Androgen Independence

If cancer progresses despite the combination therapies described above, three additional types of therapy can be used:

1. Immunotherapy
2. Radioisotope
3. Investigational therapies
4. Other therapies

Immunotherapy

These agents stimulate your body's own immune system to fight your cancer. While usually well-tolerated, they aren't effective for everyone.

• Provenge (sipuleucel-T) is custom-made from your own immune cells. First, for two to three hours, the patient's blood is run through a machine in an outpatient infusion center to extract certain immune cells. These immune cells are then mixed with a protein commonly found on prostate cancer cells, which sensitizes the immune cells to the cancer. Two days after the immune cells were harvested, the mixture is returned to the patient in an hour-long infusion. The whole process is repeated two more times over the course of a month. This cancer vaccine tells your immune system that prostate cancer cells should be attacked as if they were foreign invaders. In clinical trials, patients with hormone-refractory prostate cancer who received Provenge lived an average of four months longer than those who did not. Some patients were alive three years later. Interestingly, patients who lived longer with Provenge did not have PSA reductions or tumor shrinkage. Side effects of Provenge are mild; they include flulike symptoms that resolve within a few days and (rarely) allergic reactions at the time of infusion.
• Keytruda (pembrolizumab) has shown benefit in several advanced cancers that have abnormal DNA repair mechanisms, which is when genes regulating DNA (called mismatch repair genes) don't work correctly. The mismatch repair genes work like the body's spellcheckers and correct errors in DNA. When these genes stop functioning normally, DNA errors aren't repaired, resulting in the cancer cells becoming unstable and therefore more likely to respond to Keytruda. The FDA approved Keytruda for treating advanced cancers (including prostate) that have deficient mismatch repair and that continue to progress when all other treatment options have been exhausted. Keytruda is especially effective in patients whose tumor biopsy shows an indication labeled "MSI-H" (for microsatellite instability – high). Keytruda is also being applied with other therapies in clinical trials because it can help the body's own immune cells penetrate the cancer's defenses.

Radioisotope (radioactive isotope) therapy. 

Radioactive agents can be used to target and kill cancer cells.

• Xofigo (radium-223) is a radioactive drug that can be taken up in the bones in place of calcium (radium is chemically similar to calcium). Once it's incorporated into the bone, radium-223 emits radiation that can kill nearby metastatic cells growing in bones. A study demonstrated that six treatments with this isotope can decrease bone-related complications of the cancer as well as improve survival. It is typically used in patients who either have already received chemotherapy or aren't healthy enough for chemotherapy. Injected intravenously, Xofigo targets areas of bone that are being damaged by cancer. For most patients, side effects are mild, such as mild diarrhea. However, it's important to note that the patient's bone marrow health needs to be monitored with regular blood tests.
• Pluvicto (Lutetium-177 targeting PSMA) is a radioisotope therapy that targets a protein called PSMA (prostate-specific membrane antigen), which grows on the surface of prostate cancer cells. Over the past decade, new molecules have been developed that can attach radioactive isotopes to prostate cancer cells by targeting their PSMA proteins. When the isotope gallium-68 is used this way, it permits a PSMA PET scan to detect the cancer cells with much more accuracy and sensitivity than do other imaging technologies. When the radioactive isotope lutetium-177 is attached to the cells' PSMA, it damages and eventually kills the cancer cells. Some prostate cancer cells (approximately 5 to 10%) do not express PSMA on their surface, will not show on a PSMA PET scan, and can survive treatment with PSMA-directed lutetium-177.

DNA repair targeting

When a cell's DNA is damaged, a mechanism within the cell tries to repair the DNA. About 25% of patients with ADT-resistant disease have gene mutations – either inherited or acquired – that disable this repair mechanism.

• The most commonly mutated genes include BRCA1, BRCA2, ATM and CHEK2. Fortunately, patients with these mutations can be treated with a chemotherapy drug called carboplatin or with a class of drugs called PARP inhibitors. Patients with BRCA2 mutations appear to benefit the most from PARP inhibitors.
• Lynparza (olaparib) and Rubraca (rucaparib) have been approved for treatment of ADT-resistant prostate cancer associated with one of the common gene mutations. Your health care provider will discuss these options if they are suitable for you.

Investigational therapies

1. UCSF has an extensive clinical trials program available to virtually all patients who volunteer and qualify. Some studies are investigating experimental therapies not approved by the FDA; others are using FDA-approved therapies in new ways or in combination with experimental agents. There are many ongoing clinical trials at UCSF. In general, to be eligible for most clinical trials, your prostate cancer must be progressing. If you're responding to a particular treatment, participation in a clinical trial may not be possible at the present time but may be appropriate in the future. Your health care provider can talk to you about any in which you may be eligible to participate; you can find more information about any UCSF prostate cancer study at UCSF Prostate Cancer Clinical Trials — San Francisco Bay Area.

2. UCSF has a large program focused on obtaining biopsies from sites of metastatic disease, such as the bone and liver, from patients with metastatic prostate cancer. This important research can help us more accurately describe the types and subtypes of prostate cancer that evolve over months and years of treatment, which may eventually enable us to tailor therapies for individual patients. Your health care provider may talk to you about participating in our biopsy program.

3. UCSF has a number of experimental programs to analyze tumor cells circulating in the blood, many as part of other experimental protocols.

4. UCSF has a large phase I Developmental Therapeutics Program led by an experienced team of experts in many medical subspecialties. In general, phase I trials evaluate the safety of new treatments in a small number of patients. If you participate in a phase I trial, an oncologist who specializes in phase I trials will provide care in conjunction with your current oncologist.

Other therapies

Xgeva (denosumab) is a medication used to strengthen bones. It has been shown to reduce the rate of bone injuries (such as fractures, bone pain and new bone lesions) in patients with ADT-resistant prostate cancer who have bone metastases. Xgeva is given as a monthly injection. It can lower calcium and phosphorus levels in your blood, so these must be tested before each dose. It should be taken in combination with a calcium and vitamin D3 supplement.

Xgeva occasionally causes a condition called osteonecrosis (bone damage) of the jaw. If you're currently undergoing or planning dental work (other than a routine cleaning), please discuss this risk with your doctor and dentist.

A group of medicines called bisphosphonates can also be used to prevent the loss of bone density.

Appendix: Summary of FDA-Approved Treatments

The following table shows which treatments are appropriate for treating advanced prostate cancer, depending on whether the cancer is sensitive to androgen deprivation therapy (ADT) and whether distant metastases are present. Please note that these are general guidelines and final decisions are made by the health care provider in consultation with the patient.

This article was written by UCSF medical experts Rohit Bose, MD, PhD, and Arpita Desai, MD, and UCSF patient advocates Bruce Zweig and Stan Rosenfeld. It was last reviewed in May 2022.

This information is for educational purposes only and is not intended to replace the advice of your doctor or other health care provider. We encourage you to discuss any questions or concerns you have with your provider.