The statistics are scary—one in eight men in the US will be diagnosed with prostate cancer in his lifetime. The good news is that most of these cancers will be detected when they’re small and not likely to spread beyond the prostate, a walnut-sized gland that sits just below the bladder. In fact, many men diagnosed with localized prostate cancer now can safely delay treatment and opt instead for the relatively new protocol called active surveillance, which involves monitoring the cancer with regularly scheduled blood tests and biopsies to ensure it doesn’t progress.
Recent finding: A study of more than 1,600 men with localized prostate cancer by researchers at University of Oxford and University of Bristol found no difference in mortality rates among men who opted for surgery, radiation or active monitoring. After 15 years, the survival rate was about 97% for everyone. Even better: Active surveillance allows patients to avoid surgery’s side effects—erectile dysfunction and urinary incontinence—while also reducing the risk for overtreatment, treating prostate cancer that might never spread or create medical problems. Even though many in the active-monitoring group did eventually get treatment, 39% never received surgery or radiation by the end of 15 years.
But what about late-stage prostate cancer management? There is good news here as well—diagnosis and treatment have significantly improved in the past few years, bringing considerable hope and enhanced quality of life to patients.
In the past, men whose cancer was diagnosed at a later stage—having metastasized, spread beyond the prostate to other areas of the body including the bones, lungs and/or liver—were offered androgen deprivation therapy (ADT), a long-term hormonal therapy that blocks testosterone, a hormone that fuels prostate tumors. But ADT often causes hot flashes, weight gain and fatigue…increases heart disease risk…shrinks muscle mass…and more. And even then, the five-year survival rate for men with metastatic prostate cancer has hovered just above 30%, meaning that just 30 out of every 100 patients will be alive five years after diagnosis. Many of the causes of death, however, are due to other medical illnesses, not prostate cancer.
Today, doctors and researchers are using precision medicine—diagnostic tests and targeted treatments tailored to patients based on their genes or cancer type. A few of the recent advancements…
Advancement #1: Radioactive drugs that selectively bind to and eradicate cancer cells while sparing healthy ones. In March 2022, the Food and Drug Administration (FDA) approved lutetium-177–PSMA-617 (Lu-PSMA for short, brand name Pluvicto), the first radioligand therapy for prostate cancer. A radioligand is a drug that binds to cancer cells and uses tiny radioactive particles to kill those cells. Lu-PSMA works by attaching to a surface protein on prostate cancer cells called prostate-specific membrane antigen (PSMA). Since prostate cancer cells contain much higher concentrations of PSMA than healthy prostate cells, they send out a signal to the Lu-PSMA, inadvertently marking themselves for attack while most healthy prostate cells escape unscathed. Result: Minimal side effects—a marked difference from chemotherapy, which kills many healthy cells in the process of attacking cancerous cells. Lu-PSMA was specifically approved for metastatic castration-resistant prostate cancer (mCRPC), metastatic cancer that no longer responds to hormonal therapy. mCRPC cells contain large amounts of PSMA, making them particularly susceptible to radioligand therapy.
Promising study: In a clinical trial that helped pave the way for Lu-PSMA’s FDA approval, investigators from Memorial Sloan Kettering Cancer Center and Tulane University treated 831 men who had mCRPC with Lu-PSMA or a standard treatment such as ADT. Lu-PSMA extended life by about four months while slowing disease progression—the cancer in the men treated with the radioligand took about five months longer to resume versus men who had a different therapy.
Lu-PSMA is delivered intravenously every few weeks. Side effects can include dry mouth, nausea and bone marrow suppression, which can cause anemia and fatigue and increase infection risk. If you’ve had prior chemotherapy or radiation therapy, your doctor will monitor your bone marrow function while you’re on Lu-PSMA via regular bloodwork.
Even though Lu-PSMA is approved only for advanced metastatic prostate cancer, it eventually may be approved for earlier, nonmetastatic forms of prostate cancers but only after close monitoring of long-term adverse effects and impact on quality of life.
Advancement #2: New imaging technologies that detect and potentially treat an early form of metastatic disease. Defined by the presence of three to five tumors in other sites of the body besides the prostate (typically the lymph nodes or bone), oligometastatic disease is essentially the midpoint between localized (early) and late-stage prostate cancer—the latter of which features 10 or more tumor sites beyond the prostate. As recently as a decade ago, doctors typically deemed oligometastatic disease fatal and had no treatment options other than long-term ADT to keep the cancer under control. But the new imaging technology metastasis-directed therapy (MDT) now allows doctors to spot oligometastatic tumors that are too small to be detected via conventional scanning techniques. Once these tiny bits of cancer are found, they can be targeted and treated.
Like radioligand therapy, MDT’s success hinges on elevated levels of PSMA found in prostate tumors. First, a patient is injected with a radioactive molecular tracer that binds to metastatic tumors. These tracers then show up as glowing spots on positron emission tomography (PET) scans. Two new PSMA-specific tracers are gallium-68 PSMA-11 (Illuccix, Locametz), which uses the radioactive metal gallium…and piflufolastat F18 (Pylarify), which uses the radioactive element fluorine. Approved by the FDA in 2020 and 2021, respectively, for metastatic or recurring prostate cancer, these tracers detect oligometastatic tumors with impressive accuracy. Side effects do occur but generally are mild.
Recent finding: In a 2020 study of 302 patients who received either a gallium PSMA scan or a conventional CT scan before surgical or radiation therapy, the gallium PSMA scan detected metastases with 92% accuracy, compared with 65% accuracy via the conventional method.
Once the cancerous spots are detected, highly targeted radiation is beamed directly at them without damaging nearby healthy tissue. Alternatively, MDT may be used to guide the surgical removal of cancerous tissue. In both cases, patients often avoid long-term ADT and its systemwide side effects. MDT along with shorter-term ADT is a first step on the way to developing treatments that may in the future lead to cures of this once incurable disease. In any case, this treatment strategy delays disease progression…delays the need for ADT…or reduces the length of time ADT needs to be administered.
Exciting: In a December 2022 Mayo Clinic study, 29% of the 67 patients with a single oligometastatic tumor treated with MDT and surgery were disease-free after three years. Of the 57 patients who received MDT followed by radiation, 17% were disease-free after three years. Considering that this was previously a universally fatal disease, these numbers are quite encouraging.
Gallium-68 PSMA-11 availability is increasing. Piflufolastat F18 is more widely available.
Note: MDT typically is used with men who have previously been treated for prostate cancer with radiation or surgery, but whose PSA levels begin creeping up again months or years later.
Advancement #3: BRCA testing helps predict which men will develop aggressive prostate cancer. The BRCA1 and BRCA2 genetic mutations usually are associated with breast cancer in women. But these mutations also increase a person’s risk for other cancers, including ovarian cancer, pancreatic cancer and, in men, aggressive, difficult-to-treat forms of prostate cancer. In healthy individuals, BRCA genes work to repair DNA damage, but when those genes are defective—as in the case of BRCA1 and BRCA2 mutations—DNA damage can accumulate inside prostate cells that respond by forming tumors. According to the Harvard Medical School 2023 Annual Report on Prostate Diseases, about one in four men with aggressive prostate cancer have defects in one or both of these genes, usually in BRCA2 only.
Oncologists now routinely screen advanced prostate cancer patients for BRCA mutations with a blood or saliva test. If a mutation is found, the patient may be treated with PARP inhibitors, medications that help cells repair their damaged DNA. (BRCA mutations limit the effectiveness of MDT.) Olaparib (Lynparza) and rucaparib (Rubraca) are examples of PARP inhibitors.
When performing prostate biopsies, most urologists use a transrectal approach—a long, hollow needle is inserted through the rectum and into the prostate to gather tiny samples of tissue that are then inspected under a microscope for signs of cancer. Problem: The rectum is full of antibiotic-resistant bacteria that can lead to infections. In fact, up to 17.5% of transrectal prostate biopsy patients experience an infectious complication, including sepsis, which can be fatal.
But now an alternative biopsy method is gaining traction. With a transperineal prostate biopsy, the needle is inserted through the perineum, the area between the scrotum and rectum. This drastically reduces infection risk and the need for antibiotics while improving access to the anterior (front) portion of the prostate. That means transperineal biopsies may help identify more cancers.
Doctors have long avoided the transperineal approach because it had to be performed in an operating room under general anesthesia, but new technology and pain-blocking techniques allow it to be done in-office using local anesthesia and no sedation.
