efficacy against ovarian, breast, pancreatic, and prostate cancer.


In a phase 2 clinical trial, rucaparib showed a high level of activity against castration-resistant prostate cancer [3]. It is particularly effective in patients with castration-resistant prostate cancer who have mutations in their BRCA genes.


Phase 3 study of rucaparib


To further evaluate the efficacy and safety of rucaparib in castration-resistant prostate cancer, a larger; phase 3 clinical trial was conducted [4]. This clinical trial, called TRITON3, recruited patients who:

  • were over the age of 18 years.

  • had received a diagnosis of metastatic castration-resistant prostate cancer.

  • had mutations in their BRCA or ATM genes.

  • had not received chemotherapy for castration-resistant disease.

Patients who had received chemotherapy for castration-sensitive prostate cancer were allowed to participate. A distinctive feature of this clinical trial was that it also recruited those patients who had a history of receiving second-generation androgen-receptor pathway inhibitors (ARPI).


The participants were divided into 2 groups. The first group, called the treatment group, received rucaparib. The second group, called the control group, received the physician’s choice treatment which consisted of either docetaxel or a second-generation ARPI.


A total of 405 patients were randomly assigned to be placed in either of the 2 groups. The ratio of participants in the treatment versus control group was 2:1. The participants in the control group were allowed to switch groups after a predefined period if they had disease progression.


The primary outcome of the study was based on the duration of imaging-based progression-free survival. According to the results, the duration of imaging-based progression-free survival was 11.2 months in the treatment group as compared to 6.4 months in the control group. This means that in the patients who received rucaparib, the disease was kept in control for 4.8 months (average) longer than in the patients who received the physician’s best-choice treatment.


Rucaparib was generally safe. The common adverse effects were fatigue, nausea, and decreased hemoglobin levels leading to anemia. These adverse effects can be managed through treatment breaks or lowering the dosage.


Implications for the patients


Rucaparib showed a significant advantage over the currently available drugs in controlling the disease progression. It is a viable option for patients suffering from castration-resistant prostate cancer particularly those harboring BRCA mutations.

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. F. Saad and S. J. Hotte, “Guidelines for the management of castrate-resistant prostate cancer,” Can Urol Assoc J, vol. 4, no. 6, pp. 380–384, Dec. 2010.

3. W. Abida et al., “Rucaparib in Men With Metastatic Castration-Resistant Prostate Cancer Harboring a BRCA1 or BRCA2 Gene Alteration,” J Clin Oncol, vol. 38, no. 32, pp. 3763–3772, Nov. 2020, doi: 10.1200/JCO.20.01035.

4. 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.

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